Day: May 22, 2022

Mutations that Predispose Patients to Severe Staph Infection

Methicillin-resistant Staphylococcus aureus (MRSA) bacteria. Credit: CDC

A common culprit of skin and respiratory infections, Staphylococcus aureus is highly unpredictable, with the bacteria mostly harmlessly present in the skin of 20–30% of people. However, these bacteria can occasionally cause infections that lead to deadly complications, such as pneumonia, deep skin infections, and sepsis. This was a totally unpredictable outcome – until now.

Now, a new study published in Science identifies a mutated gene common to multiple patients who suffer life-threatening infections and suggests that people living with a genetic condition known as 5p- or Cri-du-chat syndrome may be at similar risk.

“We have characterised severe Staphylococcus aureus infection at the genetic, cellular, immunological, and clinical levels,” said András Spaan, the study’s first author. “By integrating these levels, we have established causality and provided clues for future interventions.”

A first for cell intrinsic immunity

To find out why S. aureus causes disease in some people but not others, scientists examined the protein-coding genomes of more than 100 patients who had suffered from unexplained severe staph infections.

The common genetic thread linking some of these disparate patients were mutations of a gene called OTULIN, which is perched along the short arm of chromosome 5 and codes for an enzyme involved in regulating inflammation. These individuals were not entirely bereft of OTULIN –only one of their two copies of the gene was mutated – but that deficiency appeared to be all it took to render them vulnerable to infections that would scarcely harm other people.

The scientists expected to find that OTULIN deficiency somehow cripples white blood cells or otherwise prevents the immune system from snuffing out S. aureus. But further investigation revealed that these mutations indirectly cause an unrelated protein to aggregate on the surfaces of skin and lung cells, gumming up the tools that those cells use to defend themselves from a toxin produced by S. aureus. This mechanism of defense is known as cell intrinsic immunity.

This finding was particularly surprising because, until then, specific defects in cell intrinsic immunity had only been linked to a predisposition to some viral infections, from COVID to herpes to encephalitis. It had never been shown to play a role in bacterial disease. “This is the first known instance of cell intrinsic immunodeficiency predisposing patients to bacterial infection,” Spaan says.

A larger role for OTULIN

While the individuals whom Spaan and colleagues studied were only missing one copy of OTULIN, people born without either functional copy of this gene face a bevy of early-onset inflammatory diseases, which often prove fatal in the first year of life.

This observation led Spaan to conclude that one functional copy of OTULIN is enough to prevent inflammatory disease, but insufficient to protect against life-threatening staph infections—a genetic mechanism known as haploinsufficiency. “The genetic mechanism was important to pin down,” Spaan says. “People with two functional copies of the gene appear to be healthy, those with no functional copies have autoinflammatory disease, and those with one functional copy are susceptible to severe staph infections.”

Given that general rule, the researchers hypothesized that any population missing only one copy of OTULIN would be similarly predisposed to severe infections. So they then examined a group of volunteers with 5p- syndrome, the most common chromosomal deletion disorder in humans characterized by developmental delays, intellectual disabilities and, in infants, a high-pitched cry. Most 5p- syndrome patients are missing the entire short arm of chromosome 5 and therefore invariably go about their lives with only one functional copy of OTULIN.

Indeed, upon examining six 5p- syndrome patients, the team found that one third were susceptible to lung infections. “We were able to demonstrate that this susceptibility is driven by the fact that they had only one functional copy of OTULIN,” Spaan says. “In many ways, these patients looked genetically similar to the patients we had identified with severe staph infections.”

“Both clinically, and on the cellular level, they could almost be said to have the same disease.”

The findings do not imply that everyone with OTULIN haploinsufficiency or 5p- syndrome will contract severe infections. In fact, the initial results of the study suggested that only 30 percent of individuals with these mutations develop severe disease. Why OTULIN haploinsufficiency appears to cause disease in some patients but not others—a common phenomenon that genetics researchers call “incomplete penetrance”—will be the subject of follow-up studies.

