Posts Tagged ‘infection’

Humanity tested
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The world needs mass at-home serological testing for antibodies elicited by SARS-CoV-2, and rapid and frequent point-of-care testing for the presence of the virus’ RNA in selected populations.

How did we end up here? Two ways. Gradually, then suddenly. Ernest Hemingway’s passage is a fitting description for humanity’s perception of the exponential growth of COVID-19 cases and deaths (Fig. 1). The worldwide spread of a highly infectious pathogen was only a matter of time, as long warned by many epidemiologists, public health experts, and influential and prominent voices, such as Bill Gates. Yet most of the world was unprepared for such a pandemic; in fact, most Western countries (prominently the United States1) fumbled their response for weeks. Singapore, Hong Kong and Taiwan have shown the world that, to contain the propagation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), governments need to quickly implement aggressive testing (by detecting the viral RNA through polymerase chain reaction (PCR)), the isolation of those infected and the tracing and quarantining of their contacts, while educating their citizens about the need for physical distancing and basic public health measures (in particular, frequent hand-washing and staying at home if feeling unwell). When outbreaks are not detected and acted upon sufficiently early, drastic physical distancing — of the sort implemented by China at the end of January and maintained for months — can eventually suppress the outbreak (Fig. 1). It is however unclear whether Western countries that have implemented strict physical-distancing measures later in their infection curve will be able to gradually release such lockdowns, let alone see their outbreaks controlled.

Fig. 1: Early mass testing and early containment measures save lives.
figure1
COVID-19 confirmed cases and deaths for selected countries in a 10-day window ending at each data point (successive data points on a line denote consecutive days). Numbers in colour are the estimated number of total PCR tests per million people up to the data point indicated; stars indicate when strict lockdowns were enacted. Deaths lag with respect to confirmed cases, according to the estimated two-to-three week interval10 between the onset of symptoms and death. Case fatality rates — that is, the fractions of total confirmed cases that become deaths — mostly depend on the extent of testing, on the capacity of a country’s healthcare system, on its demographics and on the availability of drugs that can significantly dampen the severity of COVID-19 in those infected. Even with mass testing, the case fatality rate of COVID-19 is expected to be a multiple of that for seasonal flu in the United States (0.1%). Countries that deployed tests for detecting SARS-CoV-2 RNA early and widely (such as South Korea), that applied contact tracing and targeted physical distancing measures for detected cases (such as South Korea and Japan), or that enacted early, strict lockdowns (such as China) are more likely to contain the disease outbreak earlier. In fact, Singapore, Hong Kong and Taiwan have contained COVID-19 outbreaks and have managed to limit COVID-19-related deaths to less than 10 (hence, these countries are not included in the figure). Data updated 6 April 2020. Individual data points can be affected by reporting errors and delays, by wilful underreporting and by location-specific definitions (and changes to them) for confirmed cases and deaths. Data sources: European Center for Disease Control and Prevention11 (cases and deaths); Our World in Data12, various government sources (tests). A regularly updated version of this graph is available13.

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Such non-pharmacological interventions aim to ‘flatten’ the infection curve by reducing the number of transmission chains and thus the virus’ basic reproduction number — that is, the average number of new cases generated by a case in an immunologically naive population. In the absence of a safe and effective vaccine — which, if current efforts end up being successful, is unlikely to become widely available within the next two years — non-pharmacological interventions will need to remain in place to reduce the threat of secondary outbreaks by maintaining the basic reproduction number below 1. However, the type and degree of the interventions could be better tailored if governments knew who are currently infected and who have been infected and recovered. For this, the world needs to see the mass deployment of serological testing for SARS-CoV-2 antibodies (which appear to be highly specific2), and frequent testing for SARS-CoV-2 RNA in those likely to be exposed to the virus (especially healthcare workers) or at a higher risk for severe respiratory disease (such as the elderly and younger individuals with relevant comorbidities).

