Artificial intelligence algorithm to predict and prevent spread of infectious diseases

Team of researchers from USC Viterbi School of Engineering has created an algorithm that can help policymakers reduce the overall spread of disease. The algorithm is optimized to make the most of limited resources, such as advertising budgets, thus helping cash strapped public health agencies.

To create the artificial intellegence algorithm, the researchers used behavioral, demographic and epidemic disease trends data to generate a model of disease spread that captures underlying population dynamics and contact patterns between people. Using computer simulations, the researchers tested the algorithm on tuberculosis (TB) spread in India and gonorrhea in the United States. In both cases, they found the algorithm did a better job at reducing disease cases than current health outreach policies by sharing information about these diseases with individuals who might be most at risk.

The study was published in the AAAI Conference on Artificial Intelligence. The authors are Bryan Wilder, a candidate for a PhD in computer science, Milind Tambe, the Helen N. and Emmett H. Jones Professor in Engineering, a professor of computer science and industrial and systems engineering and co-founder of the USC Center for AI in Society and Sze-chuan Suen, an assistant professor in industrial and systems engineering.

“Our study shows that a sophisticated algorithm can substantially reduce disease spread overall,” says Wilder, the first author of the paper. “We can make a big difference, and even save lives, just by being a little bit smarter about how we use resources and share health information with the public.”

The algorithm also appeared to make more strategic use of resources. The team found it concentrated heavily on particular groups and did not simply allocate more budget to groups with a high prevalence of the disease. This seems to indicate that the algorithm is leveraging non-obvious patterns and taking advantage of sometimes-subtle interactions between variables that humans may not be able to pinpoint. The team’s mathematical models also take into account that people move, age, and die, reflecting more realistic population dynamics than many existing algorithms for disease control.

Adapted from press release by University of South California.

Research suggests possibility of vaccine development against Staphylococcal skin infections

Researchers have discovered how the immune system might protect a person from recurrent bacterial skin infections caused by Staphylococcus aureus (staph). The findings, publishing online this week in The Journal of Clinical Investigation, provides new opportunities to developing vaccines to prevent staph skin infections, which account for 14 million outpatient visits, nearly 500,000 hospital admissions and $3 billion to $4 billion in inpatient health care costs in the U.S. per year. Research team included experts from Johns Hopkins, the University of California, Davis, and the National Institute of Allergy and Infectious Diseases.
Using mice with defective immune systems, research team found that after an initial exposure of the skin to staph, they were surprisingly protected against a second skin exposure with the same bacteria. After testing for antibodies and other “usual suspects” of the immune system against this infection, it was not at all clear what immune response was protecting the mice. The researchers then tested a drug FDA-approved for treatment of multiple sclerosis, which acts by preventing certain immune cells from leaving lymph nodes for sites of inflammation. Researchers then sequenced genes of every cell line in lymph nodes.
That genetic sequencing data revealed that specific cells substantially multiplied after the initial infection, then moved to the infection site and provided protection against the second infection. These so-called gamma delta T cells account for less than 1 percent of all the cells in the lymph node prior to infection. After infection, they accounted for more than 20 percent.
Since this work was performed in mice, the team wanted to see if its findings were applicable to people. Working with collaborators from the National Institute of Allergy and Infectious Diseases at the National Institutes of Health, the researchers tested blood from healthy individuals and people with a rare immune disorder that makes them highly susceptible to staph skin infections.
According to Lloyd Miller, M.D., Ph.D., associate professor of dermatology at the Johns Hopkins University School of Medicine, half of people with the disorder die by age 10, but if they survive to adulthood they somehow overcome their susceptibility to staph infections. In blood samples from these patients, the researchers found an increase in the percentage of gamma delta T cells, similar to what they observed in mice, which remained stable over years.
Miller hopes these new findings and especially gamma delta T cells may be targeted for developing new therapies or even a vaccine against staph skin infections. This, he says, could alleviate the burden of staph skin infections, prevent invasive complications and reduce health care costs.
Citation: Dillen, Carly A., Bret L. Pinsker, Alina I. Marusina, Alexander A. Merleev, Orly N. Farber, Haiyun Liu, Nathan K. Archer, Da B. Lee, Yu Wang, Roger V. Ortines, Steven K. Lee, Mark C. Marchitto, Shuting S. Cai, Alyssa G. Ashbaugh, Larissa S. May, Steven M. Holland, Alexandra F. Freeman, Loren G. Miller, Michael R. Yeaman, Scott I. Simon, Joshua D. Milner, Emanual Maverakis, and Lloyd S. Miller. “Clonally expanded γδ T cells protect against Staphylococcus aureus skin reinfection.” Journal of Clinical Investigation, 2018. doi:10.1172/jci96481.
Funding: MedImmune, Regeneron, Moderna Therapeutics, Pfizer, National Institutes of Health, Burroughs Wellcome Fund.
Adapted from press release by John Hopkins Medicine.