“Many genetic disorders act in this way, but it remains puzzling,” Spaan says. “Why are some people with these mutations perfectly healthy, while others get super ill and may even die?”

One potential answer has already surfaced. Spaan and colleagues found that individuals with OTULIN mutations but no sign of severe disease had high levels of antibodies that neutralise the toxin produced by S. aureus, perhaps due to prior exposure to the common skin bacteria. Individuals with severe disease, on the other hand, had precious few antibodies.

Further investigation into genetic predisposition to diseases, particularly ones as stubborn as staphylococcal infections, may help the development of future treatments. “Studies on these disorders can act as a compass,” Spaan said, “Our research clarifies the interactions between hosts and pathogens, revealing scientific insights into pathogenesis and immunity.”

Source: Rockefeller Institute

Compression Garments Offer No Exercise Recovery Benefit

Man and woman about to sprint
Source: Andrea Piacquadio on Pexels

A meta-analysis of studies on the ability of compression garments, elastic clothing on the limbs or hips, to enhance muscle recovery after exercise found that they provide no recovery benefit. Rather, they should be used to help reduce injury, the reviewers suggest.

Use of compression garments has gained popularity over the last few decades because they are thought to enhance muscle recovery following exercise.

An international research team, led by assistant professor János Négyesi, conducted a review using a generic inverse variance model, which adjusts the weight of individual studies according to sample size, to more accurately assess the effects of compression garments than previous meta-analyses.

Contrary to results found in individual research, the meta-analytical evidence suggests that wearing a compression garment during or after training does not facilitate muscle recovery.

“Even data from our previous study supported the idea that such garments have the potential to reduce strength loss after a strenuous workout,” said Dr Négyesi. “However, when we synthesized the data of all relevant studies, we found no effect of compression garments on strength recovery – even when factoring in exercise type and when and where the compression garment is applied.”

The authors think this is a perfect example of contradictory outcomes from individual studies and meta-analytical evidence. Therefore, scientists should be careful when drawing direct conclusions from the results of their studies. Rather, meta-analyses using the most appropriate models can provide more precise and reliable results.

Overall, practitioners, athletes, coaches, and therapists should reconsider compression garments as a means of reducing the harmful effects of physical exercise on muscle strength and seek alternative methods.

The review appears in Sports Medicine.

Source: Tohoku University

Did a Flu Vaccine Reduce Severe COVID Risk by 89%?

Vaccine injection
Image source: NCI on Unsplash

In a study of more than 30 000 health-care workers in Qatar, those who got a flu jab were 89% less likely to develop severe COVID over the next few months.

The study, which is published in Nature, was conducted in late 2020, before COVID vaccines were rolled out. Its findings align with previous work suggesting that ramping up the immune system using influenza vaccines and other jabs could help the body to fend off the coronavirus SARS-CoV-2.

In the early months of the pandemic, there was great interest as to whether existing vaccines could confer some protection against SARS-CoV-2. But collecting strong evidence for such an effect is difficult, because people who sought out vaccination for other diseases could also make lifestyle choices that reduce the odds of catching COVID.

To reduce this ‘healthy-user effect’, a team led by Laith Jamal Abu-Raddad, an infectious-disease epidemiologist at Weill Cornell Medicine–Qatar in Doha, analysed the health records of 30 774 medical workers in the country. There is probably less variation in health-related behaviour among such workers than in the general population, reducing (but not eliminating) bias, Abu-Raddad said.

The researchers tracked 518 workers who tested positive for SARS-CoV-2 and matched them to more than 2000 study participants who had tested negative for the virus. Those who had received an influenza vaccine that season were 30% less likely to test positive for SARS-CoV-2, and 89% less likely to develop severe COVID, compared with workers who had not (although the number of severe cases was small in both groups). The study was posted on the medRxiv preprint server on 10 May.

Günther Fink, an epidemiologist at the University of Basel in Switzerland, said that the Qatar analysis makes it less likely that other studies reporting the same link were a fluke. His team reported that flu vaccines were associated with lower mortality in hospitalised COVID patients in Brazil.

