Blood Test for HPV May Help Predict Risk in Cancer Patients

A blood test for the human papillomavirus, or HPV, may help researchers forecast whether patients with throat cancer linked to the sexually transmitted virus will respond to treatment, according to preliminary findings from the University of North Carolina Lineberger Comprehensive Cancer Center.

HPV can cause oropharyngeal cancer, which is a cancer of the throat behind the mouth, including the base of the tongue and tonsils. Studies have shown that patients with HPV-positive oropharyngeal cancer have better outcomes than patients whose cancer is not linked to the virus.

Preliminary findings presented at this year’s American Society for Radiation Oncology Annual Meeting suggest a genetic test for HPV16 in the blood could be useful to help assess risk for patients, and could help identify patients suitable for lower treatment doses.

“Our work on this blood test is ongoing, but we are optimistic that ‘liquid biopsy’ tests such as ours may be useful in the personalization of therapy for many patients with HPV-associated oropharyngeal cancer,” said the study’s senior author Gaorav P. Gupta, MD, PhD, UNC Lineberger member and assistant professor in the UNC School of Medicine Department of Radiation Oncology.

To avoid over-treating patients and to spare them from toxic treatment side effects, UNC Lineberger’s Bhisham Chera, MD, an associate professor in the radiation oncology department, led studies testing whether favorable-risk patients with HPV-positive oropharyngeal cancer can be treated successfully with lower doses of radiation and chemotherapy. A phase II clinical trial using this de-intensified regimen have shown “excellent” cancer control, Chera said.

The researchers used a number of selection criteria to identify patients who can benefit from lower-doses: patients had to be positive for HPV, and they had to have smoked fewer than 10 pack years. Chera said this system is not perfect, however. The researchers have seen cancer recur in non-smoking patients as well as “excellent” cancer control in longtime smokers.

“This has led us to question whether we can get better prognostication with other biomarkers,” Chera said.

They developed a test that can detect HPV16 circulating in the blood, and found that circulating HPV16 DNA was detectable using the test in the majority of a group of 47 favorable-risk oropharyngeal cancer patients.

In a finding that seems counterintuitive, they discovered that very low or undetectable HPV16 pretreatment levels in their blood actually had higher risk of persistent or recurrent disease for chemotherapy and radiation treatment. In contrast, patients with high pretreatment levels of HPV16 in their blood had 100 percent disease control.

They hypothesized that, potentially, the patients with undetectable/low pre-treatment HPV16 levels in the blood may have different, more radiation/chemotherapy resistant cancers.

“Our current theory is that these patients with low or undetectable levels of HPV16 have a different genetic makeup—one that is perhaps less driven purely by HPV, and thus potentially less sensitive to chemotherapy and radiation,” Gupta said. “We are performing next generation sequencing on these patients to search for additional genetic markers that may give us a clue regarding why they have a worse prognosis.”

They also identified a subset of patients who rapidly cleared the HPV16 from their blood. Researchers hypothesize that they could use their findings to further stratify patients who may be eligible for lower intensity treatment.

“A tantalizing – and yet currently untested – hypothesis is whether this subset of ultra-low risk patients may be treated with even lower doses of chemoradiotherapy,” Gupta said.

By Decoding How HPV Causes Cancer, Researchers Find a New Potential Treatment Strategy

A study that teases apart the biological mechanisms by which human papillomaviruses (HPV) cause cancer has found what researchers at Georgetown University Medical Center say is a new strategy that might provide targeted treatment for these cancers.

HPVs are responsible for the majority of cervical cancer and a substantial portion of head and neck and anal cancers, but therapy available to date is surgery and non-specific chemotherapy.

The new study, published Oct. 2 in the journal Oncotarget, found that E6, an oncoprotein produced by the virus, interacts with several other molecules in host cells in a manner that ensures infected cells cannot die. If they are immortal and continue to multiply, cancer develops.

“There is no targeted treatment now for these cancers since German virologist Harald zur Hausen, PhD, discovered in 1983 that HPV can cause cervical cancer. Recently, the numbers of HPV-linked head and neck cancers have increased in the U.S. Now we have a chance to develop and test a very specific, potentially less toxic way to stop these cancers,” says the study’s lead author, Xuefeng Liu, MD, associate professor of pathology at Georgetown University Medical Center.  Liu is director of Telomeres and Cell Immortalization for the medical center’s Center for Cell Reprogramming.

Liu and his team have previously found that the HPV E6 oncoprotein interferes with the well-known p53 tumor suppressor to increase telomerase activity that extends the life span of infected cells. A telomerase is a protein that allows a cell to divide indefinitely when it would have stopped after a certain number of divisions.

In this study, researchers found that E6 also interacts with myc, a protein produced by the Myc gene, which controls gene expression in all healthy cells. They concluded that telomerase activity is dependent on E6-myc proteins hooking on to each other.

This means, says Liu, that designing a small molecule that stops E6 from joining up with myc should shut down persistent activation of telomerase. A small molecule could bind to E6 in the same spot that myc would, or bind on to myc in the same spot that E6 would, thus preventing an E6-myc complex.

“This small molecule would not be toxic to all normal cells or, importantly, to master stem cells, because myc would not be affected,” says Liu. “It could be a unique treatment, targeted specifically to HPV cancers.”

Georgetown researchers are now working on a prototype chemical to interfere with E6/Myc binding.

Zika Virus Protein Mapped to Speed Search for Cure

A recently-published study shows how Indiana University scientists are speeding the path to new treatments for the Zika virus, an infectious disease linked to birth defects in infants in South and Central America and the United States.

Cheng Kao, a professor in the IU Bloomington College of Arts and Sciences‘ Department of Molecular and Cellular Biochemistry, has mapped a key protein that causes the virus to reproduce and spread.

“Mapping this protein provides us the ability to reproduce a key part of the Zika virus in a lab,” Kao said. “This means we can quickly analyze existing drugs and other compounds that can disrupt the spread of the virus. Drugs to target the Zika virus will almost certainly involve this protein.”

The World Health Organization reports that more than 1 million people in 52 countries and territories in the Americas have been infected with the Zika virus since 2015. The disease has also been confirmed to cause microcephaly in more than 2,700 infants born to women infected with the virus while pregnant. Symptoms include neurological disorders and a head that is significantly smaller than normal.

The virus is also transmissible through sexual activity and can trigger an autoimmune disease in adults called Guillain-Barre syndrome.

The IU-led study, conducted in collaboration with Texas A&M University, revealed the structure of the Zika virus protein NS5, which contains two enzymes needed for the virus to replicate and spread. The first enzyme reduces the body’s ability to mount an immune response against infection. The other enzyme helps “kick off” the replication process.

“We need to do everything we can to find effective drugs against the Zika virus, as changes in travel and climate have caused more tropical diseases to move into new parts of the globe,” said Kao, who has also spent 15 years studying the virus that causes hepatitis C.

“We’ve learned a lot of lessons about how to fight this class of virus through previous work on hepatitis C, as well as other work on the HIV/AIDS virus,” he added.

In addition, Kao said, the study showed that the Zika virus protein is similar in structure to proteins from viruses that cause dengue fever, West Nile virus, Japanese encephalitis virus and hepatitis C, which prompted the team to test several compounds that combat those diseases. The team also tested other compounds to disrupt the virus’s replication.

“Drugs approved to treat hepatitis C and compounds in development to treat other viral diseases are prime candidates to use against the Zika virus,” Kao said. “We’re continuing to work with industry partners to screen compounds for effectiveness against the NS5 protein.”