Researchers identify how Ebola virus disables the human immune system

A research study by scientists at the University of Texas Medical Branch in Galveston sheds light on how Ebola effectively disables the human immune system. Virologist Alex Bukreyev, UTMB professor and senior author of the study, said the research team engineered versions of the Ebola virus in order to understand its effects on immune system. The findings are described in journal PLOS Pathogens.

Previous research shown how Ebola virus inhibits Interferon mediated immune defense system. Interferons are specialized signaling proteins that are made and released in response to an invasion by a virus or other pathogen, which directly inhibit replication of viral particles in cells. These actions were mediated by two protein regions within the Ebola virus’ structure called interferon inhibiting domains, or IIDs, that prevent the host’s interferons from doing their job thus disabling the host’s immune system defenses.

A focus of current research has been how Ebola gets around the host’s cell-mediated immune response, which is another defense mechanism involving some specialized immune cells that either kill virus-infected cells or secrete antibodies that directly neutralize the virus. Researchers assessed role played by interferon inhibiting domains (IID’s) on cell mediated immunity.

The study used genetically altered strains of the Ebola virus that were designed with one or both of the interferon inhibiting domains disabled to study what they do to the host. The altered viruses were placed on specific types of immune cells isolated from human blood, called dendritic cells, T lymphocytes, B lymphocytes and natural killer cells, as these types of cells are key players in marshaling defenses.

“We found that interferon inhibiting domains work not only in ways previously established, which includes interference in cascades of protective biochemical reactions that occur in cells in response to Ebola that limit infection”, Bukreyev said. “The IID’s also counter the activity of immune cells, including T lymphocytes and natural killer cells that kill virus-infected cells as well as B lymphocytes that secrete antibodies.” “It’s a double edged sword – the IIDs not only block interferon signaling, they also prevent infected cells from activating the cell-mediated arm of the immune response,” said Patrick Younan, research scientist and co-lead author of the paper.

Citation: Lubaki, Ndongala Michel, Patrick Younan, Rodrigo I. Santos, Michelle Meyer, Mathieu Iampietro, Richard A. Koup, and Alexander Bukreyev. “The Ebola Interferon Inhibiting Domains Attenuate and Dysregulate Cell-Mediated Immune Responses.” PLOS Pathogens 12, no. 12 (2016).
doi:10.1371/journal.ppat.1006031.
Adapted from press release by the University of Texas Medical Branch at Galveston.

Gene therapy using lipid based nanoparticles

Lipid nanoparticles (SLNs and NLCs) are regarded as highly promising systems for delivering nucleic acids in gene therapy. Literature review by researchers at PharmaNanoGene describes these systems and their main advantages in gene therapy, such as their capacity to protect the gene material against degradation, to facilitate cell and nucleus internalization and to boost the transfection process.


View of lipid nanoparticles.
View of lipid nanoparticles. Credit: UPV/EHU

“At PharmaNanoGene we are working on the design and evaluation of SLNs for treating some of these diseases using gene therapy. We are studying the relationship between formulation factors and the processes involving the intracellular internalisation and disposition of the genetic material that condition the effectiveness of the vectors and which is essential in the optimisation process, and for the first time we have demonstrated the capacity of SLNs to induce the synthesis of a protein following their intravenous administration in mice,” they stressed.

The publication also includes other pieces of work by this University of the Basque Country research group on the application of SLNs in the treatment of rare diseases, such as chromosome-X-linked juvenile retinoschisis, a disorder in which the retina becomes destructured due to a deficiency in the protein retinoschisin.

