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Research opens possibility of reducing risk of gut bacterial infections with next-generation probiotic

A team of researchers is exploring the possibility that next-generation probiotics – live bacteria that are good for your health – would reduce the risk of infection with the bacterium Clostridium difficile. In laboratory-grown bacterial communities, the researchers determined that, when supplied with glycerol, the probiotic Lactobacillus reuteri produced reuterin, an antibacterial compound that selectively killed C. difficile. The study appears in Infection and Immunity.

“C. difficile causes thousands of deaths and billions of dollars in healthcare expenses in the U.S. each year. Although most patients respond to antibiotic treatment, up to 35 percent will relapse and require extended antibiotic treatments,” said first and corresponding author Dr. Jennifer K. Spinler, instructor of pathology & immunology at Baylor College of Medicine, who oversees microbial genetics and genomics efforts at the Texas Children’s Microbiome Center at Texas Children’s Hospital.

C. difficile infections are the most common cause of diarrhea associated with the use of antibiotics. If these bacteria attempt to invade the human gut, the ‘good bacteria,’ which outnumber C. difficile, usually prevent them from growing. However, when a person takes antibiotics, for example to treat pneumonia, the antibiotic also can kill the good bacteria in the gut, opening an opportunity for C. difficile to thrive into a potentially life-threatening infection.

“When repeated antibiotic treatments fail to eliminate C. difficile infections, some patients are resorting to fecal microbiome transplant – the transfer of fecal matter from a healthy donor – which treats the disease but also could have negative side effects,” Spinler said. “We wanted to find an alternative treatment, a prophylactic strategy based on probiotics that could help prevent C. difficile from thriving in the first place.”

“Probiotics are commonly used to treat a range of human diseases, yet clinical studies are generally fraught by variable clinical outcomes and protective mechanisms are poorly understood in patients. This study provides important clues on why clinical efficacy may be seen in some patients treated with one probiotic bacterium but not with others,” said senior author Dr. Tor Savidge, associate professor of pathology & immunology and of pediatrics at Baylor and the Texas Children’s Microbiome Center.

Working in the Texas Children’s Microbiome Center, Spinler and her colleagues tested the possibility that probiotic L. reuteri, which is known to produce antibacterial compounds, could help prevent C. difficile from establishing a microbial community in lab cultures.

An unexpected result with major implications for a preventative strategy

Spinler and Savidge established a collaboration with co-author Dr. Robert A. Britton, professor of molecular virology and microbiology at Baylor and member of the Dan L Duncan Comprehensive Cancer Center.

The Britton lab uses mini-bioreactor arrays – multiple small culture chambers – that provide a platform in which researchers could recreate the invasion of an antibiotic-treated human intestinal community by C. difficile.

“Using the mini-bioreactors model we showed that L. reuteri reduced the burden of C. difficile infection in a complex gut community,” Britton said. “To achieve its beneficial effect, L. reuteri requires glycerol and converts it into the antimicrobial reuterin.”

The literature reports reuterin as a broad-spectrum antibiotic; it affects the growth of a wide variety of bacteria when they are tested individually in the lab. What was intriguing in this study is that reuterin didn’t have a broad-spectrum effect in the mini-bioreactor bacterial community setting.

“I expected reuterin to have an antibacterial effect on several different types of bacteria in the community, but it only affected C. difficile and not the good bacteria, which was exciting because it has major implications for a preventative strategy,” Spinler said.

“Although these results are too preliminary to be translated directly into human therapy, they provide a foundation upon which to further develop treatments based on co-administration of L. reuteri and glycerol to prevent C. difficile infection,” said co-author Dr. Jennifer Auchtung, director of the Cultivation Core at Baylor’s Alkek Center for Metagenomics and Microbiome Research and assistant professor of molecular virology and microbiology at Baylor.