Other IU Bloomington authors on the study were Guanghui Yi and Yin-Chih Chuang in the Department of Molecular and Cellular Biochemistry and Robert C. Vaughan in the Department of Biology. Additional authors were Baoyu Zhao and Pingwei Li of Texas A&M University and Banumathi Sankaran at Lawrence Berkeley National Laboratory.

The method used to reproduce the virus protein in the lab is the subject of a U.S. patent application filed by the IU Research and Technology Corp.

The study appears in the journal Nature Communications. It was supported in part by the Johnson Center for Innovation and Translational Research at IU Bloomington.

How Prenatal Maternal Infections May Affect Genetic Factors in Autism Spectrum Disorder

Researchers find activation of maternal immune system during pregnancy disrupts expression of key genes and processes associated with autism and prenatal brain development

For some infections, such as Zika, the virus passes through the placenta and directly attacks the fetus. For others, such as the H1N1 influenza, the virus induces maternal immune activation (MIA) by triggering a woman’s immune system during pregnancy. Both Zika and MIA mechanisms may lead to potentially disastrous neurological repercussions for the unborn child, such as microcephaly (an undersized, underdeveloped brain and head) in the case of Zika or cortical abnormalities with excess numbers of neurons, patches of disorganized cortex, synapse mal-development and early brain overgrowth in some cases of MIA.

Large population-based studies suggest MIA caused by infection during pregnancy are also associated with small increases in risk for psychiatric disorders, including autism spectrum disorder (ASD). In a new study published today in Molecular Psychiatry, researchers at the University of California San Diego School of Medicine, University of Cyprus and Stanford University map the complex biological cascade caused by MIA: the expression of multiple genes involved in autism are turned up or down by MIA, affecting key aspects of prenatal brain development that may increase risk for atypical development later in life.

“We provide novel evidence that supports the link between prenatal infections and biology known to be important in the development of autism,” said senior author Tiziano Pramparo, PhD, associate research scientist at the Autism Center of Excellence at UC San Diego School of Medicine. “There are different routes of importance. We highlight a specific pathway that seems to be key in driving downstream early abnormal brain development.”

“Our work adds to growing evidence that prenatal development is an important window for understanding key biology of relevance to neurodevelopmental conditions like autism,” added lead author Michael Lombardo, PhD, at the University of Cyprus. “MIA is an environmental route of influence on fundamental biological processes important for brain development. The influence it exerts overlaps with key processes known to be important in how the brain in autism develops.”

Pramparo said the effects are not caused by the infectious agents themselves — virus or bacterium — but from the maternal immune response itself. “Although the mechanisms are not entirely known, it has to do with the cascade of altered events regulating production and function of neurons, their synapses and how they arrange themselves in the brain that are triggered when a mother’s immune system is activated.”

For example, increased levels of maternal cytokines (small signaling molecules driven by the immune response) may directly or indirectly alter gene expression in the fetus’ brain.

“These up- and down-regulated genes may lead to an excess or reduction in the normal amounts of proteins required for normal brain development,” Pramparo said. “Importantly, we have found that MIA-induced effects involve both single genes and pathways (many genes working in a coordinated way to serve some dedicated biological purpose) essential for early fetal neurodevelopment.” Among the large number of genes whose activity is altered by the maternal immune response, are a few that, when mutated, are thought to cause more genetic forms of autism in a small subset of all ASD toddlers.

Pramparo suggested the findings have multiple clinical implications.

“In general, the more we know and understand about a disrupted mechanism, the higher the chance of finding amenable targets for potential therapeutic intervention or for informing how to prevent such risk from occurring in the first place.”

Another implication, he said, is the potential to define the effects and clinical phenotypes based upon the underlying mechanisms: genetic, environmental or both.

“The MIA effects are transient but very potent during fetal development and perhaps even more potent than the effects induced by certain types of mutations in single gene forms of autism. Also, depending on when MIA occurs during gestation, the clinical characteristics may vary. The finding of MIA affecting the expression genes known to be important in autism supports the hypothesis that a genetic-by-environment interaction may lead to amplified effects at the clinical level. For example, more severe cases of autism.”

Body’s Immune Response to Bioterrorism Bacteria That Causes Tularemia Is Focus of Ongoing Research

Meenakshi Malik, Ph.D., an Associate Professor in the Department of Basic and Clinical Sciences at Albany College of Pharmacy and Health Sciences, has been awarded a three-year research grant totaling $480,000 to expand her study of Francisella tularensis, a bacterium that causes a potentially fatal disease called tularemia.

The grant, which is being funded by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH), is the “competing continuation” of a previously-funded NIH research grant that Dr. Malik received in 2013.

“HIGHEST RISK TO THE PUBLIC AND NATIONAL SECURITY”

Francisella tularensis has been classified by the Centers for Disease Control as a Category A bioterrorism agent. Organisms or toxins in this class are defined as “posing the highest risk to the public and national security.” Other Category A agents include pathogens causing anthrax, plague, and smallpox.

Francisella tularensis is particularly dangerous because it can be easily aerosolized and survive in small droplets for prolonged periods of time. If infected and left untreated, the mortality rate can be as high as 60%. There is currently no FDA approved vaccine for preventing tularemia.

INITIAL RESEARCH FINDINGS (2013 – 2016)

If someone becomes infected by a disease-causing organism, the body’s immune system instinctively responds as the first line of defense. But with Francisella tularensis, the immune response is effectively muted in the first 48-72 hours following infection, thereby inhibiting the body’s ability to successfully fight off the bacterium.

The focus of Dr. Malik’s first NIH grant was to explore how Francisella tularensis stifles the immune system and try to determine what causes the protective immune response to “kick in” after this initial period.

Over the course of this grant, Dr. Malik’s lab found several genetic factors that play a role in temporarily disabling the body’s initial immune response to a Francisella infection. Upon identifying these factors, Dr. Malik removed the genes encoding these factors from the bacterium and saw the immune response improve – an encouraging sign that may begin to point the way towards the development of a vaccine.

Over the period of the grant, she authored six publications in peer reviewed journals including Molecular Microbiology and the Journal of Biological Chemistry. Her findings and related publications in part led the NIH committee who reviewed her new grant application to write, “the productivity during the last project period [was] outstanding.”

FUTURE DIRECTION OF RESEARCH (2016 – 2019)

The human body has two types of immune responses to an infection: (1) innate immunity and (2) adaptive immunity. Innate immunity is a general immune response that begins at the onset of any infection and typically continues for 5-7 days. After this initial period, the body begins developing antibody and “cell-mediated” immune responses that are targeted towards the specific infection; this is adaptive immunity.

Until recently, it was believed that these immune responses were two separate actions, but a growing body of evidence now suggests that the innate immune response plays an important role in shaping the adaptive immune responses.

Dr. Malik will focus her efforts over the next three years on studying the connection between the innate and adaptive immune responses in Francisella tularensis infections. Specifically, she will seek to determine if an improved innate immune response can lead to a more effective adaptive immune response, and ultimately, help in the development of an effective vaccine against tularemia.

In parallel with these efforts, she will continue searching for additional factors that may be responsible for muting the body’s initial immune response to a Francisella tularensis infection.

Personalized Cancer Therapy on the Horizon Thanks to New Genomic Cancer Research Partnership

Gene Editing Institute at Christiana Care Health System partners with NovellusDx in BIRD Foundation Grant

Wilmington, Del, Jan. 30, 2017 – For its enormous potential to accelerate the development of personalized cancer therapies, the Gene Editing Institute of Christiana Care Health System’s Helen F. Graham Cancer Center & Research Institute has been awarded a grant of $900,000 from the U.S.-Israel Binational Industrial Research and Development (BIRD) Foundation in partnership with the biotechnology company NovellusDx.

