A breath of fresh air
Respiratory virus researcher Masfique Mehedi tackles RSV, COVID, and influenza at the UND School of Medicine & Health Sciences
As with many papers in the sciences, a series of seemingly benign phrases belied a more significant result: “We confirmed RSV infects primarily ciliated cells by detecting RSV [nucleoprotein] mRNA in the infected ciliated but not in the goblet or basal cells,” wrote Masfique Mehedi, Ph.D., and his research team in a paper published in Virus Research early in 2023.
Translation: we now know what’s happening at the cellular level that makes respiratory syncytial virus (RSV) dangerous for infants in particular – and it’s not systemic in nature.
This is all good news, said Mehedi, an assistant professor in the UND School of Medicine & Health Sciences (SMHS) Department of Biomedical Sciences specializing in RSV, in so far as knowing better the pathology of the virus allows researchers to focus on better treatments for the disease.
This knowledge also, somewhat fortuitously, helps researchers understand just a bit more about that other high-profile lung infection: SARS-CoV-2, the coronavirus behind the COVID-19 pandemic.
RSV and/or bronchiolitis?
But first RSV.
Identified in 1956, RSV is a common viral infection of the lower airway. It takes its name from the fact that infected cells fuse to produce multi-nucleus cells, or syncytia, in the airway’s outermost cell wall, or epithelium. These infected cells become inflamed and expand into the airway, narrowing the host’s bronchioles (those branches within the human lung that end in the alveoli where oxygen is absorbed) and complicating respiration in a condition known as bronchiolitis.
While the infection is usually unremarkable in healthy adults and children ages two and up, it can be serious for infants in particular because the inflammation of babies’ already tiny airways can obstruct breathing very quickly.
But the specific mechanism of that inflammation, which is key to how the virus functions, has been less well-known, said Mehedi.
“In our bronchial model, upper-layer cells are infected by RSV and the infection is limited to that specific cell type – it does not infect other cell types,” explained Mehedi to North Dakota Medicine from his second-floor office in the SMHS. “As a result, [RSV] does not damage the epithelium. This means that over a period of time the infection resolves on its own. It may recapitulate – some of us may get RSV often – but most adults have no problem.”
More specifically, Mehedi’s team found that the bronchiolitis experienced by RSV patients was occurring because the cytoskeletons of infected airway cells – the complex network of interlocking proteins in cells’ cytoplasm – was swelling, in some cases to double the size of uninfected cells. Despite this swelling, RSV left the cells’ membrane or “skin” intact, resulting in an undamaged cell wall after the inflammation had subsided, almost as if there had never been an infection in the first place.
“RSV is diagnosed as ‘bronchiolitis’ 99% of the time, so physicians previously didn’t even test for it,” continued Mehedi, speaking of the pre-COVID adult population, which is typically given nothing by way of treatment other than the tried-and-true prescriptions of bedrest, fluids, and anti-inflammatory medications – with the occasional bronchodilator. “They know that bronchiolitis is RSV, so what’s happening is that adults are generally okay during and after infection.”
A baby’s airway is much thinner, though, which is why providers tend to see “severe pathophysiology” in that population. So it is that finding novel treatments for the infection feels especially important this year, Mehedi added, given the high rate of RSV infection among children that providers have seen of late.
As Mehedi put it, the United States experienced a surprisingly early and notably severe surge in cases of RSV in late-2022. Pointing to one Centers for Disease Control and Prevention (CDC) report, Mehedi noted too that after a few years of reduced prevalence of the virus – due likely to the infection control protocols brought on by the pandemic – the rate of RSV hospitalizations jumped by a factor of ten in Nov. 2022, relative to Nov. 2019.
“Because we don’t have a vaccine for people under age 60, or therapeutics to treat RSV, the virus still causes 34 million acute lower respiratory infections globally,” he said. “Pre-term babies, infants, and young children are the most vulnerable to getting a severe disease from RSV infection, so we need to find better ways of helping this population.”
All of this begs two questions: why the surge now and what is the status of an RSV vaccine, for children in particular?
This is where the conversation gets thorny, admitted Mehedi, who, after working with former National Institute of Allergy and Infectious Diseases (NIAID) principal investigator and RSV specialist Dr. Peter L. Collins, has been managing his own lab at UND since 2017.
On the surge question, it’s likely that the increased incidence of RSV is due not only to a relaxing of pandemic protocols but the more frequent testing of children for the virus, Mehedi said, which is another result of COVID-19.
“Generally, clinicians confidently identified RSV as the cause of bronchiolitis without generic RSV testing, since RSV is known to cause bronchiolitis,” he said. “However, since 2022, RSV has been included in the diagnostic panel with COVID testing. Therefore, RSV has been detected in higher numbers than usual.”
Concerning the vaccine, Mehedi, who is very much in favor of vaccination generally, admits that the necessity of an RSV vaccine for a large majority of the population and for infants remains an open question in the field. Citing the distinction between the variety of potential RSV vaccines currently undergoing clinical trial, Mehedi suggests that the “live attenuated” vaccines – which utilize a reduced form of the virus in question to induce the immune system to produce antibodies against that virus – seem to be the safest and most effective option for the infant population.
But not all vaccines being reviewed are live attenuated. And recently, the FDA approved an adjuvanted RSV vaccine for patients age 60 and older only.
“For kids, the vaccine platform should be live attenuated,” Mehedi insisted, referencing one paper authored by Collins that notes how the “live-attenuated approach continues to offer a number of advantages for development of an RSV vaccine for RSV-naïve infants and young children.” “That is the best way of vaccination for those under two years old.”
RSV vs COVID
And given his interest in infections of the airway, Mehedi was obviously primed to study SARS-CoV-2 as soon as it emerged in 2019. Since 2020 his team has contributed to five published papers on coronavirus, helping researchers and physicians understand the differences between SARS-CoV-2 and RSV.
“Both viruses use a similar droplet or airway transmission, but they differ in their pathophysiology,” explained Mehedi, adding that while both viruses contact the bronchial wall, only RSV sticks. “What I mean by that is that RSV always causes bronchiolitis, and only in rare cases pneumonia. But SARS-CoV-2 never causes bronchiolitis. It very often causes pneumonia – and almost anything you can name – because it becomes a systemic infection.”
This ability to move past the epithelium and, thus, enter the bloodstream is what has made SARS-CoV-2 so serious, he added.
Discussing one of his other papers from 2023 that records the “translocation” of mRNA and “spike” protein from the cytoplasm into the nucleus of the SARS-CoV-2 virus – something no researcher had seen before in the laboratory setting in a coronavirus – Mehedi chooses his words carefully.
Researchers have seen this “nuclear localization signal” in viruses before, he said, just not in the spike protein of SARS-CoV-2. Given the media hype over the virus’s origins, this discovery is both a big deal and remains difficult to explain in so far as proving definitively that the insertion of such protein and/or mRNA into a nucleus was done intentionally, as opposed to being the result of one or more genetic mutations, is hard to do.
In any case, this novel feature of SARS-CoV-2 may be the culprit behind what is being called “long COVID” wherein some COVID sufferers feel the virus’s aftereffects – brain fog, loss of taste/ smell, headache, lethargy – for months after infection.
COVID-19 aside, RSV at least remains incapable of producing such systemic or long-term illness. And Mehedi and his lab are doing everything in their power to help keep it that way.