In the future, this potential treatment could be administered prophylactically to patients before they take antibiotics known to disrupt normal gut microbes. The L. reuteri/glycerol formulation would help maintain the healthy gut microbial community and also help prevent the growth of C. difficile, which would result in decreased hospital stay and costs and reduced long-term health consequences of C. difficile recurrent infections.

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Penn study details impact of antibiotics, antiseptics on skin microbiomes

The use of topical antibiotics can dramatically alter communities of bacteria that live on the skin, while the use of antiseptics has a much smaller, less durable impact. The study, conducted in mice in the laboratory of Elizabeth Grice, PhD, an assistant professor of Dermatology in the Perelman School of Medicine at the University of Pennsylvania, is the first to show the long-term effects of antimicrobial drugs on the skin microbiome. Researchers published their findings today in the journal Antimicrobial Agents and Chemotherapy.

The skin, much like the gut, is colonized by a diverse multitude of microorganisms which generally coexist as a stable ecosystem — many of which are harmless or even beneficial to the host. However, when that ecosystem is disturbed or destabilized, colonization and/or infection by more dangerous microbes can occur. Antiseptics, such as ethanol or iodine, are commonly used to disinfect the skin prior to surgical procedures or following exposure to contaminated surfaces or objects. Topical antibiotics may be used to decolonize skin of specific types of bacteria or for rashes, wounds, or other common conditions.

In the gut, research shows medication that alters microbial communities can lead to complications like Clostridium difficile, or C. diff — which causes diarrhea and is the most common hospital-acquired infection. But when it comes to the skin, the impact of these medications on bacteria strains like Staphylococcus aureus, or S. aureus — the most common cause of skin infections — is still largely unstudied.

“We know antibiotics and antiseptics can be effective in stopping the growth of certain bacteria, but we wanted to know about the larger impact these treatments can have on the resident microbial communities on the skin,” said the study’s lead author, Adam J. SanMiguel, PhD, a researcher in the Grice Laboratory at Penn.

Researchers treated the skin of hairless mice with a variety of antibiotics, including a narrowly targeted mupirocin ointment and a broadly applicable triple-antibiotic ointment (TAO) containing bacitracin, neomycin, and polymyxin B. All of the antibiotics changed the makeup of the microbial communities, and, in a key finding of the study, the impact of that change lasted for days after treatment stopped.

“The problem in this case isn’t antibiotic resistance, but instead, how long the disruption of the skin microbiomes continues,” SanMiguel said. “That disruption opens the door for colonization by an unwanted strain.”

The researchers similarly evaluated antiseptics, using alcohol or povidone-iodine and comparing those treatments with two control groups – mice treated with water and mice entirely untreated. They found neither antiseptic caused responses similar enough to cluster the mice together into groups based on their microbiomes. They also found no clear difference between the treatment groups and the control groups when comparing the relative number of individual bacteria strains.

“We thought antiseptics would be even more disruptive to microbial communities than antibiotics since they are less targeted, but it turns out the opposite is true,” SanMiguel said. “It shows how stable the skin microbiome can be in the face of stress.”

However, both antibiotic and antiseptic treatments removed skin resident bacteria that compete against the pathogenic S. aureus to colonize the skin. Colonization with S. aureus is a risk factor for developing a skin infection.

“This gives us a better understanding of how topical antimicrobials affect the skin microbiome and what kind of impact their disturbance can have in the context of pathogenic colonization,” said Grice, the study’s senior author. “This helps us anticipate their potential effects.”

The researchers say this work can provide the foundation for greater understanding of how the skin defends against infection. They have already begun similar testing in humans.

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New Arsenal Against MRSA: New Study Reports Cannabinoids Effective Against Antibiotic-Resistant MRSA

Researchers have found that cannabinoid-based therapies have unique anti-bacterial properties that fight MSRA and other infectious bacteria. In vitro studies demonstrated that bactericidal synergy was achieved against multiple species of methicillin-resistant Staphylococcus aureus (MRSA) utilizing a proprietary cannabinoid-based therapeutic platform. MRSA species tested included community acquired- (CA-MRSA), healthcare-acquired- (HA-MRSA), and mupirocin-resistant (MR-MRSA) strains of MRSA.