The BIRD Foundation promotes collaboration between U.S. and Israeli companies in a wide range of technology fields for the purpose of joint product development. Projects submitted to the BIRD Foundation undergo evaluation by the U.S. National Institute of Standards and Technology of the U.S. Department of Commerce and by the Israel Innovation Authority.

The grant allows the Gene Editing Institute to partner with Jerusalem-based NovellusDx on a new series of state-of-the-art gene editing technologies that help identify the genetic mechanism responsible for both the onset and progression of many types of cancer. The two organizations are collaborating on a licensing agreement to commercialize the gene editing technologies that result from the research.

“Thanks to this generous BIRD Foundation grant, this partnership promises to be a catalyst that will speed progress in personalized medicine for many forms of cancer, accelerating the path to prevention, diagnosis, treatment, and ultimately, to a cure of cancer,” said Nicholas J. Petrelli, M.D., the Bank of America endowed medical director of the Helen F. Graham Cancer Center & Research Institute at Christiana Care Health System.

“We are honored to partner with the exceptional team at NovellusDx to advance genomic cancer research and to discover new gene editing techniques,” said Eric Kmiec, Ph.D., director of the Gene Editing Institute. “Our partnership is not only based on the skills of both organizations, but on the unique opportunity to license our gene editing technology with a company capable of commercializing it. The due diligence and peer review process for this award are extensive. I’m enormously grateful to the Research Institute at the Philadelphia-Israeli Chamber of Commerce for its invaluable support of our application.”

NovellusDx has established a unique approach to identify unknown “driver” gene mutations that often accelerate or facilitate cancer progression. With clinical partners throughout the world, including at MD Anderson Cancer Center and Massachusetts General Hospital in the U.S., NovellusDx obtains DNA sequence information and creates a personal profile of the genetic mutations from individual patients. The Gene Editing Institute will use its expertise in gene editing to re-create these mutations that allows NovellusDx and its partners to identify, design and implement the most effective therapy for each patient.

Cancer genomics plays a critical role in pharmacogenomics, or the study of how genes impact a patient’s response to drugs. “With our joint research, we hope to develop gene editing technologies that help develop effective, safe medications and doses that can be tailored to a person’s genetic profile,” Dr. Kmiec said. “This will lead to precision and personalized cancer therapy at its very best.”

“We have been working closely with Dr. Kmiec and the Gene Editing Institute for the last nine months to generate preliminary data to support this ground-breaking idea and grant application,” said Haim Gil-Ad, CEO of NovellusDx. “We are excited that the BIRD Foundation with its stringent review process found our application worthy of the generous funding, which also provides external validation. This work has the potential to change the way functional genomics is done. Once the genetic makeup is known, we will be immediately able to test and monitor the effect of the patient mutations in live cells.”

The BIRD Foundation grant recognizes the Gene Editing Institute’s pioneering work to advance gene editing toward clinical applications in cancer research. The Gene Editing Institute is partnering with The Wistar Institute to develop translational genetic approaches to melanoma cancer research, and with Bio-Rad Inc. to advance a gene editing educational curriculum. In addition, with funding from the U.S. National Institutes of Health, the Gene Editing Institute is developing a gene editing strategy for the treatment of sickle cell anemia.

The BIRD Foundation supports projects without receiving any equity or intellectual property rights in the participating companies or in the projects themselves. BIRD funding is repaid as royalties from sales of products that were commercialized as a result of BIRD support. The Foundation shares the risk and does not require repayment if the project fails to reach the sales stage.

The Gene Editing Institute at the Graham Cancer Center is a worldwide leader in personalized genetic medicine. Founded and led by Dr. Kmiec, the Gene Editing Institute is unlocking the genetic mechanisms that drive cancer and that can lead to new therapies and pharmaceuticals to revolutionize cancer treatment. The Gene Editing Institute also provides instruction in the design and implementation of these precise new genetic tools.

Large Integrated Health Outcomes Study Reveals Shifting Epidemiology In Drug-Resistant Organisms

A first-of-its-kind study of 900,000 hospital admissions from an integrated health system has yielded insights into shifts in the epidemiology of multi-drug resistant organisms (MDROs) in the community.

New research, funded by OpGen (NASDAQ: OPGN) and conducted by Intermountain Healthcare and Enterprise Analysis Corporation (EAC), found that Methicillin Resistant Staphylococcus aureus (MRSA), Clostridium difficile (C. difficile) and ESBL harboring Gram-negative rods were the most common organisms treated by the Intermountain Healthcare system over an eight-year period between January 1, 2008 and December 31, 2015.

The study examined data from Intermountain Healthcare over an eight-year period to characterize the trends occurring in C. difficile and MDROs. The abstracted electronic data was pulled from patients seen at Intermountain’s 22 hospitals and affiliated clinics who had clinical cultures positive for antibiotic resistant Gram-positive or Gram-negative bacteria and/or laboratory tests positive for toxigenic C. difficile.

The researchers discovered that resistant organisms were found in 1.4 percent of the 900,000 hospital admissions during the study period with most originating from the ambulatory setting. Additionally, researchers found that a 222% increase was observed in the prevalence of C. difficile as well as a 322% increase in ESBL positive organisms. The good news is that the prevalence of MRSA decreased by 32%.

The study measured both the prevalence of infections, as well as impacts on patient care. Economic data are still being analyzed and will be revealed in a future presentation.

Results from the study were presented on Thursday, Oct. 27 at 1:30 p.m., EDT, in the Poster Hall at IDWeek 2016 in New Orleans by Bert Lopansri, M.D., lead author of the study at Intermountain Medical Center, the flagship hospital of Intermountain Healthcare.

Highlights of the study:

• Of the 900,000 hospital admissions during the study period, 12,905 (1.4%) were from patients positive for an MDRO and/or C. difficile.
• While MRSA continues to be the most common MDRO, rates have declined.
• MRSA, ESBL and CRE forms of E. coli were less frequently acquired in the hospital while VRE, multi-drug resistant Pseudomonas, and other CRE’s were more frequently encountered in a healthcare setting.
• 70% of all MDROs and C. difficile cases originated from an ambulatory setting.
• While all-cause, in hospital mortality was relatively low (7%), significantly more patients with MDRO require continued medical care in some capacity.

“For the last 10 to 15 years, the number of antibiotic-resistant bacteria continues to increase. We wanted to turn on the lights and look at all the different types of antibiotic-resistant bacteria that have been highlighted as serious and urgent threats by the Centers for Disease Control to see what the landscape looks like in our system,” said Dr. Lopansri, Chief of the Infectious Diseases Division at Intermountain Medical Center. “Although MRSA still poses the greatest challenge, the rise in ESBLs is a major concern and mirrors findings reported at other centers in the U.S. One concern with ESBLs is that the most common antibiotic used to treat them are carbapenems, known as ‘last-resort’ antibiotics.”

“Our support for a study of this magnitude provides a benchmark to hospitals and health systems on what could be lurking in their facilities as we seek to validate the health and economic impact of our rapid MDRO products and services to improve infection control,” said Evan Jones, Chairman and CEO of OpGen. “The next step in this collaboration will revolve around leveraging our technologies to guide rapid clinical decisions with a goal of reducing the spread of these infections and improving health outcomes.”

