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Neutrophils are the body’s first line of defence against infection, which can be activated when foreign pathogens stress the body. When overactivated, neutrophils can damage the body’s own tissues. Lung tissue is saturated with blood vessels, making them very susceptible to neutrophil attacks. If severe enough, acute lung injuries can lead to acute respiratory distress syndrome (ARDS), the leading cause of death due to COVID.

Reporting in JCI Insight, Cold Spring Harbor Laboratory (CSHL) researchers have found a drug candidate that can prevent lethal lung inflammation in mice by inhibiting a protein called PTP1B. Their discovery may help develop better treatments for severe inflammatory conditions like sepsis and COVID.

“When you think about COVID, acute lung injury and ARDS underlie the fatal aspects of the disease,” leader researcher Nicholas Tonks, professor of cancer research says. “And so, when the pandemic took hold, we were wondering whether there was anything we could do to help, to provide an understanding of this aspect of the disease and suggest ways it could be treated.”

Tonks’ graduate student Dongyan Song investigated whether using a PTP1B inhibitor drug candidate could dampen the lethal consequences of overactive neutrophils in mice. She found that pretreating mice with the PTP1B inhibitor reduced lung tissue damage. When untreated, less than half of the mice survived acute lung injuries and ARDS. But when pretreated, they all survived.

The researchers exploited a natural process, called neutrophil aging, that the body uses to control the immune cell’s lifespan. As they age, neutrophils become less dangerous. Tonks’ team discovered PTP1B inhibition speeds up neutrophil aging. “An aged neutrophil is like a soldier without a weapon,” Song explains. “So regardless of how many neutrophils flood an area, they won’t be able to do serious damage.”

Going forward, he and Song are working to increase the understanding of how PTP1B inhibitors affect the immune system. Tonks hopes his lab’s continued research leads to new treatments and preventative measures for various inflammatory diseases.

Tonks’ lab studies signal transduction, the process that controls how cells respond to signals from their environment. In particular, they focus on the PTP protein family, which Tonks discovered over 30 years ago. Since then, he’s sought to develop small molecule drug candidates that target these proteins, which can provide new approaches for treating major human diseases including cancer and metabolic and neurodegenerative diseases.

Source: Cold Spring Harbor Laboratory

Researchers have found that a recently discovered virus in a Russian bat that is similar to SARS-CoV-2 may be able to infect humans and, if it were to spillover, is resistant to current vaccines.

Reporting in PLOS Pathogens, researchers discovered that spike proteins from the bat virus, named Khosta-2, can infect human cells and is resistant to both the monoclonal antibodies and serum from individuals vaccinated for SARS-CoV-2. Both Khosta-2 and SARS- CoV-2 belong to the same sub-category of coronaviruses known as sarbecoviruses.

“Our research further demonstrates that sarbecoviruses circulating in wildlife outside of Asia – even in places like western Russia where the Khosta-2 virus was found – also pose a threat to global health and ongoing vaccine campaigns against SARS-CoV-2,” said Michael Letko, WSU virologist and corresponding author of the study.

Letko said the discovery of Khosta-2 highlights the need to develop universal vaccines to protect against sarbecoviruses in general, rather than just against known variants of SARS-CoV-2. 

“Right now, there are groups trying to come up with a vaccine that doesn’t just protect against the next variant of SARS-2 but actually protects us against the sarbecoviruses in general,” Letko said. “Unfortunately, many of our current vaccines are designed to specific viruses we know infect human cells or those that seem to pose the biggest risk to infect us. But that is a list that’s everchanging. We need to broaden the design of these vaccines to protect against all sarbecoviruses.”

While hundreds of sarbecoviruses have been discovered in recent years, predominantly in bats in Asia, the majority are not capable of infecting human cells. The Khosta-1 and Khosta-2 viruses were discovered in Russian bats in late 2020, and it initially appeared they were not a threat to humans.

“Genetically, these weird Russian viruses looked like some of the others that had been discovered elsewhere around the world, but because they did not look like SARS-CoV-2, no one thought they were really anything to get too excited about,” Letko said. “But when we looked at them more, we were really surprised to find they could infect human cells. That changes a little bit of our understanding of these viruses, where they come from and what regions are concerning.”

Letko teamed with a pair of researchers in Washington State University’s to study the two newly discovered viruses. They determined Khosta-1 posed low risk to humans, but Khosta-2 demonstrated some troubling traits.

The team found that like SARS-CoV-2, Khosta-2 can use its spike protein to infect cells by attaching to a receptor protein, called angiotensin converting enzyme 2 (ACE2), found throughout human cells. They next set out to determine if current vaccines protect against the new virus.