Researchers also found that using unique strategic cannabinoid-based cocktails, fractional-inhibitory concentration (FIC) levels demonstrating synergy between mixtures of individual cannabinoid-based components ranged from 0.06 to 0.28. FIC findings below 0.5 indicate significant killing potential of the mixture. The work was led by NEMUS BIoscience, Inc. and the company’s discovery and research partner, the University of Mississippi (UM).

Dr. Mahmoud ElSohly, professor at the National Center for Natural Products Research (NCNPR) at the University of Mississippi commented: “Historically, many types of anti-infective compounds are derived from plants so to have a series of cannabinoid-related compounds exhibit activity against this dangerous pathogen is in keeping with prior efforts of drug development. I believe that these compounds, in addition to the bacterial killing capability, could also offer benefits associated with anti-inflammatory and anti-fibrotic properties that could enhance healing, especially against an organism associated with skin and soft tissue infections. The University, in conjunction with Nemus, is looking to expand the anti-infective capabilities of this series of compounds.”

Recently, the World Health Organization (WHO) placed MRSA on their list as one of the top six organisms that pose a global public health threat. “This anti-infective platform will constitute the NB3000 series of Nemus molecules and formulations.  While there are a number of compounds in the development pipeline against MRSA, we believe that this family of drug candidates could possess an excellent safety profile in addition to efficacy in neutralizing this bacterium,” stated Brian Murphy, M.D., C.E.O. and Chief Medical Officer of Nemus. “These unique botanically derived components establish an anti-infective platform which could potentially be expanded into other types of bacteria, as well as viruses, and fungi.”

The University of Mississippi, the state’s flagship institution, is among the elite group of R-1: Doctoral Universities – Highest Research Activity in the Carnegie Classification. The university has a long history of producing leaders in public service, academics, research and business. Its 15 academic divisions include a major-medical school, nationally recognized schools of accountancy, law and pharmacy, and an Honors College acclaimed for a blend of academic rigor, experiential learning and opportunities for community action.

Nemus will work with Dr. Elsohly, the University lead researcher on this project, to have this data submitted to a future scientific meeting and anticipates performing further testing against a variety of other bacterial species. Commercially, the company looks to actively pursue partnering opportunities for these candidate molecules. “This work highlights the importance of Nemus’ relationship with the University which has significant experience and intellectual capital related to cannabinoid chemistry and physiology, dating back to 1968,” added Dr. Murphy.

Nemus Bioscience is a biopharmaceutical company, headquartered in Costa Mesa, California, focused on the discovery, development, and commercialization of cannabinoid-based therapeutics for significant unmet medical needs in global markets. Utilizing certain proprietary technology licensed from the University of Mississippi, NEMUS is working to develop novel ways to deliver cannabinoid-based drugs for specific indications, with the aim of optimizing the clinical effects of such drugs, while limiting potential adverse events. NEMUS’s strategy is to explore the use of natural and synthetic compounds, alone or in combination with partners. The Company is led by a highly-qualified team of executives with decades of biopharmaceutical experience and significant background in early-stage drug development.

For more information, visit http://www.nemusbioscience.com.

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Study Suggests Gut Bacteria Can Aid Recovery From Spinal Cord Injury

Researchers from The Ohio State University have discovered that spinal cord injury alters the type of bacteria living in the gut and that these changes can exacerbate the extent of neurological damage and impair recovery of function. The study, “Gut dysbiosis impairs recovery after spinal cord injury,” by Kristina A. Kigerl et al., which will be published online October 17 ahead of issue in The Journal of Experimental Medicine, suggests that counteracting these changes with probiotics could aid patients’ recovery from spinal cord injuries.