Cytomegalovirus Infection Relies On Human RNA-Binding Protein

Viruses hijack the molecular machinery in human cells to survive and replicate, often damaging those host cells in the process. Researchers at the University of California San Diego School of Medicine discovered that, for cytomegalovirus (CMV), this process relies on a human protein called CPEB1. The study, published October 24 inNature Structural and Molecular Biology, provides a potential new target for the development of CMV therapies.

“We found that CPEB1, one of a family of hundreds of RNA-binding proteins in the human genome, is important for establishing productive cytomegalovirus infections,” said senior author Gene Yeo, PhD, professor of cellular and molecular medicine at UC San Diego School of Medicine.

CMV is a virus that infects more than half of all adults by age 40, and stays for life. Most infected people are not aware that they have CMV because it rarely causes symptoms. However, CMV can cause serious health problems for people with compromised immune systems, or babies infected with the virus before birth. There are currently no treatments or vaccines for CMV.

In human cells, RNA is the genetic material that carries instructions from the DNA in a cell’s nucleus out to the cytoplasm, where molecular machinery uses those instructions to build proteins. CPEB1 is a human protein that normally binds RNAs that are destined to be translated into proteins.

Yeo’s team discovered that CPEB1 levels increase dramatically in human cells infected by CMV. Using genomics technologies, the researchers also found that increased CPEB1 levels in CMV-infected cells leads to abnormal processing of RNAs encoding thousands of human genes. In addition, they were surprised to find that CPEB1 was necessary for proper processing of viral RNAs. Without the host CPEB1 protein, viral RNA did not mature properly and the virus was weakened.

CMV-infected human cells undergo abnormal changes and produce more virus, which ultimately infects other cells. In collaboration with Deborah Spector, PhD, Distinguished Professor at UC San Diego School of Medicine and Skaggs School of Pharmacy and Pharmaceutical Sciences, the team went on to show that suppressing CPEB1 levels during CMV infection reversed these harmful cellular changes and reduced viral production tenfold.

“CPEB1 was previously shown to play a role in neuronal development and function, but this involvement in active viral infections is unexpected,” said first author Ranjan Batra, PhD, a postdoctoral fellow in Yeo’s lab. “This discovery has important implications for many viral infections.”

Yeo said the next steps are to determine the therapeutic value of inhibiting CPEB1 in CMV infections and identify other RNA-binding proteins that may be important in other viral infections.

Flesh-Eating Infections In Rheumatoid Arthritis Patients Spur New Discovery

Rheumatoid arthritis patients taking medications that inhibit interleukin-1beta (IL-1beta), a molecule that stimulates the immune system, are 300 times more likely to experience invasive Group A Streptococcal infections than patients not on the drug, according to University of California San Diego School of Medicine researchers. Their study, published August 19 in Science Immunology, also uncovers a critical new role for IL-1beta as the body’s independent early warning system for bacterial infections.

“The more we know about each step in the body’s immune response to bacterial infections, the better equipped we are to design more personalized, targeted therapies for autoimmune diseases — therapies that are effective, but minimize risk of infection,” said senior author Victor Nizet, MD, professor of pediatrics and pharmacy at UC San Diego School of Medicine and Skaggs School of Pharmacy and Pharmaceutical Sciences.

IL-1beta is a molecule that stimulates an immune response, calling white blood cells to the site of an infection so they can engulf and clear away invading pathogens. The body first produces the molecule in a longer, inactive form that must be cleaved to be activated. The scientific community long believed that only the body itself could cleave and activate IL-1beta, by employing a cellular structure known as the inflammasome. But in experiments using cell cultures and mouse models of infection, Nizet and team found that SpeB, an enzyme secreted by strep bacteria, also cleaves and activates IL-1beta, triggering a protective immune response.

“This finding may explain why some of the more invasive, flesh-eating strep strains have a genetic mutation that blocks SpeB production — it helps them avoid tripping the alarm and setting off an immune response,” said first author Christopher LaRock, PhD, a postdoctoral researcher in Nizet’s lab.

The researchers hypothesize that for less invasive strains, like those that cause strep throat, producing SpeB and activating IL-1beta might be advantageous — the resulting immune response may wipe out competing bacteria and help strep establish a foothold in the body.

While the human immune system can quickly recognize and respond to bacterial infections, sometimes this reaction can go overboard, leading to autoimmune diseases such as rheumatoid arthritis. In this case, a person’s own immune system attacks “self” proteins instead of just foreign invaders.

In their efforts to investigate IL-1beta function, Nizet, LaRock and team analyzed a U.S. Food and Drug Administration (FDA) database on adverse events in rheumatoid patients who took anakinra, a drug that dampens autoimmunity by inhibiting IL-1beta. They found that patients receiving anakinra were more than 300 times more likely to experience invasive, flesh-eating strep infections than patients not taking the drug.

“A likely explanation for this increased risk is that with IL-1beta out of the picture, as is the case with patients taking anakinra, strep strains can progress to invasive infection even while producing SpeB, which goes unnoticed by the immune system,” LaRock said.

This finding underscores IL-1beta’s importance as an early warning system that’s triggered not only by the host, but also directly by bacterial enzymes, essentially “taking out the middle man,” Nizet said. The UC San Diego researchers believe this capacity for direct pathogen detection represents IL-1beta’s original role in immunity, going all the way back in evolution to simpler animals, such as fish.

“Inhibiting the body’s bacterial sensor can put a person at risk for invasive infection,” Nizet said, “but just the fact that we now know that this patient population is at higher risk and why means we can take simple steps — such as close monitoring and prophylactic antibiotics — to prevent it from happening. ”

Largest HIV Transmission Study Conducted

A new study has found that neither gay men nor heterosexual people with HIV transmit the virus to their partner, provided they are on suppressive antiretroviral treatment.

The PARTNER study, which is the world’s largest study of people with HIV who have had condomless sex with their HIV negative partners, was conducted by investigators from the University of Liverpool, University College London, Royal Free NHS and Rigshospitalet (one of the largest hospitals in Denmark).

This work was funded by the National Institute for Health Research (NIHR) and was sponsored by UCL (University College London).

More than 800 couples monitored

The study monitored 888 couples from 14 different European countries, in which one of the partners was on effective treatment for HIV. Of the 888 couples, 548 were heterosexual and 340 were gay men.

All the couples had sex regularly without using a condom. They have now been monitored for several years and not one instance of transmission of the virus has been recorded. The results have just been published in the prestigious Journal of the American Medical Association.

In the period following the study, a total of 11 HIV-negative partners were infected with HIV. Led by Professor Anna Maria Geretti, researchers from the University of Liverpool‘s Institute of Infection and Global Health undertook phylogenetic analyses of the 11 new HIV cases and their partners’ virus.

No HIV transmission between couples

Professor Geretti, said: “The HIV virus can be divided into several sub-groups, each with its own genetic characteristics, and this makes it possible to see whether the virus is genetically similar to a partner’s. In all cases the results showed that the virus came from someone other than the partner under treatment.

“This research is vital for us to gain an even better understanding the risks associated with this particular virus.”

Professor Jens Lundgren from Rigshospitalet, senior author of the study and head of CHIP (the Centre for Health and Infectious Diseases), said: “The results clearly show that early diagnosis of HIV and access to effective treatment are crucial for reducing the number of new HIV cases. As soon as a patient with HIV is on treatment with a suppressed viral load, the risk of transmission becomes minimal.”

More data on the way

Gay couples in the study will continue to be monitored for three more years to obtain even more data in this area for anal sex.

Get a clue: Biochemist studies fruit fly to understand Parkinson’s disease, muscle wasting

The fruit fly may help us be less clueless about human muscle development and Parkinson’s disease.