Medical-device companies and government and research laboratories around the world have rushed to adapt and scale up nucleic acid tests (mostly employing PCR, but also CRISPR-based detection and loop-mediated isothermal amplification) to detect the virus’ RNA, and government agencies are scrambling to assess them via emergency routes (such as the Emergency Use Authorization program3 by the United States Food and Drug Administration (FDA)). Point-of-care PCR kits — based on lateral-flow technology or cartridge-based instruments for sample preparation, nucleic acid amplification and detection — also require RNA extraction from nasal or throat swabs (or both) but can speed up the time-to-result from a few hours to roughly 30 minutes4 (and in one test, positive results can be obtained in five minutes5), with near-perfect sensitivity and specificity if sample acquisition and preparation and device operation are carried out appropriately by trained personnel. This limits the usefulness of these kits for at-home use, which would significantly raise the fraction of false negatives. Immunoassays incorporating monoclonal antibodies specific for SARS-CoV-2 antigens (for instance, a domain of the virus’ spike protein) should be amenable to home use, yet they are more difficult to develop (the antibodies are typically obtained via the immunization of transgenic animals) and are less accurate than nucleic acid testing.

Lateral flow immunoassays (akin to the pregnancy test) and enzyme-linked immunosorbent assays to detect antibodies elicited by the virus are also being rapidly developed (mostly by Chinese companies thus far). Tens of at-home lateral-flow devices6 are already being commercialized, having obtained the European Union’s CE mark or been authorized for emergency use by the FDA or the Chinese FDA. In many of these kits, the recombinant viral antigens bind to SARS-CoV-2-specific immunoglobulin M (IgM) and immunoglobulin G (IgG) within 15 min; hence, these tests can also detect early-stage infection (of which IgM levels are a marker), but at the expense of sensitivity and accuracy (which can exceed 90% and 99% for IgG7. The real-world performance of such serology tests, which is currently unknown, will depend on the actual prevalence of COVID-19 in the population. For example, at a 5% pre-test probability of having the disease, a test with 99% sensitivity and 95% specificity would lead to as many true positives as false positives. Hence, before wide deployment, governments need to ensure that these finger-prick antibody tests are clinically validated8.

The world should roll out both antibody and nucleic acid tests on a wide scale. Widely available and inexpensive serological testing would help governments to tailor non-pharmacological interventions to specific locations and populations, to decide when to relax them and to permit citizens immune to the virus to help those who remain susceptible to it. Mass testing would also provide valuable data to pressing unknowns: what are the infection rates across locations and populations? What fraction of the population is immune? How long does immunity last and how does it depend on age and on the severity of infection? Wider deployment of nucleic acid tests would also provide clues about the prevalence of a wider range of COVID-19 symptoms, the role of children in spreading the disease, and the epidemiological characteristics of superspreaders9 and of those who were infected and asymptomatic. Testing should be complemented by privacy-minded digital surveillance, via phone apps, aiding contact tracing and permitting lighter levels of physical distancing — as done in Singapore, South Korea and Taiwan. The downside is that any invasion of privacy via the tracking of people can last longer than necessary. De-identified and aggregated health data, such as heart rate and activity levels collected via commercial wearables, might also predict (https://detectstudy.org) the emergence and location of outbreaks.

In our globalized world, the risk of further waves of COVID-19 outbreaks, and thus of prolonged drastic economic consequences, will remain substantial as long as any outbreak anywhere remains. It is in the world’s best interest that richer countries provide test kits, technical and public-health knowledge, personnel, personal protective equipment and, eventually, the necessary vaccine doses to poorer countries to assist them in their efforts to reduce and contain the spread of SARS-CoV-2. This is humanity’s next test.

References
1.
Shear, M. D. et al. The lost month: how a failure to test blinded the U.S. to Covid-19. The New York Times https://www.nytimes.com/2020/03/28/us/testing-coronavirus-pandemic.html (2020).

2.
Ju, B. et al. Preprint at https://doi.org/10.1101/2020.03.21.990770 (2020).

3.
Emergency Use Authorization (U.S. Food & Drug Administration, 2020); https://www.fda.gov/medical-devices/emergency-situations-medical-devices/emergency-use-authorizations

4.
Accula test: SARS-CoV-2 test. U.S. Food & Drug Administration https://www.fda.gov/media/136355/download (2020).

5.
Abbott realtime SARS-CoV-2 assay. Abbott https://www.molecular.abbott/us/en/products/infectious-disease/RealTime-SARS-CoV-2-Assay (2020).