The trillions of bacteria that live in the gastrointestinal tract are collectively known as the gut microbiome. Disruption of this microbial community, or dysbiosis, occurs when nonpathogenic gut bacteria are depleted or overwhelmed by pathogenic inflammatory bacteria. Autoimmune diseases (including multiple sclerosis, type I diabetes, and rheumatoid arthritis) have been linked to dysbiosis, and it has been implicated in the onset or progression of neurological disorders, including autism, pain, depression, anxiety, and stroke.

Traumatic spinal cord injuries have secondary effects or comorbidities, including loss of bowel control, that are likely to cause dysbiosis. The authors reasoned that if any changes in the gut microbiome occur, they might, in turn, affect recovery after spinal cord injury.

Under the direction of Phillip G. Popovich at the Center for Brain and Spinal Cord Repair, the researchers found that spinal cord injury significantly altered the gut microbiome of mice, inducing the migration of gut bacteria into other tissues of the body and the activation of proinflammatory immune cells associated with the gut.

Mice that showed the largest changes in their gut bacteria tended to recover poorly from their injuries. Indeed, when mice were pretreated with antibiotics to disrupt their gut microbiomes before spinal cord injury, they showed higher levels of spinal inflammation and reduced functional recovery. In contrast, when injured mice were given daily doses of probiotics to restore the levels of healthy gut bacteria, they showed less spinal damage and regained more hindlimb movement.

The probiotics, containing large numbers of lactic acid–producing bacteria, activated a type of gut-associated immune cell—regulatory T cells—that can suppress inflammation. These cells could prevent excessive damage to the spinal cord after injury. Additionally, the probiotic bacteria may boost spinal cord recovery by secreting molecules that enhance neuronal growth and function. “Either or both of these mechanisms could explain how post-injury disruption of the gut microbiome contributes to the pathology of spinal cord injuries and how probiotics block or reverse these effects,” Popovich explains.

“Our data highlight a previously unappreciated role for the gut-central nervous system–immune axis in regulating recovery after spinal cord injury,” Popovich continues. “No longer should ‘spinal-centric’ repair approaches dominate research or standards of clinical care for affected individuals.”

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Antibiotics Weaken Alzheimer’s Disease Progression Through Changes in the Gut Microbiome

Long-term treatment with broad spectrum antibiotics decreased levels of amyloid plaques, a hallmark of Alzheimer’s disease, and activated inflammatory microglial cells in the brains of mice in a new study by neuroscientists from the University of Chicago.

The study, published July 21, 2016, in Scientific Reports, also showed significant changes in the gut microbiome after antibiotic treatment, suggesting the composition and diversity of bacteria in the gut play an important role in regulating immune system activity that impacts progression of Alzheimer’s disease.

“We’re exploring very new territory in how the gut influences brain health,” said Sangram Sisodia, PhD, Thomas Reynolds Sr. Family Professor of Neurosciences at the University of Chicago and senior author of the study. “This is an area that people who work with neurodegenerative diseases are going to be increasingly interested in, because it could have an influence down the road on treatments.”

Two of the key features of Alzheimer’s disease are the development of amyloidosis, accumulation of amyloid-ß (Aß) peptides in the brain, and inflammation of the microglia, brain cells that perform immune system functions in the central nervous system. Buildup of Aß into plaques plays a central role in the onset of Alzheimer’s, while the severity of neuro-inflammation is believed to influence the rate of cognitive decline from the disease.

For this study, Sisodia and his team administered high doses of broad-spectrum antibiotics to mice over five to six months. At the end of this period, genetic analysis of gut bacteria from the antibiotic-treated mice showed that while the total mass of microbes present was roughly the same as in controls, the diversity of the community changed dramatically. The antibiotic-treated mice also showed more than a two-fold decrease in Aß plaques compared to controls, and a significant elevation in the inflammatory state of microglia in the brain. Levels of important signaling chemicals circulating in the blood were also elevated in the treated mice.

While the mechanisms linking these changes is unclear, the study points to the potential in further research on the gut microbiome’s influence on the brain and nervous system.