Erika Geisbrecht, Kansas State University associate professor of biochemistry and molecular biophysics, is studying the fruit fly, or Drosophila melanogaster, to understand a gene called clueless, or clu. Geisbrecht and her research team have found a connection between clu and genes that cause Parkinson’s disease.

Geisbrecht’s team is among the first to focus on the connection between clu and mitochondrial function in fruit fly muscle cells. The researchers recently published their work in the journal Human Molecular Genetics.

“We are trying to understand how muscles develop and how healthy muscles are maintained throughout the entire life of a fruit fly in the hopes of applying this knowledge to the human body,” Geisbrecht said.

Geisbrecht uses fruit fly muscles as a model for human muscles because of their similar structures — approximately 85 percent of the human disease genes have corresponding genes in the fruit fly. Fruit flies also have a short lifecycle of 10 days from when the egg is laid to when adults emerge, which allows for the rapid observation of muscle development and maintenance.

The connection between fruit fly and human muscles has made it possible to understand the role of the clu gene that — when mutated — causes defects in the localization and turnover of damaged mitochondria. A buildup of damaged mitochondria ultimately affects the ability of muscles and nerves to function properly. Geisbrecht and her team are just beginning to understand how clu interacts with a gene called parkin that — when mutated in humans — results in Parkinson’s disease.

People who are born with mutations in the parkin gene do not develop Parkinson’s disease until later in adult life. The same is true for fruit flies with defects in clu or parkin: These fruit flies proceed through the larval and pupal stage of insect development and emerge as adults, but quickly die because their muscles and neurons degenerate.

“If you think about a tissue in the body that uses more energy than anything else, of course it’s your muscle tissue,” Geisbrecht said. “Proper mitochondrial function is essential to having healthy, developed muscles. It’s an important connection.”

Geisbrecht’s team plans to continue studying fruit flies to better understand the connection between human disease genes and muscle function. Their work could lead to better treatment for Parkinson’s disease or other muscle diseases.

Aside from muscle or neurodegenerative diseases, maintaining healthy muscle tissue also is important in the general population, where common diseases can also lead to muscle problems. For example, muscle wasting, or muscle deterioration, can be a huge problem for people with diabetes or cancer.

“Muscle wasting for people with end-stage diabetes or cancer is often a bigger problem than the cancer or diabetes itself because it causes people to become immobile and lose the ability to make their muscles function well again,” Geisbrecht said. “We want to understand what happens at the cellular level — what these genes or proteins are doing.”

Treatment of both Humans and Pigs May Reduce Endemic Tapeworm Infection

The transmission of Taenia solium, a pork tapeworm species that infects humans and causes late-onset seizures and epilepsy, can be stopped on a population-wide level with mass treatments of both pigs and humans, researchers have shown.

Researchers from several institutions, including Georgia State University, contributed to the study and published their findings in The New England Journal of Medicine.

Humans can become infected after eating contaminated pork or through fecal-oral exposure. This study was aimed at eliminating Taenia solium from the villages of Tumbes Province in Peru, a highly endemic region for the disease.

Researchers screened and treated pigs and humans in the first two phases of the program. In the final phase, mass treatment was given to 81,170 people in 107 villages, and 55,638 pigs received treatment and vaccination. Mass treatment included chemotherapy with niclosamide in humans and with oxfendazole in pigs, in combination with pig vaccination.

The researchers found only three of 342 pigs had live, nondegenerated cysts, but no infected pigs were found in 105 of 107 villages. The researchers showed the transmission of Taenia solium infection can be interrupted on a regional scale in a highly endemic region.

The researchers say they expect this effect will only be temporary if it is not bolstered by additional activities.

FDA Approves Vaccine for Cholera

In a milestone that was years in the making, a vaccine to prevent cholera, invented and developed by researchers at the University of Maryland School of Medicine’s Center for Vaccine Development, was approved today by the U.S. Food and Drug Administration (FDA).

The vaccine, Vaxchora, is the only approved vaccine in the U.S. for protection against cholera. Its licensure allows for use in people traveling to regions in which cholera is common, including travelers, humanitarian aid workers, and the military.

PaxVax, a global biotechnology company based in California, received marketing approval from the FDA for Vaxchora, a single-dose oral, live attenuated cholera vaccine that is indicated for use in adults 18 to 64 years of age. Vaxchora is the only vaccine available in the U.S. for protection against cholera and the only single-dose vaccine for cholera currently licensed anywhere in the world.

The vaccine was invented in the 1980s at Center for Vaccine Development (CVD). Since 2009, CVD researchers have worked closely with PaxVax to develop the vaccine and secure FDA licensure approval.

“This important FDA decision is the culmination of years of dedicated work by many researchers,” said Myron M. Levine, MD, DTPH, the Simon and Bessie Grollman Distinguished Professor at the University of Maryland School of Medicine (UM SOM). “For travelers to the many parts of the world where cholera transmission is occurring and poses a potential risk, this vaccine helps protect them from this disease. It is a wonderful example of how public-private partnerships can develop medicines from bench to bedside.” Dr. Levine is co-inventor of the vaccine, along with James B. Kaper, PhD, Professor and Chairman of the UM SOM Department of Microbiology and Immunology, and the senior associate dean for academic affairs at the school.

Cholera is an acute intestinal diarrheal infection acquired by ingesting contaminated food or water. Globally, cholera cases have increased steadily since 2005 and, millions of people are affected by this disease each year. Cholera can cause severe dehydration and death in less than 24 hours, if left untreated. While some cholera cases are rarely acquired in the U.S. from ingestion of uncooked seafood from the Gulf of Mexico, the vast majority of cases of domestic cholera cases occur in travelers to areas with epidemic or endemic cholera (for example, parts of Africa, Asia, or the Caribbean). A report from the U.S. Centers for Disease Control and Prevention suggests that the true number of cholera cases in the U.S. is at least 30 times higher than observed by national surveillance systems. The currently recommended intervention to prevent infection is to avoid contaminated water and food. But studies have shown that 98 percent of travelers do not follow these precautions.

Vaxchora is expected to be commercially available later this year. The FDA approval is based on results from a phase 1 safety and immunogenicity trial, a phase 3 efficacy trial, and a phase 3 trial to test manufacturing consistency. The first two of these trials were led by Wilbur H. Chen, MD, MS, associate professor of medicine at UM SOM, and chief of the CVD’s Adult Clinical Studies section. The pivotal efficacy trial, which demonstrated protection from cholera of more than 90 percent at 10 days and 80 percent at 3 months after vaccination, is the first instance the FDA has based the decision to approve a product on a human experimental challenge model. Therefore, the licensure of Vaxchora marks a significant regulatory milestone. The most common adverse reactions to Vaxchora in the clinical trials were tiredness, headache, abdominal pain, nausea/vomiting, lack of appetite and diarrhea.

Cholera is chiefly a disease of poverty, poor sanitation, and lack of access to safe drinking water, so the global health burden of cholera rests on those populations residing in vulnerable developing countries. The World Health Organization estimates the burden of cholera to be between 1.4 and 4.3 million cases per year globally. Dr. Chen said that the next steps for this cholera vaccine are to explore formulations that could be developed into successful strategies to prevent and control cholera in countries where cholera is common. These future activities would involve immunizing young children in developing countries; this group has the highest risk of dying from cholera.

“The FDA approval of a new vaccine for a disease for which there has been no vaccine available is an extremely rare event. The approval of Vaxchora is an important milestone for PaxVax and we are proud to provide the only vaccine against cholera available in the U.S.,” said Nima Farzan, chief executive officer and president of PaxVax. “We worked closely with the FDA on the development of Vaxchora and credit the agency’s priority review program for accelerating the availability of this novel vaccine. In line with our social mission, we have also begun development programs focused on bringing this vaccine to additional populations such as children and people living in countries affected by cholera.”