6.
SARS-CoV-2 Diagnostic Pipeline (Find, 2020); https://www.finddx.org/covid-19/pipeline/

7.
COVID-19 Coronavirus rapid test casette. SureScreen Diagnostics https://www.surescreen.com/products/covid-19-coronavirusrapid-test-cassette (2020).

8.
The Associated Press. Virus test results in minutes? Scientists question accuracy. The New York Times https://www.nytimes.com/aponline/2020/03/27/world/europe/bc-virus-outbreakscramble-for-tests.html (2020).

9.
Hu, K. et al. Preprint at https://doi.org/10.1101/2020.03.19.20026245 (2020).

10.
Verity, R. et al. Lancet Infect. Dis. https://doi.org/10.1016/S1473-3099(20)30243-7 (2020).

11.
Today’s Data on the Geographic Distribution of COVID-19 Cases Worldwide (European Centre for Disease Prevention and Control, 2020); https://www.ecdc.europa.eu/en/publications-data/download-todays-data-geographic-distribution-covid-19-cases-worldwide

12.
Roser, M., Ritchie, H. & Ortiz-Ospina, E. Coronavirus Disease (COVID-19) – Statistics and Research (Our World in Data, 2020); https://ourworldindata.org/coronavirus

13.
Pàmies, P. Tracking COVID-19 cases and deaths. Nature Research Bioengineering Community https://bioengineeringcommunity.nature.com/users/20986-pep-pamies/posts/64985-tracking-covid-19-cases-and-deaths (2020).

https://www.nature.com/articles/s41551-020-0553-6?utm_source=Nature+Briefing&utm_campaign=5907ab71f9-briefing-dy-20200408&utm_medium=email&utm_term=0_c9dfd39373-5907ab71f9-44039353

By Michael Le Page

Eating too much salt may impair the body’s ability to fight bacterial infections, according to studies in mice and in 10 human volunteers.

Christian Kurts at the University Hospital of Bonn in Germany and his team first showed that mice given a high salt diet were less able to fight kidney infections caused by E. coli and body-wide infections caused by Listeria monocytogenes, a common cause of food poisoning.

“The bacteria caused more damage before the immune system got rid them,” says Kurts.

Next, the team gave 10 healthy women and men who were 20 to 50 years old an extra 6 grams of salt a day on top of their normal diet, in the form of three tablets a day. After a week, some of their immune cells, called neutrophils, had a greatly impaired ability to engulf and kill bacteria compared with the same tests done on each individual before they took extra salt.

The team didn’t examine the effect of high salt intake on the body’s ability to fight viral infections.

The World Health Organization recommends that people eat no more than 5 grams of salt a day to avoid high blood pressure, which can cause strokes and heart disease. In the UK, people eat 8 grams on average, suggesting many consume as much or more than the volunteers in the study.

The team thinks two mechanisms are involved. First, when we eat lots of salt, hormones are released to make the body excrete more salt. These include glucocorticoids that have the side effect of suppressing the immune system throughout the body.

Second, there is a local effect in the kidney. Kurts found that urea accumulates in the kidney when salt levels are high, and that urea suppresses neutrophils.

Journal reference: Science Translational Medicine, DOI: 10.1126/scitranslmed.aay3850

https://www.newscientist.com/article/2238629-eating-too-much-salt-seems-to-impair-bodys-ability-to-fight-bacteria/?utm_source=NSDAY&utm_campaign=8ea0a51a66-EMAIL_CAMPAIGN_2020_03_25_04_56&utm_medium=email&utm_term=0_1254aaab7a-8ea0a51a66-374123611

by Debora MacKenzie

We may finally have found a long-elusive cause of Alzheimer’s disease: Porphyromonas gingivalis, the key bacteria in chronic gum disease. That’s bad, as gum disease affects around a third of all people. But the good news is that a drug that blocks the main toxins of P. gingivalis is entering major clinical trials this year, and research published this week shows it might stop and even reverse Alzheimer’s. There could even be a vaccine.

Alzheimer’s is one of the biggest mysteries in medicine. As populations have aged, dementia has skyrocketed to become the fifth biggest cause of death worldwide. Alzheimer’s constitutes some 70 per cent of these cases and yet, we don’t know what causes it. The disease often involves the accumulation of proteins called amyloid and tau in the brain, and the leading hypothesis has been that the disease arises from defective control of these two proteins. But research in recent years has revealed that people can have amyloid plaques without having dementia. So many efforts to treat Alzheimer’s by moderating these proteins have failed, and the hypothesis has now been seriously questioned.