“This is an important piece of evidence,” says Mihai Netea, an infectious-disease specialist at Radboud University Medical Center in Nijmegen, the Netherlands. The observation that influenza vaccines are linked to a reduction in not just SARS-CoV-2 infections, but also disease severity, strongly suggests that the protection is genuine, he adds.

How long this protection lasts is unclear. Among those in the Qatar study who had the flu jab and later contracted COVID, Abu-Raddad’s team recorded SARS-CoV-2 infections occurring, on average, about six weeks after vaccination. “I don’t expect to see this effect lasting long at all,” he says. Netea guesses that the benefits last for between six months and two years.

Exactly why flu vaccines, which are inactivated viruses, would also protect against COVID is unclear. Vaccines teach the immune system about specific pathogens, but they also stimulate broad-acting antiviral defences, said Netea, who has found signs of such responses in flu-vaccine recipients.

Netea’s team is also working to better quantify the benefits of vaccines targeting influenza and other diseases against COVID. His team has launched a randomised, placebo-controlled trial in Brazil that will test whether influenza and measles–mumps–rubella vaccines can protect against COVID, fully excluding the healthy-user effect.

Knowing that vaccines for flu and other diseases can offer protection against COVID, even if only partial and for a limited period, could limit the damage caused by a future pandemic before a vaccine for that disease is developed, Netea argues. “If you have something in the beginning, you could save millions of lives.”

Source: Nature

80 Cases of Monkeypox Reported in 12 Countries

Close-up of monkeypox lesions on the arm and leg of a female child. Credit: Wikimedia Commons

On Friday, May 20, the World Health Organization has reported that there were 80 cases of monkeypox reported in 12 countries, but has not mentioned which countries those are. However, the National Institute for Communicable Diseases has not reported any cases in South Africa, though there has now been a case reported in Australia.

Update: as of 23 May, the NICD has reported that there are 145 cases in 15 countries, but confirms there are no local cases.

Normally endemic to certain countries where it resides in animal reservoirs, monkeypox is rarely encountered in countries outside those regions. The WHO notes that this is “atypical” for the zoonotic orthopoxvirus, which causes smallpox-like symptoms but with a lower mortality. European public health agencies have so far reported that the UK, Spain, Portugal, Germany, Belgium, France, the Netherlands, Italy and Sweden have seen cases. The first patient in the UK with the virus had returned from a trip to Nigeria, likely catching it there. Cases have been reported in the US and Canada.

The WHO advises that, “As monkeypox spreads through close contact, the response should focus on the people affected and their close contacts. People who closely interact with someone who is infectious are at greater risk for infection: this includes health workers, household members and sexual partners.”

At present, it is unclear why this unusual outbreak is happening now, especially amid the heightened vigilance of the COVID pandemic. One possibility is that some mutation is responsible, though there is little evidence at present to suggest a new variant is responsible.

Another explanation could be that this is simply a matter of the right place and time for the virus. It may also be easier for monkeypox to spread nowadays compared to when there was more widespread use of smallpox vaccine.

Source: BBC News

Analysis Finds that Early Interventions in Autism are Effective

Children
n Photo by Ben Wicks on Unsplash

In a Cochrane analysis of therapeutic or educational interventions for very young children with or at high likelihood for autism, researchers found that certain types of interventions were beneficial. The analysis, published in Developmental Medicine & Child Neurology, included seven reviews which summarised the results of 63 studies from 2009 to 2020.

The analysis found that naturalistic developmental behavioural interventions, developmental interventions, and behavioural interventions were effective.

Heterogeneity in design, intervention and control group, dose, delivery agent, and measurement approach was noted. Inconsistent methodological quality and potential biases were identified.

“We have a growing evidence base that supports the importance of early intervention and its ability to promote communication, adaptive behavior, and facilitate social interactions and relationships. However, there are limitations to this evidence base, which leaves families with some work to do in order to understand which approach is the best fit for themselves, their child, or their family,” said lead author Lauren Franz, MBChB, MPH, of Duke University Medical Center.

Source: Wiley