“This approval is an excellent example of how our researchers are entering into public-private partnerships to help further science in tangible ways,” said UM SOM Dean E. Albert Reece, MD, PhD, MBA, who is also the vice president for Medical Affairs, University of Maryland, and the John Z. and Akiko K. Bowers Distinguished Professor. “This vaccine shows once again that work by scientists here has an impact not only nationally, but globally.”

Novel Metagenomics Pathogen Detection Tool Could Change How Infectious Diseases Are Diagnosed

Scientists at the University of Utah, ARUP Laboratories, and IDbyDNA, Inc., have developed ultra-fast, meta-genomics analysis software called Taxonomer that dramatically improves the accuracy and speed of pathogen detection. In a paper published today in Genome Biology, the collaborators demonstrated the ability of Taxonomer to analyze the sequences of all nucleic acids in a clinical specimen (DNA and RNA) and to detect pathogens, as well as profile the patient’s gene expression, in a matter of minutes.

Infectious diseases are one of the biggest killers in the world. Almost 5 million children under age 5 die each year from infectious diseases worldwide, yet many infections are treatable if the pathogen culprit can be quickly and accurately identified.

“In the realm of infectious diseases, this type of technology could be as significant as sequencing the human genome,” says co-author Mark Yandell, PhD, professor of human genetics at the University of Utah (U of U), H.A. & Edna Benning Presidential Endowed Chair holder, co-director of the USTAR Center for Genetic Discovery, and co-founder of IDbyDNA. “Very few people have inherited genetic disease. But at some point, everyone gets sick from infections.”

It is difficult for infectious pathogens to hide when their genetic material is laid bare. Taxonomer opens up an entirely new approach for infectious disease diagnosis, driven by sophisticated genomic analysis and computational technologies. After a patient’s sample is sequenced, the data are uploaded via the internet to Taxonomer. In less than one minute, the tool displays a thumbnail inventory of all pathogens in the sample, including viruses, bacteria, and fungi. The interactive, real-time user interface of Taxonomer is powered by the IOBIO system developed by the laboratory of Gabor Marth, DSc, professor of human genetics at the U of U and co-Director of the USTAR Center for Genetic Discovery.

“Our benchmark analyses show Taxonomer being ten to a hundred times faster than similar tools,” says co-author Robert Schlaberg, MD, Dr Med, MPH, a medical director at ARUP Laboratories and cofounder of IDbyDNA. Schlaberg was awarded a $100,000 grant from the Bill and Melinda Gates Foundation to apply Taxonomer toward decreasing high mortality rates of children with infectious diseases in resource-limited settings.

Schlaberg points out that current diagnostic testing still relies heavily on growing cultures of suspected pathogens in the laboratory, which is often inconclusive and time consuming. Even with much faster tests like PCR, the number of pathogens that can be detected is limited.

Schlaberg explains that Taxonomer can identify an infection without the physician having to decide what to test for, something a PCR-based test cannot do. In other words, a doctor doesn’t have to suspect the cause of a patient’s infection, but can instead simply ask, “What does my patient have?” and Taxonomer will identify the pathogens.

In the new study, Taxonomer was put to the test with real-world cases using data published by others and samples provided by ARUP Laboratories and the Centers for Disease Control and Prevention (CDC). Taxonomer determined that some patients who exhibited Ebola-like symptoms in the recent African outbreak did not have Ebola but severe bacterial infections that likely caused their symptoms. “This technology can be applied whenever we don’t know the cause of the disease, including the detection of sudden outbreaks of disease. It is very clear we urgently need more accurate diagnostics to greatly enhance the ability of public health response and clinical care,” says Seema Jain, MD, medical epidemiologist at the CDC.

Another unique feature of Taxonomer is its ability to delve into human gene expression profiling, which provides information on how or if the patient’s body is reacting to an infection. “As a clinician, this gives you a better idea, when we identify a pathogen whether it is really the cause of the disease,” says Carrie L. Byington, MD, professor of pediatrics of the U of U and co-director of the Center for Clinical and Translational Science. “This tool will also allow us to determine if the patient is responding to a bacterial or viral infection when we don’t find a pathogen or when we find multiple potential causes.” She says that she sees the exceptional value of this tool for treating children, who experience more life-threatening infections early in life. “Seeing how a host [patient] reacts is extremely valuable; I believe this is a paradigm shift in how we diagnose people. It is why I wanted to be involved.”

In a previous paper published in the Journal of Clinical Microbiology, Schlaberg and his collaborators demonstrated that high-throughput sequencing in combination with Taxonomer can reliably detect pathogens, and identify previously missed pathogens, in patient samples. “Taxonomer provides a critical step forward, as it is extremely fast, accurate, and easy enough to use for implementation in diagnostic laboratories,” says Schlaberg.

How Do You Kill a Malaria Parasite? Clog It with Cholesterol

Drexel University scientists have discovered an unusual mechanism for how two new antimalarial drugs operate: They give the parasite’s skin a boost in cholesterol, making it unable to traverse the narrow labyrinths of the human bloodstream. The drugs also seem to trick the parasite into reproducing prematurely.

Malaria is a mosquito-borne disease caused by Plasmodium parasites. After a person is bitten, the parasite invades the victim’s red blood cells. There, it eventually divides into daughter parasites, which continue to destroy each red blood cell they infect.

There are several drugs under development that interrupt this life cycle, including a class of compounds discovered in 2014 by Akhil Vaidya, PhD, a professor at Drexel University College of Medicine. In their 2014 study, Vaidya and his research team found that these drugs increase levels of sodium within the parasites’ cells, causing them to swell and erupt.

However, in a new study, published recently in PLOS Pathogens, the researchers have revealed that this sodium increase actually triggers a more complex cascade of events, eventually changing the parasite’s outer membrane and also tricking it into early reproduction, which renders the parasite inert.

“Nobody suspected something like this to be the mode of action,” said Vaidya, who also directs Drexel’s Center for Molecular Parasitology. “The mechanism is a lot more complicated and interesting than we originally thought.”

In this study, the scientists focused on two small-molecule drugs, one of which is undergoing clinical trials. Despite very different molecular structures, both drugs initially increase sodium within the parasite and subsequently kill the pathogen. Until now, scientists have not understood why the increase in sodium concentration leads to the malaria parasite’s demise.

To explore this question, the researchers first tested the properties of the Plasmodium plasma membrane — or the parasite’s outer skin — before and after exposure to antimalarial drugs. The Plasmodium membrane is unusual, because it contains very low levels of cholesterol, a major lipid component of most other membranes, including those of human red blood cells.

The Drexel scientists hypothesized that the low cholesterol content permits greater flexibility for the parasite to travel through the human bloodstream and to withstand the stress of blood circulation. They propose that the sodium increase, caused by the antimalarial drugs, somehow interferes with that elasticity.

The researchers used a cholesterol-dependent detergent to detect the presence of lipids in the parasite membrane. They found that indeed both drug treatments appeared to add a significant amount of cholesterol to the Plasmodium plasma membrane.

“We believe that the cholesterol makes the parasite rigid, and then the parasite can no longer pass through very small spaces in the bloodstream,” Vaidya said, adding that the parasite cannot continue its lifecycle if it cannot enter red blood cells.