Indeed, evidence has been growing that the function of amyloid proteins may be as a defence against bacteria, leading to a spate of recent studies looking at bacteria in Alzheimer’s, particularly those that cause gum disease, which is known to be a major risk factor for the condition.

Bacteria involved in gum disease and other illnesses have been found after death in the brains of people who had Alzheimer’s, but until now, it hasn’t been clear whether these bacteria caused the disease or simply got in via brain damage caused by the condition.

Gum disease link

Multiple research teams have been investigating P. gingivalis, and have so far found that it invades and inflames brain regions affected by Alzheimer’s; that gum infections can worsen symptoms in mice genetically engineered to have Alzheimer’s; and that it can cause Alzheimer’s-like brain inflammation, neural damage, and amyloid plaques in healthy mice.

“When science converges from multiple independent laboratories like this, it is very compelling,” says Casey Lynch of Cortexyme, a pharmaceutical firm in San Francisco, California.

In the new study, Cortexyme have now reported finding the toxic enzymes – called gingipains – that P. gingivalis uses to feed on human tissue in 96 per cent of the 54 Alzheimer’s brain samples they looked at, and found the bacteria themselves in all three Alzheimer’s brains whose DNA they examined.

“This is the first report showing P. gingivalis DNA in human brains, and the associated gingipains, co-lococalising with plaques,” says Sim Singhrao, of the University of Central Lancashire, UK. Her team previously found that P. gingivalis actively invades the brains of mice with gum infections. She adds that the new study is also the first to show that gingipains slice up tau protein in ways that could allow it to kill neurons, causing dementia.

The bacteria and its enzymes were found at higher levels in those who had experienced worse cognitive decline, and had more amyloid and tau accumulations. The team also found the bacteria in the spinal fluid of living people with Alzheimer’s, suggesting that this technique may provide a long-sought after method of diagnosing the disease.

When the team gave P. gingivalis gum disease to mice, it led to brain infection, amyloid production, tangles of tau protein, and neural damage in the regions and nerves normally affected by Alzheimer’s.

Cortexyme had previously developed molecules that block gingipains. Giving some of these to mice reduced their infections, halted amyloid production, lowered brain inflammation and even rescued damaged neurons.

The team found that an antibiotic that killed P. gingivalis did this too, but less effectively, and the bacteria rapidly developed resistance. They did not resist the gingipain blockers. “This provides hope of treating or preventing Alzheimer’s disease one day,” says Singhrao.

New treatment hope

Some brain samples from people without Alzheimer’s also had P. gingivalis and protein accumulations, but at lower levels. We already know that amyloid and tau can accumulate in the brain for 10 to 20 years before Alzheimer’s symptoms begin. This, say the researchers, shows P. gingivalis could be a cause of Alzheimer’s, but it is not a result.

Gum disease is far more common than Alzheimer’s. But “Alzheimer’s strikes people who accumulate gingipains and damage in the brain fast enough to develop symptoms during their lifetimes,” says Lynch. “We believe this is a universal hypothesis of pathogenesis.”

Cortexyme reported in October that the best of their gingipain blockers had passed initial safety tests in people, and entered the brain. It also seemed to improve participants with Alzheimer’s. Later this year the firm will launch a larger trial of the drug, looking for P. gingivalis in spinal fluid, and cognitive improvements, before and after.

They also plan to test it against gum disease itself. Efforts to fight that have led a team in Melbourne to develop a vaccine for P. gingivalis that started tests in 2018. A vaccine for gum disease would be welcome – but if it also stops Alzheimer’s the impact could be enormous.

Journal reference: Science Advances

https://www.newscientist.com/article/2191814-we-may-finally-know-what-causes-alzheimers-and-how-to-stop-it/


Case Western Reserve researchers cure drug-resistant infections without antibiotics

Biochemists, microbiologists, drug discovery experts and infectious disease doctors have teamed up in a new study that shows antibiotics are not always necessary to cure sepsis in mice. Instead of killing causative bacteria with antibiotics, researchers treated infected mice with molecules that block toxin formation in bacteria. Every treated mouse survived. The breakthrough study, published in Scientific Reports, suggests infections in humans might be cured the same way.