 “One of the main achievements of our studies in this field has been to demonstrate, also for the first time, the capacity of a non-viral vector to transfect the retina of animals lacking the gene that encodes this protein and partially restore its structure, showing than non-viral gene therapy is a viable, promising therapeutic tool for treating degenerative disorders of the retina,” specified the researchers.
The application of SLNs for treating Fabry disease, a serious, multi-system metabolic disorder of a hereditary nature, has also been studied at PharmaNanoGene.

 “This is a monogenic disease linked to the X-chromosome which is caused by various gene mutations in the gene that encodes the galactosidase A enzyme. In cell models of this disease we have demonstrated the capacity of SLNs to induce the synthesis of galactosidase A enzyme”. They have also reviewed the application of lipid nanoparticles to the treatment of infectious diseases: “Our work in this field shows that SLNs with RNA interference are capable of inhibiting a replicon of the hepatitis C virus in vitro, which was used as proof-of-concept of the use of SLN-based vectors as a new therapeutic strategy for treating this infection and others related to it”.

Citation: Ana del Pozo-Rodríguez, María Ángeles Solinís, Alicia Rodríguez-Gascón, Applications of lipid nanoparticles in gene therapy, European Journal of Pharmaceutics and Biopharmaceutics, Volume 109, December 2016, Pages 184-193.
DOI: 10.1016/j.ejpb.2016.10.016.
Adapted from press release by University of the Basque Country.

Research shows reduced Surgical Site Infections with use of Antimicrobial Sutures

New analyses of the published clinical studies indicate that antimicrobial sutures are effective for preventing surgical site infections (SSIs), and they can result in significant cost savings. The results are published in the British Journal of Surgery.

In one analysis that included 21 randomized clinical trials, investigators found a risk of 138 surgical site infections per 1000 procedures, and the use of sutures coated with the antimicrobial triclosan reduced this by 39. Investigators noted that sufficient evidence exists for a 15 percent relative risk reduction in SSIs when triclosan-coated sutures are used.

In an economic analysis of results from 34 studies, triclosan sutures were linked with an average cost savings per surgical procedure of  91.25 pounds across all wound classes when compared with non-antimicrobial-coated sutures.

“Antimicrobial sutures ought to be included into SSI care bundles and provide a further significant saving to National Health Service (England) surgical practice,” said Prof. David Leaper, lead author of the economic analysis.

Citations:

S. W. de Jonge, J. J. Atema, J. S. Solomkin and M. A. Boermeester. Meta-analysis and trial sequential analysis of triclosan-coated sutures for the prevention of surgical-site infection. British Journal of Surgery.
DOI: 10.1002/bjs.10445

D. J. Leaper, C. E. Edmiston Jr and C. E. Holy. Meta-analysis of the potential economic impact following introduction of absorbable antimicrobial sutures. British Journal of Surgery.
DOI: 10.1002/bjs.10443

Adapted from press release by Wiley publications.

Proton pump inhibitors linked with increased risk of infectious gastroenteritis

Research has found a link between proton pump inhibitors and an increase in the risk of infectious gastroenteritis. The study led by The Australian National University (ANU) and based on data from the Sax Institute’s 45 and Up Study, found people who take proton pump inhibitors (PPIs), had a 70 per cent increase in the risk of being admitted to hospital with infectious gastroenteritis.

Lead author Dr Yingxi Chen from the ANU National Centre for Epidemiology and Population Health said the research examined data from the study to look at cases of infectious gastroenteritis in Australians older than 45.

We found that taking PPIs increased the risk of hospitalization with infectious gastroenteritis by up to 70 per cent because they significantly reduce the amount of acid made by stomach, which increases risk of infectious gastroenteritis” Dr Chen said.

The research builds on a report by the ANU National Centre for Epidemiology and Population Health which found 15.1 million gastroenteritis cases in Australia in 2010.

“There is no doubt that PPIs are an effective treatment for reflux and heartburn. However, clinicians and the patients using them should be fully aware of the side effects when considering PPI use and dosage,” Dr Chen said.

“The elderly and those with chronic bowel problems are most at risk. These patients should be having a conversation with their doctor to ensure that they are on right dose and that these drugs are the right fit for them.”