Just two hours after treatment, the scientists also saw that many of the parasites showed fragmented nuclei and interior membranes, which are the precursors to cell division. But these changes happened without any sign that the parasite’s genome had multiplied — a step that is necessary for a cell to divide and survive.

The researchers hypothesize that sodium influx is a normal step during the malaria parasite’s division. The antimalarial drugs prematurely induce this signaling event, and the parasite begins dividing before it should.

“The parasite is not ready to divide yet, so it can not survive. It is like premature delivery of an infant,” Vaidya said. “This whole cascade of events is triggered by these drug treatments.”

Malaria is the world’s deadliest parasitic disease. It kills more than 300,000 people per year, according to the World Health Organization, and affects up to 300 million.

One of the biggest challenges for treating malaria is drug resistance. The drugs that are currently available are quickly losing their potency, so researchers are scrambling to develop stronger treatments.

By understanding exactly how new drug candidates stop malaria, Vaidya and his team aim to reveal more about the parasite’s vulnerabilities. This, they hope, will eventually lead to the creation of more effective drugs against the disease. Vaidya noted that the best defense against malaria will always be a combination of treatments.

New International Initiative Will Focus on Immunology Research and Treatments

Immunology – and the idea that many diseases can best be addressed by boosting the body’s own immune response – is one of the hottest areas in medical research and clinical treatment. University of California San Diego School of Medicine and Chiba University School of Medicine in Japan have announced a new collaborative research center to investigate the most promising aspects of immunology, especially the area of mucosal immunology, and to speed development of clinical applications.

The Chiba University-UC San Diego Immunology Initiative and associated research center, to be based at UC San Diego School of Medicine, will be established with a $2 million contribution from Chiba University, the funding allocated over five years together with support from UC San Diego.

“This agreement reflects our shared interest in furthering scientific understanding of the human immune system, what happens when things go wrong and how best to remedy them,” said David Brenner, MD, vice chancellor, UC San Diego Health Sciences and dean of the School of Medicine.

“The microbiome has a major impact upon human health, particularly mucosal immune responses that affect virtually every type of disease, from acute and chronic conditions like infection, allergy, asthma, inflammatory bowel disease and arthritis to type 1 diabetes, multiple sclerosis and cancer. Hundreds of millions of people worldwide are affected by immune system dysfunction so the need to find new, effective treatments is incredibly powerful and compelling.”

The effort, which will be co-directed by Peter Ernst, DVM, PhD, professor of pathology at UC San Diego School of Medicine, and Hiroshi Kiyono, DDS, PhD, professor, University of Tokyo and Chiba University, will involve exchanges of faculty, researchers, staff and students. Initial joint projects will focus on medical and veterinary science, vaccine development, allergy, inflammation, infectious diseases, mucosal immunology and the interactions between mucosal immunity and commensal microbiota that promote health.

“This is a collaboration of partners, both with a deep interest in advancing immunology research across disciplines,” said Ernst, who also directs the Center for Veterinary Sciences and Comparative Medicine. “The topics we are grappling with are global in scale. We want to be leaders in both understanding mucosal immunology and in how to use that knowledge to prevent and treat a vast array of diseases such as infectious, allergic and inflammatory diseases. We want to cultivate the next generation of scientists, here, in Japan and around the world.”

Specifically, the agreement outlines creation of multiple affiliated laboratories with principal investigators at Chiba University, UC San Diego and the La Jolla Institute for Allergy and Immunology, which last year formed a multi-year partnership with UC San Diego to boost collaborative basic research of immune system diseases. The Chiba-UC San Diego initiative would also contribute to a new graduate program in immunology.

“Through collaboration and combined resources, we hope to develop new concepts and technologies that ultimately lead to development a preventive vaccine against infectious diseases, allergies and cancers, boosting the body’s ability to block the transmission of agents entering through mucous membranes,” said Takeshi Tokuhisa, MD, PhD, president of Chiba University. “It would be a new approach to next-generation vaccines.”

Temple Scientists Eliminate HIV-1 From Genome of Human T-Cells

a team of researchers in the Lewis Katz School of Medicine at Temple University became the first to successfully eliminate the HIV-1 virus from cultured human cells. Fewer than two years later, the team has made further strides in its research by eliminating the virus from the genome of human T-cells using the specialized gene editing system they designed.

In a new study published in Scientific Reports, the researchers show that the method can both effectively and safely eliminate the virus from the DNA of human cells grown in culture.

How this research differs
In previous work, the team—led by Kamel Khalili, professor and chair of the Department of Neuroscience at Temple—had demonstrated the ability of their technology to snip out HIV-1 DNA from normal human cells. The newest findings used that same technology to snip out the virus from latently and productively infected CD4+ T-cells, which host the virus in persons infected with HIV.

In this round of research, the scientists used blood drawn from actual patients living with HIV. These ex vivo experiments allowed T-cells from patients infected with HIV to be grown in cell culture and treated with the gene editing system. Results showed that the treatment system can eliminate the virus and protect cells against reinfection.

Another major component of the study addressed questions about potential side effects and toxicity. The researchers used the gold standard in genomic assessment known as ultra-deep whole-genome sequencing to analyze the genomes of HIV-1-eradicated cells for mutations in genes outside the region targeted by the process. Their analyses ruled out off-target effects on genes and showed that HIV-1-eradicated cells were growing and functioning normally.

Yeast Infection Linked to Mental Illness

In a study prompted in part by suggestions from people with mental illness, Johns Hopkins researchers found that a history of Candida yeast infections was more common in a group of men with schizophrenia or bipolar disorder than in those without these disorders, and that women with schizophrenia or bipolar disorder who tested positive for Candida performed worse on a standard memory test than women with schizophrenia or bipolar disorder who had no evidence of past infection.

The researchers caution that their findings, described online on May 4 in npj Schizophrenia — a new publication from Nature Publishing Group — do not establish a cause-and-effect relationship between mental illness and yeast infections but may support a more detailed examination into the role of lifestyle, immune system weaknesses and gut-brain connections as contributing factors to the risk of psychiatric disorders and memory impairment.

“It’s far too early to single out Candida infection as a cause of mental illness or vice versa,” says Emily Severance, Ph.D., assistant professor of pediatrics and member of the Stanley Division of Developmental Neurovirology at the Johns Hopkins University School of Medicine. “However, most Candida infections can be treated in their early stages, and clinicians should make it a point to look out for these infections in their patients with mental illness.” She adds that Candida infections can also be prevented by decreased sugar intake and other dietary modifications, avoidance of unnecessary antibiotics, and improvement of hygiene.

Candida albicans is a yeastlike fungus naturally found in small amounts in human digestive tracts, but its overgrowth in warm, moist environments causes burning, itching symptoms, thrush (rashes in the throat or mouth) in infants and those with weakened immune systems, and sexually transmittable genital yeast infections in men and women. In its more serious forms, it can enter the bloodstream. In most people, the body’s own healthy bacteria and functioning immune system prevent its overgrowth.

Severance says she and her team focused on a possible association between Candida susceptibility and mental illness in the wake of new evidence suggesting that schizophrenia may be related to problems with the immune system, and because some people with weakened immune systems are more susceptible to fungal infections.

Also, she says, patients and parents of patients had shared personal stories and testimonials with the researchers about their experience with yeast infections, and these discussions prompted the investigation into possible links between mental illness and the microbiome — the body’s natural collection of bacteria. The researchers, she adds, chose to focus on Candida because it is one of the most common types of yeast in the body.