The molecules cling to a toxin-making protein found across Gram-positive bacterial species, called AgrA, rendering it ineffective. Treating mice with the therapeutic molecules effectively cured infections caused by methicillin-resistant Staphylococcus aureus (MRSA). S. aureus is notorious for its ability to overcome even the most potent antibiotics. Its resistance arsenal is broad, limiting therapeutic options to treat infections.

In a mouse model of S. aureus sepsis, treatment with small molecules alone resulted in 100 percent survival, while 70 percent of untreated animals died. The small molecules were as effective in promoting survival as antibiotics currently used to treat S. aureus infections. The molecules also appear to give antibiotics a boost. Septic mice treated with a combination of the small molecules and antibiotics had 10x fewer bacteria in their bloodstream than mice treated with antibiotic alone.

“For relatively healthy patients, such as athletes suffering from a MRSA infection, these molecules may be enough to clear an infection,” said Menachem Shoham, associate professor of biochemistry at Case Western Reserve University School of Medicine and senior author on the study. “For immunocompromised patients, combination therapy with the molecules and a low-dose antibiotic may be in order. The antibiotic in the combination could be one to which the bacteria are resistant in monotherapy, because our small molecules enhance the activity of conventional antibiotics, such as penicillin.”

With support from the small molecules, previously obsolete antibiotics could reenter the clinic.

Said Shoham: “This could provide a partial solution to the looming, global threat of antibiotic resistance.”

If available, antibiotics kill most bacteria, but a small number of bacteria with natural resistance survive. Over time, antibiotic-resistant bacteria multiply and spread. By Centers for Disease Control and Prevention estimates, at least two million Americans get an antibiotic-resistant infection annually. For some infections, effective antibiotics are no longer available. Disarming bacteria of disease-causing toxins represents a promising alternative to dwindling antibiotics.

Eliminating toxins frees up the immune system to eliminate bacterial pathogens instead of antibiotics, said Shoham, who also is affiliated with Q2 Pharma, Ltd., Haifa, Israel. “Without the toxins the bacteria become harmless. And since they don’t need the toxins to survive, there is less pressure to develop resistance.”

The small molecules work against multiple bacterial species. The new study included preliminary experiments showing the molecules prevent three other bacterial species from killing immune cells.

“These results indicate broad-spectrum efficacy against Gram-positive pathogens,” wrote the authors.

Added Shoham: “We have proven efficacy not only against MRSA but also against Staphylococcus epidermidis, which is notorious for clogging catheters, Streptococcus pyogenes that causes strep throat, Streptococcus pneumoniae, and other pathogens.”

Shoham led the study in collaboration with colleagues from the departments of biochemistry and dermatology and the Center for RNA and Therapeutics at Case Western Reserve University. The researchers developed two small molecules, F12 and F19, both of which potentiate antibiotic efficacy in the mouse models. The researchers are now working to commercialize both potential drugs. Case Western Reserve University has issued a license to Q2Pharma, Ltd., a biopharmaceutical startup company in Israel, to perform additional preclinical studies and develop F12 and F19 for clinical trials. Their initial trials will focus on patients suffering from systemic multi-drug resistant infections.

This research was supported by a Transformational Award to Menachem Shoham by the Dr. Ralph and Marian Falk Medical Research Trust Bank of America, N.A., Trustee. Some in vitro studies were supported by NIH/NIAID Preclinical Services under contract numbers HHSN272201100012I and HHSN27200007.

Greenberg, M, et al. “Small-molecule AgrA inhibitors F12 and F19 act as antivirulence agents against Gram-positive pathogens.” Scientific Reports. 2018 Oct 1;8(1):14578. doi: 10.1038/s41598-018-32829-w. PMID: 30275455.

By Richard Kemeny

According to much of the scientific literature, dominance in social animals goes hand-in-hand with healthier lives. Yet leaders of the pack might not be healthier in all aspects, and according to a study published last week (February 26) in Scientific Reports, they are more at risk of parasite infection.

“While high-ranking animals often have the best access to food and mates, these advantages appear to come with strings attached,” says study coauthor Elizabeth Archie, a behavioral and disease ecologist at the University of Notre Dame, in an email to The Scientist. “These strings take the form of higher parasite exposure and susceptibility.”