Dr Martin McNamara, Head of Research Assets at the Sax Institute said these findings demonstrated the value of the 45 and Up Study as a national research resource.

“The 45 and Up Study is the largest ongoing study of healthy ageing in the Southern Hemisphere, allowing hundreds of Australia’s world class researchers to investigate big and complex issues and deliver answers in ways that are easily accessible to policy makers,” he said.

Citation: Yingxi Chen, Bette Liu, Kathryn Glass, Wei Du, Emily Banks & Martyn Kirk. ” Use of Proton Pump Inhibitors and the Risk of Hospitalization for Infectious Gastroenteritis.” PLoS ONE 11(12): e0168618.
DOI: 10.1371/journal.pone.0168618
Adapted from press release by Sax Institute.

Research unveils structure of crucial bacterial cell wall protein

Duke University researchers have provided the first close-up glimpse of a protein, called MurJ, which is crucial for building the bacterial cell wall and protecting it from outside attack. The research is published in Nature Structural and Molecular Biology.

Researchers at Duke University solved the structure of an enzyme that is crucial for helping bacteria build their cell walls. The molecule, called MurJ (shown in green), must flip cell wall precursors (purple) across the bacteria’s cell membrane before these molecules can be linked together to form the cell wall. This new structure could be important to help develop new broad-spectrum antibiotics. Credit: Alvin Kuk, Duke University

“Until now, MurJ’s mechanisms have been somewhat of a ‘black box’ in the bacterial cell wall synthesis because of technical difficulties studying the protein,” said senior author Seok-Yong Lee, Ph.D., associate professor of biochemistry at Duke University School of Medicine. “Our study could provide insight into the development of broad spectrum antibiotics, because nearly every type of bacteria needs this protein’s action.”

A bacterium’s cell wall is composed of a rigid mesh-like material called peptidoglycan. Molecules to make peptidoglycan are manufactured inside the cell and then need to be transported across the cell membrane to build the outer wall.

In 2014, another group of scientists had discovered that MurJ is the transporter protein located in the cell membrane that is responsible for flipping these wall building blocks across the membrane. Without MurJ, peptidoglycan precursors build up inside the cell and the bacterium falls apart. Many groups have attempted to solve MurJ’s structure without success, partly because membrane proteins are notoriously difficult to work with.

In this study, Lee’s team was able to crystallize MurJ and determine its molecular structure to 2-angstrom resolution by an established method called X-ray crystallography, which is difficult to achieve in a membrane protein. The structure, combined with follow-up experiments in which the scientists mutated specific residues of MurJ, allowed them to propose a model for how it flips peptidoglycan precursors across the membrane.

After determining the first structure of MurJ, Lee’s team is now working to capture MurJ in action, possibly by crystallizing the protein while it is bound to a peptidoglycan precursor. “Getting the structure of MurJ linked to its substrate will be key. It will really help us understand how this transporter works and how to develop an inhibitor targeting this transporter,” Lee said.

Lee’s group is continuing structure and function studies of other key players in bacterial cell wall biosynthesis as well. Last year, they published the structure of another important enzyme, MraY, bound to the antibacterial muraymycin.

Citation: Kuk, Alvin CY, Ellene H. Mashalidis, and Seok-Yong Lee. “Crystal structure of the MOP flippase MurJ in an inward-facing conformation.” Nature Structural & Molecular Biology (2016).
DOI: 10.1038/nsmb.3346
Research funding: Duke University
Adapted from press release by the Duke University.

Zika virus research: Structure of immature virus revealed

Researchers at Purdue University have determined the high-resolution structure of immature Zika virus, a step toward better understanding how the virus infects host cells and spreads.

Purdue researchers have determined the high-resolution structure of the immature Zika virus. This composite image of the surface (left), and cross-sectional region (right), reflect the new findings. Research into a virus’s structure provides insights important to the development of effective antiviral treatments and vaccines.
Credit: Purdue University image courtesy of Kuhn and Rossmann research groups.