“We don’t propose that a long-term course of antibiotics is going to be a treatment—that’s just absurd for a whole number of reasons,” said Myles Minter, PhD, a postdoctoral scholar in the Department of Neurobiology at UChicago and lead author of the study. “But what this study does is allow us to explore further, now that we’re clearly changing the gut microbial population and have new bugs that are more prevalent in mice with altered amyloid deposition after antibiotics.”

The study is the result of one the first collaborations from the Microbiome Center, a joint effort by the University of Chicago, the Marine Biological Laboratory and Argonne National Laboratory to support scientists at all three institutions who are developing new applications and tools to understand and harness the capabilities of microbial systems across different fields. Sisodia, Minter and their team worked with Eugene B. Chang, Martin Boyer Professor of Medicine at UChicago, and Vanessa Leone, PhD, a postdoctoral scholar in Chang’s lab, to analyze the gut microbes of the mice in this study.

Minter said the collaboration was enabling, and highlighted the cross-disciplinary thinking necessary to tackle a seemingly intractable disease like Alzheimer’s. “Once you put ideas together from different fields that have largely long been believed to be segregated from one another, the possibilities are really amazing,” he said.

Sisodia cautioned that while the current study opens new possibilities for understanding the role of the gut microbiome in Alzheimer’s disease, it’s just a beginning step.

“There’s probably not going to be a cure for Alzheimer’s disease for several generations, because we know there are changes occurring in the brain and central nervous system 15 to 20 years before clinical onset,” he said. “We have to find ways to intervene when a patient starts showing clinical signs, and if we learn how changes in gut bacteria affect onset or progression, or how the molecules they produce interact with the nervous system, we could use that to create a new kind of personalized medicine.”

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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.”

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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.”

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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.

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New Research Explains Why HIV Is Not Cleared by the Immune System

Scientists at the University of North Carolina (UNC) School of Medicine and Sanford Burnham Prebys Medical Discovery Institute (SBP) have identified a human (host) protein that weakens the immune response to HIV and other viruses. The findings, published today in Cell Host & Microbe, have important implications for improving HIV antiviral therapies, creating effective viral vaccines, and advance a new approach to treat cancer.

“Our study provides critical insight on a paramount issue in HIV research: Why is the body unable to mount an efficient immune response to HIV to prevent transmission?” said Sumit Chanda, Ph.D., professor and director of SBP’s Immunity and Pathogenesis Program and co-senior author of the study. “This research shows that the host protein NLRX1 is responsible—it’s required for HIV infection and works by repressing the innate immune response.”

The innate immune response works by producing a cascade of signaling chemicals (interferons and cytokines) that trigger cytotoxic T cells to kill pathogens. Increasing evidence suggests that mounting an early, potent innate immune response is essential for the control of HIV infection, and may improve the effectiveness of vaccines.

“Importantly, we were able to show that deficiencies in NLRX1 reduce HIV replication, suggesting that the development of small molecules to modulate the innate immune response may inhibit viral transmission and promote immunity to infection,” said Chanda. “We anticipate expanding our research to identify NLRX1 inhibitors.”

How NLRX1 reduces innate immunity to HIV

Although HIV is a single-stranded RNA virus, after it infects an immune cell it’s rapidly reverse transcribed into DNA, increasing the level of DNA found in the fluid portion of a cell (cytosol). Elevated cytosolic DNA triggers a sensor called STING (stimulator of interferon genes) that turns on the innate immune response.

“Until now, the mechanism by which NLRX1 promoted HIV infection was unexplored. We have shown that NLRX1 interacts directly with STING, essentially blocking its ability to interact with an enzyme called TANK-binding kinase 1 (TBK1),” said Haitao Guo, Ph.D., senior postdoctoral research associate in the laboratory of Jenny Ting, Ph.D., a University of North Carolina Lineberger Comprehensive Cancer Center member, the William R. Kenan Jr. Professor of Microbiology and Immunology at the UNC School of Medicine and lead author of the study. “The STING-TBK1 interaction is a critical step for interferon production in response to elevated cytosolic DNA, and initiates the innate immune response.”