Lower social status is usually linked to poorer health, according to previous studies. Animals towards the bottom of hierarchies have to struggle more for resources, and are often subjected to aggressive behavior from their superiors. In many species of birds, mice, and nonhuman primates, for instance, poorer physical condition is more common for subordinates. Female macaques of low social status, for example, have been shown to have lower bone density and an increased risk of developing inflammatory diseases.

Yet the relationship between social subordination and infectious disease risk hasn’t been clearly measured, according Archie and her coauthors. To look at the relationship between social status and one particular malady—parasite infections—they carried out a meta-analysis of 39 studies spanning 31 species, searching for patterns of parasitism.

In the majority of studies, those individuals in dominant positions—in particular, dominant males—were found to be more at risk of being infected. The effect was strongest in mammals, and in ordered hierarchical societies where social status is correlated with sexual activity.

These findings support two previous hypotheses about the links between social status and parasitism. One relates infection risk to resource access: exposure to infection is more common when animals feed and mate more. Dominant reindeer, for example, spend more time eating than subordinate individuals, and are more likely to become infected by nematodes. And greater sexual activity brings more risk of transmitted infections. Take, for instance, dominant feral cats, whose sexual proclivity increases the chances of developing Feline Immunodeficiency Virus.

The other hypothesis proposes a trade-off between reproductive effort and immunity to disease. In other words, those in dominant positions expend more energy on mating, and therefore invest less into costly immune defences.

“When you put it in the context [of these hypotheses], it does make a lot of sense,” says Jennifer Koop, a biologist at the University of Massachusetts-Dartmouth, who was not involved in the study.

Archie doesn’t think that individuals will deliberately opt for lower status in order to avoid infection. “High status comes with so many other advantages that the cost of a few more parasites might not be enough for individuals to shun high social status,” she says.

It’s also conceivable that there are benefits to both parasite and host in this relationship, says Nicole Mideo, an evolutionary biologist at the Univeristy of Toronto, who was not involved in the study. “The parasites are exploiting the resources of the host, so if you have a host that doesn’t get access to much food, then the parasite isn’t going to get access to much food,” she says.

This study mostly focused on parasitic worms, a limitation the researchers want to expand beyond. Additionally, the toll on dominant animals’ health of the increased risk of parasite infections was not explored. Mideo explains that there could be subtle advantages here, as research has shown worms can alter immune systems, and might protect against other infections. “It’s entirely possible that having worm infections does confer some sort of advantage in the context of other potential diseases,” she says.

Habig et al., “Social status and parasitism in male and female vertebrates: a meta-analysis,” Scientific Reports, doi:10.1038/s41598-018-21994-7, 2018.

https://www.the-scientist.com/?articles.view/articleNo/52003/title/Social-Dominance-Comes-At-a-Cost/

by Jennifer Brown

The recent Ebola outbreak in West Africa has claimed more than 11,300 lives—a stark reminder of the lack of effective options for treating or preventing the disease.

Progress has been made on developing vaccines, but there is still a need for antiviral therapies to protect health care workers and local populations in the event of future outbreaks.

Now, a new study suggests that gamma interferon, an FDA-approved drug, may have potential as an antiviral therapy to prevent Ebola infection when given either before or after exposure to the virus.

The findings, published in the journal PLOS Pathogens, show that gamma interferon, given up to 24 hours after exposure, inhibits Ebola infection in mice and completely protects the animals from death.

Ebola infection appears to be a stepwise process. First, the virus targets and infects macrophages or dendritic cells, two types of immune system cells found in the liver, spleen, and lymph nodes. Ebola then replicates in those cells. Following this initial infection, which happens at day 3 or 4 in non-human primates, Ebola virus is released into the blood and infects a plethora of other different cell populations.

“It goes from an early stage with a very targeted infection of only these few cell types, to everything being infected,” says Wendy Maury, professor of microbiology at the University of Iowa.

“We think what’s happening with gamma interferon is that it’s targeting macrophages and blocking the infection of those initial cell targets so you don’t get the second round of infection.”