Zika belongs to a family of viruses called flaviviruses, which includes dengue, West Nile, yellow fever, Japanese encephalitis and tick-borne encephalitic viruses. Although only the mature forms of flaviviruses are considered infectious, the virus population secreted from host cells is a mixture of mature, partially mature and immature virus particles. “It is, therefore, probable that the immature form of Zika also plays a role in virus infection and spread,” said Michael Rossmann, Purdue’s Hanley Distinguished Professor of Biological Sciences.

The research team was led by Rossmann, with Richard Kuhn, both professors in Purdue’s Department of Biological Sciences, as well as postdoctoral research associate Vidya Mangala Prasad. Findings are detailed in a research paper published in the journal Nature Structural & Molecular Biology .

The researchers used a technique called cryo-electron microscopy to reconstruct the immature virus’s structure at 9 Ångstroms resolution, or about a thousand times better resolution than would be possible with a conventional light microscope.

The genome of the virus is housed inside a protective envelope that includes a lipid membrane, an envelope protein, a precursor membrane protein and a capsid protein. The Purdue researchers are the first to learn the position of the capsid protein in the immature virus, which plays the critical role of recognizing the virus’s genetic material and acts as a chaperone to guide these RNA strands into the virus for assembly. The envelope protein is essential for the virus’s binding, attachment and fusion to host cells during the infection process. The membrane protein cleaves from the mature virus as it is released from the host to infect other cells.

A map of the immature virus’s structure revealed details about the proteins, showing that the envelope and precursor membrane proteins are arranged in 60 spike-like features on the virus’s surface, whereas the capsid protein is located on the internal side of the lipid membrane. The structure differs from the mature Zika virus in that the membrane protein in the mature virus is covered by the envelope protein. Both proteins exist on the surface of the immature version of the virus. Findings also show differences between the immature Zika virus and immature versions of other flaviviruses. Notably, it contains a “partially ordered capsid protein shell” that is less prominent in other immature flaviviruses.

“I think these findings open the door to begin to explore the assembly process of the virus,” said Kuhn, director of the Purdue Institute of Inflammation, Immunology and Infectious Disease (PI4D). And researchers feel that the structure of the virus is likely to play a major role in the disease, transmission, and pathology.

Citation: Prasad, Vidya Mangala,  Andrew S Miller, Thomas Klose, Devika Sirohi, Geeta Buda, Wen Jiang, Richard J Kuhn & Michael G Rossmann. “Structure of the immature Zika virus at 9 Å resolution.” Nature Structural & Molecular Biology 2017.
DOI: 10.1038/nsmb.3352
Research funding: NIH
Adapted from press release by Purdue University.

New approach to tuberculosis treatment: targeting LD-transpeptidase enzyme

Researchers at Johns Hopkins report they have laid the foundation to develop novel antibiotics that work against incurable, antibiotic-resistant bacteria like tuberculosis by targeting an enzyme essential to the production and integrity of bacterial cell walls. The findings, they say, suggest that antibiotic drugs specifically targeting the recently discovered LD-transpeptidase enzyme, which is needed to build bacterial cell walls in some bacteria, could potentially cure many antibiotic-resistant infections.

An additional implication of the research, the Johns Hopkins team says, is that drugs targeting the enzyme could offer quicker, cheaper and more easily accessible treatment against tuberculosis, a disease that still kills more people worldwide than any other infection, according to the Centers for Disease Control and Prevention. A summary of the findings is published on Nov. 7 in Nature Chemical Biology.

At the root of their investigation, Gyanu Lamichhane, Ph.D. associate professor of medicine at the Johns Hopkins University School of Medicine says, is the fact than more than half of antibiotics prescribed today are of a class called beta-lactams, which work by interrupting the function of the DD-transpeptidase enzyme that creates bacterial cell walls. Without it, bacteria quickly die. However, in 2005, a team of researchers found a second wall-building enzyme, LD-transpeptidase, that allows bacteria like the ones that cause TB to survive antibiotic treatments.

Pankaj Kumar, Ph.D., postdoctoral fellow in infectious diseases at the Johns Hopkins University School of Medicine, began the research in the new study by extracting LD-transpeptidase from many species of bacteria and examining its detailed molecular structure with a sophisticated imaging system known as protein X-ray crystallography using the Advanced Photon Source at the Argonne National Laboratory in Chicago.