“This research expands our understanding of the role of host proteins in viral replication and the innate immune response to HIV infection, and can be extended to DNA viruses such as HSV and vaccinia,” added Guo.

Relevance to cancer

“Our discovery that NLRX1 reduces the immune response to HIV is similar to the discovery of host immune checkpoints, such as PD-L1 and CTLA-1, that control the immune response to cancer,” said Ting, co-senior author of the study.

Immune checkpoints are immunological “brakes” that prevent the over-activation of the immune system on healthy cells. Tumor cells often take advantage of these checkpoints to escape detection of the immune system. Several FDA-approved drugs that target checkpoints, called checkpoint inhibitors, are now available to treat certain cancers.

“Checkpoint inhibitors have made a huge impact on cancer treatment, and significant investment by the biotech/pharmaceutical sector is being made to identify STING inhibitors as the next generation of immune-oncology therapeutics,” said Ting. “This study, showing that NLRX1 is a checkpoint of STING, sheds more light on the topic and will help advance those efforts.”

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Harvard Scientists Report on Novel Method for Extending the Life of Implantable Devices in situ

Blood-contacting implantable medical devices, such as stents, heart valves, ventricular assist devices, and extracorporeal support systems, as well as vascular grafts and access catheters, are used worldwide to improve patients’ lives. However, these devices are prone to failure due to the body’s responses at the blood-material interface; clots can form and inflammatory reactions can prevent the device from performing as indicated. Currently, when this occurs, the only solution is to replace the device.

In a paper published in the April 13 issue of Nature Communications, investigators from Harvard report on a novel biochemical method that enables the rapid and repeated regeneration of selected molecular constituents in situ after device implantation, which has the potential to substantially extend the lifetime of bioactive films without the need for device removal. Their approach could also be used to load and release a number of material-bound constituents for controlled drug loading and delivery.

Newer implantable devices have thin films with bioactive molecules and/or drugs that help prevent clots and inflammation while also enhancing device integration and local tissue repair, as well as inhibiting microbe colonization. For example, the blood-thinner heparin has been coated on the surfaces of cardiovascular devices to prevent clot formation on or within the devices. However, the newer devices have limitations.

“Not only do they have a finite reservoir of bioactive agents, but the surface components of the thin films also degrade or lose their effectiveness when exposed to the physiological environment over time. Presently the only solution is to replace the entire device,” said lead author Elliot Chaikof, MD, PhD, Chair of Surgery at Beth Israel Deaconess Medical Center (BIDMC). Dr. Chaikof is also Professor of Surgery at Harvard Medical School, an associate faculty member of Harvard’s Wyss Institute of Biologically Inspired Engineering, and a faculty member of the Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology.

A number of approaches have been attempted to improve the stability and activity of thin-film constituents of implantable devices. But despite some progress, a surface coating that reliably retains its biological activity over extended, clinically relevant time periods has not been developed.

The new approach relies on an enzyme, Staphylococcus aureus Sortase A, which catalyzes the linking of two peptide sequences. By inducing a series of mutations, David Liu, PhD, Professor of Chemistry and Chemical Biology at Harvard University and a Howard Hughes Medical Institute Investigator, developed a laboratory-evolved enzyme, Staphylococcus aureus Sortase A (eSrtA), which has an enhanced catalytic activity of approximately 120-fold over the non-mutated, wild-type enzyme. eSrtA catalyzes not only linking of peptides but also breaking them apart, which it can do repeatedly.

“We found that through a two-step process of removing and replacing bioactive coatings, eSrtA enables rapid, repeated thin-film regeneration in the presence of whole blood in vitro and in vivo,” said Liu. “We also developed a series of new enzymes that recognize a variety of distinct peptide sequences that could be put to work in a similar manner.”

“But, we know that there are many questions that only further research can answer,” said Chaikof. “For instance, eSrtA is a bacterial enzyme, and while there is a precedent for the clinical use of such enzymes – for example, streptokinase, uricase, and asparaginase – studies must be done to determine how immunogenic this enzyme might be.”