For the study, colleagues from the Sheppard Pratt Health System took blood samples from a group of 808 people between the ages of 18 and 65. This group was composed of 277 controls without a history of mental disorder, 261 individuals with schizophrenia and 270 people with bipolar disorder. The researchers used the blood samples to quantify the amount of IgG class antibodies to Candida, which indicates a past infection with the yeast. After accounting for factors like age, race, medications and socioeconomic status, which could skew the results, they looked for patterns that suggested links between mental illness and infection rates.

Significantly, the team says, it found no connection between the presence of Candida antibodies and mental illness overall in the total group. But when the investigators looked only at men, they found 26 percent of those with schizophrenia had Candida antibodies, compared to 14 percent of the control males. There wasn’t any difference found in infection rate between women with schizophrenia (31.3 percent) and controls (29.4 percent). The higher infection rate percentages in women over men likely reflects an increased susceptibility for this type of infection in all women.

Men with bipolar disorder had clear increases in Candida as well, with a 26.4 percent infection rate, compared to only 14 percent in male controls. But, after accounting for additional variables related to lifestyle, the researchers found that the association between men with bipolar disorder and Candida infection could likely be attributed to homelessness. However, the link between men with schizophrenia and Candida infection persisted and could not be explained by homelessness or other environmental factors. Many people who are homeless are subjected to unpredictable changes in stress, sanitation and diet, which can lead to infections like those caused by Candida.

Severance says the data add support to the idea that environmental exposures related to lifestyle and immune system factors may be linked to schizophrenia and bipolar disorder, and that those factors may be different for each illness. Similarly, specific mental illnesses and related symptoms may be very different in men versus women.

This Johns Hopkins research group, led by Robert Yolken, M.D., director of the Stanley Division of Developmental Neurovirology, had previously shown that toxoplasmosis infection could trigger schizophrenia, and this could lead to neurocognitive problems. The organism that causes toxoplasmosis is a parasite that uses cats as its primary host, but it can also infect humans and other mammals.

To determine whether infection with Candida affected any neurological responses, all participants in the new study took a 30-minute assessment of cognitive tasks to measure immediate memory, delayed memory, attention skills, use of language and visual-spatial skills.

Each of the five skills tests are scored based on an adjusted 100-point system. Results showed that control men and women with and without prior Candida infection had no measureable differences in scores in the five neurological responses.

However, the researchers noticed that women with schizophrenia and bipolar disorder who had a history of Candida infection had lower scores on the memory portions of this test compared to those women with no prior infection. For example, women with schizophrenia and the highest Candida antibody levels scored about an average of 11 points lower on the test for immediate memory than the controls, from a score of 68.5 without infection to 57.4 with infection. And the women with schizophrenia and the highest Candida antibody levels scored almost 15 points lower on the test for delayed memory, from a score of 71.4 without infection to 56.2 with infection. The effect of Candida infection in women with bipolar disorder on memory test scores was smaller than that seen in women with schizophrenia but was still measureable.

“Although we cannot demonstrate a direct link between Candida infection and physiological brain processes, our data show that some factor associated with Candida infection, and possibly the organism itself, plays a role in affecting the memory of women with schizophrenia and bipolar disorder, and this is an avenue that needs to be further explored,” says Severance. “Because Candida is a natural component of the human body microbiome, yeast overgrowth or infection in the digestive tract, for example, may disrupt the gut-brain axis. This disruption in conjunction with an abnormally functioning immune system could collectively disturb those brain processes that are important for memory.”

Severance says they plan to take their studies of the gut-brain connection into mouse models to test for a cause-and effect-relationship with Candida and memory deficits.

The researchers emphasized that the current study design had limitations. For example, they were unable to tell where in the body the infection was located and whether or not participants had a current or past infection of Candida. The researchers were also not able to account for every possible lifestyle variable that might contribute to these results.

The researchers in the Stanley Division of Developmental Neurovirology are investigating whether pathogens, such as bacteria or viruses, may contribute or trigger certain mental disorders.

According to the National Institute of Mental Health, about 1 percent of people in the U.S. have schizophrenia and about 2 percent have bipolar disorder. Although these diseases have a genetic component, there is evidence that they may also be triggered by environmental factors and stress.

Researchers Discover Potential Treatment for Sepsis and Other Uncontrollable Responses to Infection

Researchers at the Icahn School of Medicine at Mount Sinai say that tiny doses of a cancer drug may stop the raging, uncontrollable immune response to infection that leads to sepsis and kills up to 500,000 people a year in the U.S. The new drug treatment may also benefit millions of people worldwide who are affected by infections and pandemics.

Their study reported in Science, demonstrates in both cells and animals that a small dose of topoisomerase I (Top 1) inhibitor can dampen an acute inflammatory reaction to infection while still allowing the body’s protective defense to take place. The title of the study is “Topoisomerase 1 inhibition suppresses the transcriptional activation of innate immune responses and protects against inflammation-induced death.”

The treatment may help control not only sepsis — deadly infections often acquired in hospital by patients with a weak immune system — but also new and brutal assaults on human immunity such as novel influenza strains and pandemics of Ebola and other singular infections, says the study’s senior investigator, Ivan Marazzi, PhD, an Assistant Professor of Microbiology at the Icahn School of Medicine at Mount Sinai.

“Our results suggest that a therapy based on Top 1 inhibition could save millions of people affected by sepsis, pandemics, and many congenital deficiencies associated with acute inflammatory episodes — what is known as a cytokine, or inflammatory, storm,” says Marazzi.

“These storms occur because the body does not know how to adjust the appropriate level of inflammation that is good enough to suppress an infection but doesn’t harm the body itself,” he says. “This drug appears to offer that life-saving correction.”

Sepsis is caused by an excessive host response to infection, which in turn leads to multiple organ failure and death. With an overall mortality rate between 20 and 50%, sepsis is the tenth leading cause of death in the U.S. — it kills more people than do HIV and breast cancer.

“To date there has been no targeted treatment for sepsis, or for other infections that promote this inflammatory storm,” says Dr. Marazzi. “Such treatment is desperately needed.”

For example, sepsis is a leading cause of death in infants and children, he says. “Septic shock and lung destruction can occur when a child is suffering from a pneumonia caused by co-infection with a virus and a bacteria even when antibiotic therapy is being used. The elderly are also especially vulnerable to sepsis.”

Following a challenge from the National Institutes of Health to repurpose existing drugs for new uses, the research team used a simple cellular screen to find candidate drugs that could tamp down rampant inflammation.

They discovered that the Top 1 inhibitor class of cancer drugs — four have been previously approved for a variety of cancers — also blocks a set of genes that are activated immediately by immune cells to combat an infection. “These genes are the ones that have the strongest inflammatory effects,” says Marazzi.

The Mount Sinai team found that use of one to three doses of a Top 1 inhibitor that is 1/50th the strength of normal chemotherapy was enough to rescue 70-90 % of mice from an inflammatory storm death due to either acute bacterial infection, liver failure, or virus-bacteria co-infection. The treatment did not produce overt side effects.

They also tested the inhibitor in cells infected with influenza, Ebola, and other viral and bacterial microbes that over-stimulate the immune system, and found the drug blunted a dangerous immune reaction.

“We observed a striking effect of Top-1 inhibitors on expression of pro-inflammatory molecules induced by Ebola virus infection. This study contributes our understanding of pathogenesis of Ebola virus disease and also suggests a direction to develop treatments,” says Alexander Bukreyev, PhD, Professor in the Department of Pathology and Microbiology & Immunology at the Galveston National Laboratory at the University of Texas Medical Branch.

“Finding remedies for these infection-induced inflammatory storms is a global focus, and we look forward to testing the ability of Top-1 inhibitors to save lives,” adds Marazzi.