The University of Iowa does not have a specializing BioSafety Level 4 (BSL4) lab that is required for experiment using Ebola virus, so the researchers made their initial findings using a surrogate virus, which targets and infects the same cells as Ebola, but does not cause the disease.

This Ebola lookalike—a sheep in wolf’s clothing—consists of a less dangerous vesicular stomatitis virus (VSV) that expresses Ebola glycoproteins on its surface.

All of the results found using the surrogate virus were then repeated using mouse-adapted Ebola virus in the BSL4 lab of Maury’s longtime collaborator Robert Davey at Texas Biomedical Institute in San Antonio, Texas.

Gamma interferon inhibits the virus’s ability to infect human and mouse macrophages, in part by blocking virus replication in the cells. Pre-treating mice with interferon gamma 24 hours before exposure protects the animals from infection and death. The researchers were surprised to find that treatment up to 24 hours after what would have been a lethal exposure also completely protected the animals from death, and they could no longer detect any Ebola virus in the mouse’s cells.

The findings suggest that interferon gamma may be useful both as a prophylaxis and post-exposure treatment against Ebola. The team still has to determine how late gamma interferon can be given to the mice and still prevent infection. However, the results suggest a window of time after exposure when gamma interferon may be an effective antiviral therapy.

“My guess is that if you delay the gamma interferon too much, you miss this window of opportunity to block the infection in macrophage cells and the gamma interferon can no longer provide protection,” Maury says.

Maury and colleagues investigated how gamma interferon might be helping the cells fight off the Ebola virus. They identified that the expression of more than 160 genes in human macrophages is stimulated by gamma interferon. Introduction of some of these genes into cells was sufficient to prevent Ebola infection.

“This mechanistic information might suggest more precise drug targets rather than the broad effects, including adverse side-effects, that are produced by gamma-interferon,” she says.

Gamma interferon is already approved by the FDA to treat chronic granulomatous disease (an immune disease) and severe malignant osteopetrosis.

In addition to moving the studies into larger animal models, Maury next plans to study the ability of gamma interferon to inhibit Ebola infection in conjunction with other developing antivirals.

“Right now, there are no FDA-approved antiviral therapies for Ebola, but there are some being developed that target virus entry,” she says. “We know that gamma interferon blocks replication but not entry into cells. So combining an entry inhibitor with gamma interferon may allow us to reduce amount of gamma interferon needed and target two different steps in the virus’s life cycle, which has been shown in HIV to be critically important for controlling the virus.”

http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1005263

http://now.uiowa.edu/2015/12/fda-approved-drug-protects-mice-ebola

A one thousand year old Anglo-Saxon remedy for eye infections which originates from a manuscript in the British Library has been found to kill the modern-day superbug MRSA in an unusual research collaboration at The University of Nottingham.

Dr Christina Lee, an Anglo-Saxon expert from the School of English has enlisted the help of microbiologists from University’s Centre for Biomolecular Sciences to recreate a 10th century potion for eye infections from Bald’s Leechbook an Old English leatherbound volume in the British Library, to see if it really works as an antibacterial remedy. The Leechbook is widely thought of as one of the earliest known medical textbooks and contains Anglo-Saxon medical advice and recipes for medicines, salves and treatments.

Early results on the ‘potion’, tested in vitro at Nottingham and backed up by mouse model tests at a university in the United States, are, in the words of the US collaborator, “astonishing”. The solution has had remarkable effects on Methicillin-resistant Staphylococcus aureus (MRSA) which is one of the most antibiotic-resistant bugs costing modern health services billions.

The team now has good, replicated data showing that Bald’s eye salve kills up to 90% of MRSA bacteria in ‘in vivo’ wound biopsies from mouse models. They believe the bactericidal effect of the recipe is not due to a single ingredient but the combination used and brewing methods/container material used. Further research is planned to investigate how and why this works.

The testing of the ancient remedy was the idea of Dr Christina Lee, Associate Professor in Viking Studies and member of the University’s Institute for Medieval Research. Dr Lee translated the recipe from a transcript of the original Old English manuscript in the British Library.

The recipe calls for two species of Allium (garlic and onion or leek), wine and oxgall (bile from a cow’s stomach). It describes a very specific method of making the topical solution including the use of a brass vessel to brew it in, a straining to purify it and an instruction to leave the mixture for nine days before use.