Using serum derived from COVID-vaccinated human populations, the team saw that Khosta-2 was not neutralised by current vaccines. They also tested serum from people who were infected with the omicron variant, but the antibodies, too, were ineffective.

Fortunately, Letko said the new virus is lacking some of the genes believed to be involved in pathogenesis in humans. There is a risk, however, of Khosta-2 recombining with a second virus like SARS-CoV-2.

“When you see SARS-2 has this ability to spill back from humans and into wildlife, and then there are other viruses like Khosta-2 waiting in those animals with these properties we really don’t want them to have, it sets up this scenario where you keep rolling the dice until they combine to make a potentially riskier virus,” Letko said.

Source: Washington State University

The majority of people who were likely infected with the Omicron variant were unaware they had the virus, according to a new study published in JAMA Network Open.

“More than one in every two people who were infected with Omicron didn’t know they had it,” said Susan Cheng, MD, MPH, corresponding author of the study. “Awareness will be key for allowing us to move beyond this pandemic.” 

Previous work estimated that between 25% and 80% of people infected with SARS-CoV-2 may be asymptomatic. Compared to other variants, Omicron is associated with generally less severe symptoms that may include fatigue, cough, headache, sore throat or a runny nose.

“Our study findings add to evidence that undiagnosed infections can increase transmission of the virus,” said Sandy Y. Joung, MHDS, an investigator at Cedars-Sinai and first author of the study. “A low level of infection awareness has likely contributed to the fast spread of Omicron.”

As part of research into the effects of COVID and the impact of vaccines, the investigators began collecting blood samples from healthcare workers more than two years ago. In the second half of 2021, just before the start of the Omicron variant surge, the investigators were able to expand enrolment to include patients. Of the healthcare workers and patients who have participated in the research, investigators identified 2479 people who had contributed blood samples just prior to or after the start of the Omicron surge. The investigators identified 210 people who likely were infected with the Omicron variant based on newly positive levels of SARS-CoV-2 antibodies. 

Study participants were invited to provide health status updates through surveys and interviews. Only 44% of study participants testing positive were aware of their infection. Of the 56% of study participants who were unaware, only 10% reported having any recent symptoms that they attributed to a common cold or other type of infection. 

More studies involving larger numbers of people from diverse ethnicities and communities are needed to learn what specific factors are associated with a lack of infection awareness, according to the investigators.

Cheng and colleagues are also studying patterns and predictors of reinfections and their potential to offer long-lasting immunity to SARS-CoV-2. In addition to raising awareness, this information could help people manage their individual risk.

Source: Cedars-Sinai

Dupilumab, a monoclonal antibody that suppresses interleukin-13 can improve survival rates for patients with moderate to severe COVID, according to the results of a small clinical trial published in the Open Forum of Infectious Diseases.

Dupilumab is most often prescribed for skin conditions such as atopic dermatitis, asthma, and sinus congestion and swelling. The treatment also proved safe in the small study, as expected, because dupilumab is already a safe and effective allergy medicine.

The small trial, designed and led by Dr Jennifer Sasson, found that dupilumab improved patient survival at 60 days and reduced the number of patients who needed intensive care. Almost 90% of patients who received dupilumab in the randomised trial were alive at 60 days, compared with 76% of patients who did not.

“Our clinical trial suggests that treatment with the anti-allergy medicine dupilumab may decrease deaths due to COVID,” said Dr Sasson, of the University of Virginia School of Medicine. “A large multi-institution study to validate these preliminary results is being designed. If successful, this multi-site trial will open a new window to treatment of COVID and potentially other viral pneumonias.”

Cytokine levels inspire trial

The researchers were inspired to launch the trial after discovering that COVID patients were at significantly greater risk of needing a ventilator if their blood contained high levels of the cytokine interleukin-13. Dupilumab, which received FDA approval in 2017, works by blocking the effects of IL-13 and reducing inflammation.

To see if dupilumab could improve the body’s immune response to COVID, Sasson and her collaborators enrolled 40 patients with moderate to severe cases in a clinical trial. The trial was double-blinded, meaning neither the patients nor the doctors knew whether the patient was receiving the antibody or a placebo. Both groups of trial participants otherwise received standard care.

After 28 days, no difference was seen between the two groups in ventilator-free survival or in adverse events. But by 60 days, there were only two deaths among the patients receiving dupilumab and five deaths among those receiving placebo. 

Among the patients who were not already in the intensive care unit when they joined the trial, three receiving dupilumab were ultimately admitted to the ICU, compared to six receiving placebo.

Source: University of Virginia