Additionally, it is unknown how often a bioactive coating would need to be regenerated, how long it would last, or whether the bioactive constituents could become inaccessible over time due to biologic processes.

“Many thousands of people depend on implantable devices with bioactive constituents for their health and well-being, so finding a strategy that will ensure the long-term efficacy of these devices is of paramount importance,” said Chaikof. “While this research is relatively early stage, it opens the door to a new way of approaching and addressing this clinical challenge.”

In addition to Chaikof and Liu, co-authors are BIDMC researchers, Hyun Ok Ham, PhD, Carolyn Haller, PhD, Erbin Dai, PhD, Wookhyun Kim, PhD, and Zheng Qu, PhD, also of the Georgia Institute of Technology; and Brent Dorr, PhD, of Harvard University.

This research is supported by a grant to Drs. Chaikof and Liu from the National Institutes of Health.

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New Potent Nanodrug to Combat Antibiotic-Resistant Infections

A research team led by University of Arkansas chemist Jingyi Chen and University of Arkansas for Medical Sciences microbiologist Mark Smeltzer has developed an alternative therapeutic approach to fighting antibiotic-resistant infections.

The novel method uses a targeted, light-activated nanodrug consisting of antibiotic-loaded nanoconstructs, which are nanoscale cages made of gold and coated with polydopamine. The antibiotic is loaded into the polydopamine coating. The gold nanocages convert laser irradiation to heat, resulting in the photothermal effect and simultaneously releasing the antibiotic from the polydopamine coating.

“We believe that this approach could facilitate the effective treatment of infections caused by antibiotic-resistant bacteria, including those associated with bacterial biofilms, which are involved in a wide variety of bacterial infections,” said Chen, assistant professor in the Department of Chemistry and Biochemistry in the J. William Fulbright College of Arts and Sciences.

Microbial resistance to antibiotics has become a growing public health concern in hospitals and the community at large, so much so that the Infectious Diseases Society of America has designated six bacterial species as “ESKAPE pathogens” – Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter species. This designation reflects the limited availability of antibiotics that can be used to treat infections caused by these species.

“It is also estimated that 80 percent of all bacterial infections involve formation of a biofilm, and all of these infections share the common characteristic of intrinsic resistance to conventional antibiotic therapy,” said Smeltzer, professor in the Department of Microbiology and Immunology at UAMS and director of the Center for Microbial Pathogenesis and Host Inflammatory Responses. “Intrinsic resistance refers to the fact that bacteria within a biofilm exhibit a therapeutically relevant level of resistance to essentially all antibiotics.”

Researchers in Smeltzer’s laboratory study the ESKAPE pathogen Staphylococcus aureus. They focus on how the pathogen causes biofilm-associated bone infection and infections associated with orthopaedic implants. But, as Smeltzer explains, there are many other examples in infections – intravenous catheters and vascular grafts, for example – caused by Staphylococcus aureus.

The team used Staphylococcus aureus as the proof-of-principle pathogen to demonstrate the potency of their nanodrug. The combination of achieving a photothermal effect and controlled release of antibiotics directly at the site of infection was achieved by laser irradiation at levels within the current safety standard for use in humans. The therapeutic effects of this approach were validated using planktonic bacterial cultures – bacterial cells that are free-floating rather than contained with a biofilm – of both methicillin-sensitive and methicillin-resistant Staphylococcus aureus strains. However, the method was subsequently shown to be effective even in the context of an intrinsically resistant biofilm.

“The even better news is that the technology we developed would be readily adaptable to other bacterial pathogens that cause such infections, including the other ESKAPE pathogens,” Smeltzer said.

The researchers’ work was recently published in ACS Infectious Diseases, a publication of the American Chemical Society (ACS) and “the first journal to highlight chemistry and its role in the multidisciplinary and collaborative field of infectious disease research.”