RSV and flu’s intimate connection
Respiratory syncytial virus (RSV) and influenza typically circulate contemporaneously, meaning co-infections are common. Clinical studies of such co-infection have so far yielded conflicting results, but some research suggests that it can put people at an increased risk of developing pneumonia.
Researchers at the University of Glasgow, UK, have shown that when RSV and the influenza A virus (IAV) are present in the same cell, they can conjoin to form hybrid viral particles.
The work was conducted solely in cell culture, using cell lines derived from human lungs and lab-adapted virus strains. But if future work shows that such hybrid particles also form in natural co-infections, this research could have significant clinical implications.
RSV and IAV were seen to physically conjoin in two ways. But because respiratory viruses spread by filamentous particles budding off from cell membranes, the group focused on the hybrid particles that were located on infected cells’ membranes with a filament-based structure.
These particles had necks made of proteins and genomic RNA from RSV, and forked heads consisting of IAV proteins and RNA. And the particles could, indeed, bud off and infect more cells.
Importantly, these hybrid particles were able to use RSV proteins to enter cells that did not have the receptor that would ordinarily allow IAV to enter. IAV usually targets only the upper and middle respiratory tract, but this mechanism could theoretically allow hybridized flu viruses to enter the lower respiratory tract that RSV infects.
Antibodies against RSV were able to neutralize the hybrid particles. But antibodies that usually bind to the flu virus could only weakly target the hybrid particles, suggesting that the particles could escape immunity against flu.
A final experiment showed the two viruses present in the same cultured airway cells taken from volunteers, but the researchers have not shown that this generates hybrid particles — nor that such particles occur naturally.
RSV and flu have long co-circulated, meaning that this phenomenon, if it occurs naturally, is unlikely to be new. Nevertheless, viral hybridization might represent a new frontier in the study of co-infections.
RSV’s toll on older people
RSV is mainly thought of as a childhood illness, but two meta-analyses have assessed the threat it poses to older people. The first study confirms that RSV is a significant health burden in older populations and the second concludes that the threat is akin to that of influenza.
Miloje Savic and Yolanda Penders at the pharmaceutical company GSK’s campus in Wavre, Belgium, led a review of previous estimates of RSV infections and hospitalization rates — they also looked at the case-fatality rate among those who were hospitalized. The researchers focused on people over the age of 60 in high-income countries because data were limited elsewhere in the world.
On average, 1.6% of people over 60 years old are infected with RSV annually, and 15 in every 10,000 people in this age group are hospitalized. Of those hospitalized, around 7% die. The epidemiologists estimated that in 2019, this corresponded to 5.2 million infections, almost 470,000 hospital admissions and 33,000 in-hospital deaths. Meanwhile, Stefania Maggi at Italy’s National Research Council in Padova and her collaborators from across Europe, compared studies that recorded hospitalization and mortality rates due to RSV or influenza infections (again, mostly in high-income countries).
This revealed that RSV and flu account for comparable numbers of hospitalizations and deaths.
Both groups lamented the lack of routine RSV testing in adults and called for better RSV monitoring — especially in low- and middle-income countries where more than 80% of the global population live. Both groups stressed that their findings support the use of preventative measures to protect older people.
Waste not, want not
For RSV interventions to be most effective, public-health specialists need surveillance data on how much of the virus is circulating, and where. But RSV testing is rarely carried out on a routine basis. And even in hospital settings, today’s outbreak monitoring remains coarse.
Researchers in the United States provided evidence that wastewater epidemiology might offer a solution.
Drawing on previous studies that indicate that RSV can be shed in the stool of infected individuals, the team developed an assay to quantify viral RNA levels in sewage. Throughout 2021, they collected samples of solid waste from two publicly owned treatment works in the San Francisco Bay Area and measured the amount of viral RNA present. They then plotted these numbers against the best available surveillance data, which were sourced from a state governmental laboratory that records the percentage of clinical samples that test positive for RSV. At both sewage-treatment sites, there was a striking correlation between wastewater RSV content and the confirmed clinical infection rate. Notably, in 2021 RSV cases began to increase in June rather than in October as they normally do, and the wastewater data tracked this.
A main advantage of wastewater testing is that it can indicate community infection rates without requiring active participation from individuals. Such methods are already used to monitor gastrologically associated viruses, such as norovirus, and analogous efforts to track the coronavirus SARS-CoV-2 have quickly matured. This study suggests that wastewater surveillance could provide real-time data about RSV outbreaks to guide public-health responses.
The threat of zoonotic reservoirs
The 2020 discovery that pangolins hosted coronaviruses that were genetically similar to those that cause COVID-19 made global headlines and remains a contentious issue in establishing the origins of the pandemic. Fresh research shows that these animals can also be infected with RSV.
Scientists in China examined frozen tissue from 30 pangolins that were seized by customs officers in Guangxi, China, between August 2017 and July 2018. The animals had fallen sick and died while being smuggled from southeast Asia into China. The researchers isolated full-length or near full-length RSV genomes from 12 pangolins (from which, 4 had also carried the coronaviruses). There were three distinct sub-strains of RSV. Each genome was more than 99% identical to an RSV previously identified in human infections.
The authors speculate that the animals were probably infected by their human handlers, with potential pangolin-to-pangolin transmission following. The fact that 12 of the 30 pangolins were infected, the researchers say, might be due to an artificially inflated infection rate because the samples came from a group of sick animals. Whether the pangolins died of RSV or were culled because they were ill is unknown.
The fact that pangolins can host RSV underscores public-health concerns about viral transmission between people and animals, and suggests that further monitoring and analysis of RSV in non-human species is warranted.
Nose organoids, from swab to dish
Researchers at Baylor College of Medicine in Houston, Texas, have developed a human-nose organoid that they say can be used to research respiratory viruses and to aid the development of therapies.
Organoids are 3D cell cultures grown from stem cells, which divide and differentiate into a mixture of cell types that self-organize to capture, to some degree, the structure and function of in vivo organs. When such models are made from human cells, they can provide pre-clinical models that do not use animal tissues.
Previous efforts to make nasal organoids required taking biopsies from people to harvest stem cells. However, this work, by microbiologist Anubama Rajan and her colleagues, showed that the stem cells needed for creating organoids can be gathered through non-invasive methods such as a nasal wash or swab.
The harvested cells were grown in such a way that they formed layered structures. The underside of the organoids were bathed in a liquid culture medium and the upper surfaces were exposed to the air — just as in the nose. The organoids contained multiple cells that are characteristic of human airways, including mucus-producing cells and ciliated cells, in which hair-like protrusions moved just as they would naturally.
When infected with RSV or SARS-CoV-2, the organoids showed hallmark features of respiratory infections, including viral shedding, ciliary damage, innate immune responses and increased mucus secretion. RSV and SARS-CoV-2 infections of the organoids differed in important ways — for instance, RSV caused abundant secretion of mucus and of an important immune signalling molecule, whereas SARS-CoV-2 caused neither. These effects reflect what happens in natural infections. The authors also showed that a monoclonal antibody used to protect people against RSV also halted RSV infections in the organoids.
The combination of these characteristics suggests that the researchers have created an organoid that accurately reflects the complexity of human nasal tissue. The researchers say this model could be optimized to offer a tool for studying RSV biology.