By analyzing the enzyme’s structure, Johns Hopkins researchers were able to design new compounds in the carbapenem group, a subclass of the beta-lactam antibiotics that bind to the LD-transpeptidase wall-building enzyme and stop its function.

In live bacterial cultures, the carbapenems were shown by Lamichhane’s and Townsend’s groups to stop the enzyme’s wall-building activity. The new compounds were even effective against the ESKAPE pathogens, a group of six bacterial species that the Centers for Disease Control and Prevention has identified as a threat because of their propensity for developing antibiotic resistance.
Following these successes, Amit Kaushik, Ph.D., a postdoctoral fellow in infectious diseases at the Johns Hopkins University School of Medicine, tested two carbapenems in vivo against TB in mice infected with TB.

Researchers infected mice with tuberculosis bacteria and separated them into different treatment groups. The rodents’ lungs were sampled periodically over a period of three weeks, and the results showed that even without use of classic TB antibiotic treatments, the new carbapenems, specifically biapenem, cured TB infection in mice.

Townsend and Lamichhane say the focus of their research is now on creating variations of their original compound that are designed to target specific bacteria. The researchers are now in the process of initiating clinical trials to test the safety and efficacy of some of these new compounds.

Citation: Pankaj Kumar, Amit Kaushik, Evan P Lloyd, Shao-Gang Li, Rohini Mattoo, Nicole C Ammerman, Drew T Bell, Alexander L Perryman, Trevor A Zandi, Sean Ekins, Stephan L Ginell, Craig A Townsend, Joel S Freundlich & Gyanu Lamichhane. “Non-classical transpeptidases yield insight into new antibacterials”. Nature Chemical Biology (2016)
DOI: http://dx.doi.org/10.1038/nchembio.2237
Research funding: National Institutes of Health, DOE/Office of Biological and Environmental Research
Adapted from press release by Johns Hopkins University School of Medicine.

Polysorbate, a food additive found to be protective against E. coli poisoning

Polysorbate, a safe additive found in everything from ice cream to cosmetics, has been proven to slow the toxic effects of E. coli poisoning. The findings, featured in the current issue of the journal Biofouling, show that polysorbates attack the protective biofilm in which E. coli lives and renders the deadly bacteria harmless, said Chris Waters, Michigan State University associate professor of microbiology and molecular genetics whose laboratory led the research.

Specifically, the team focused on the potent strain isolated from Germany that swept through Europe in 2011, causing thousands of infections and more than 50 deaths. This strain had been previously studied by Waters and Shannon Manning. Having samples of the bacteria at MSU helped the team, led by Rudolph Sloup, MSU microbiology and molecular genetics graduate student, isolate compounds that inhibited biofilms.

“During our animal infection studies, polysorbate 80 had no effect on the numbers of infecting E. coli. This was a little shocking, especially based on how promising our earlier tests had been,” Waters said. “Later, though, our pathology tests showed that polysorbate 80 essentially blocked all toxicity, even though it didn’t reduce the number of bacteria.”

The later confirmation of the successful in vivo experiment using mice models essentially showed that polysorbate 80 strips E. coli of its ability to cause disease allowing the bacteria to pass through the body’s intestinal tract without causing damage. So instead of killing the E. coli like traditional antibiotics, a strategy that works until the E. coli develops resistance to the treatment, this finding suggests an anti-virulence strategy can be quite effective.

Since polysorbate 80 is categorized as a GRAS (generally regarded as safe) compound, it doesn’t require FDA approval to be used as a treatment. Along with its potential for disarming the deadly German E. coli outbreak, polysorbate 80 could potentially help tackle more-common E. coli infections such as traveler’s diarrhea.

The next steps for this research will be to identify how polysorbate 80 inhibits biofilm formation and test its activity in other infection models.

Citation: Sloup, Rudolph E., Roberto J. Cieza, David B. Needle, Robert B. Abramovitch, Alfredo G. Torres, and Christopher M. Waters. “Polysorbates prevent biofilm formation and pathogenesis of Escherichia coli O104: H4.” Biofouling 32, no. 9 (2016): 1131-1140.
DOI: http://dx.doi.org/10.1080/08927014.2016.1230849
Research funding: National Institutes of Health
Adapted from press release by Michigan State University