The scientists at Nottingham made four separate batches of the remedy using fresh ingredients each time, as well as a control treatment using the same quantity of distilled water and brass sheet to mimic the brewing container but without the vegetable compounds.

The remedy was tested on cultures of the commonly found and hard to treat bacteria, Staphylococcus aureus, in both synthetic wounds and in infected wounds in mice.

The team made artificial wound infections by growing bacteria in plugs of collagen and then exposed them to each of the individual ingredients, or the full recipe. None of the individual ingredients alone had any measurable effect, but when combined according to the recipe the Staphylococcus populations were almost totally obliterated: about one bacterial cell in a thousand survived.

The team then went on to see what happened if they diluted the eye salve – as it is hard to know just how much of the medicine bacteria would be exposed to when applied to a real infection. They found that when the medicine is too dilute to kill Staphylococcus aureus, it interfered with bacterial cell-cell communication (quorum sensing). This is a key finding, because bacteria have to talk to each other to switch on the genes that allow them to damage infected tissues. Many microbiologists think that blocking this behaviour could be an alternative way of treating infection.

Dr Lee said: “We were genuinely astonished at the results of our experiments in the lab. We believe modern research into disease can benefit from past responses and knowledge, which is largely contained in non-scientific writings. But the potential of these texts to contribute to addressing the challenges cannot be understood without the combined expertise of both the arts and science.

“Medieval leech books and herbaria contain many remedies designed to treat what are clearly bacterial infections (weeping wounds/sores, eye and throat infections, skin conditions such as erysipelas, leprosy and chest infections). Given that these remedies were developed well before the modern understanding of germ theory, this poses two questions: How systematic was the development of these remedies? And how effective were these remedies against the likely causative species of bacteria? Answering these questions will greatly improve our understanding of medieval scholarship and medical empiricism, and may reveal new ways of treating serious bacterial infections that continue to cause illness and death.”

University microbiologist, Dr Freya Harrison has led the work in the laboratory at Nottingham with Dr Steve Diggle and Research Associate Dr Aled Roberts. She will present the findings at the Annual Conference of the Society for General Microbiology which starts on Monday 30th March 2015 in Birmingham.

Dr Harrison commented: “We thought that Bald’s eyesalve might show a small amount of antibiotic activity, because each of the ingredients has been shown by other researchers to have some effect on bacteria in the lab – copper and bile salts can kill bacteria, and the garlic family of plants make chemicals that interfere with the bacteria’s ability to damage infected tissues. But we were absolutely blown away by just how effective the combination of ingredients was. We tested it in difficult conditions too; we let our artificial ‘infections’ grow into dense, mature populations called ‘biofilms’, where the individual cells bunch together and make a sticky coating that makes it hard for antibiotics to reach them. But unlike many modern antibiotics, Bald’s eye salve has the power to breach these defences.”

Dr Steve Diggle added: “When we built this recipe in the lab I didn’t really expect it to actually do anything. When we found that it could actually disrupt and kill cells in S. aureus biofilms, I was genuinely amazed. Biofilms are naturally antibiotic resistant and difficult to treat so this was a great result. The fact that it works on an organism that it was apparently designed to treat (an infection of a stye in the eye) suggests that people were doing carefully planned experiments long before the scientific method was developed.”

Dr Kendra Rumbaugh carried out in vivo testing of the Bald’s remedy on MRSA infected skin wounds in mice at Texas Tech University in the United States. Dr Rumbaugh said: “We know that MRSA infected wounds are exceptionally difficult to treat in people and in mouse models. We have not tested a single antibiotic or experimental therapeutic that is completely effective; however, this ‘ancient remedy’ performed as good if not better than the conventional antibiotics we used.”

Dr Harrison concludes: “The rise of antibiotic resistance in pathogenic bacteria and the lack of new antimicrobials in the developmental pipeline are key challenges for human health. There is a pressing need to develop new strategies against pathogens because the cost of developing new antibiotics is high and eventual resistance is likely. This truly cross-disciplinary project explores a new approach to modern health care problems by testing whether medieval remedies contain ingredients which kill bacteria or interfere with their ability to cause infection”.

http://www.nottingham.ac.uk/news/pressreleases/2015/march/ancientbiotics—a-medieval-remedy-for-modern-day-superbugs.aspx