University Of Glasgow Discovers New Pathogen That Can Evade Immune System

0
43

Researchers from MRC-University of Glasgow Centre for Virus Research, School of Infection and Immunity – United Kingdom have identified a new pathogen that can evade the human host immune system,

The new pathogen is hybrid virus comprising of fused viral particles from the RSV (respiratory syncytial virus) and the IAV (influenza A virus) viruses.

The study findings were published in the peer reviewed journal: Nature Microbiology. 

https://www.nature.com/articles/s41564-022-01242-5

Respiratory viruses share a common tropism for the human respiratory tract and cause significant disease burden. Although there is increasing evidence that interactions among viruses play an important role in virus dynamics and transmission, most of what is known about virus biology and pathogenesis is based on a tractable but reductionist research approach, whereby each virus is studied in isolation.

Recent work provided evidence that interactions among respiratory viruses occur and have measurable outcomes at multiple levels, from populations, to individuals and tissues 24,25,26,27,28. However, studies characterizing direct virus–virus interactions within cells are scarce.

Here we report previously unknown interactions between IAV and RSV, two clinically important respiratory viruses that belong to different taxonomical families.

We show that in coinfections, IAV replicates to equivalent or marginally higher titres compared to single IAV infections, whereas RSV replication is reduced. The consistency in IAV replication kinetics in the presence or absence of RSV contrasts with the inhibition of IAV replication in coinfections with rhinovirus 26. This indicates that the consequences of coinfections are highly dependent on the viruses involved as they trigger virus-specific cellular responses.

We also show compelling evidence that coinfections can generate infectious HVPs composed of structural, genomic and functional components of both parental viruses. As HVPs can evade IAV-targeted neutralization and infect cells lacking IAV receptors suggests that coinfections can generate viruses with altered antigenicity and expanded tropism.

Using palivizumab, we showed that RSV F mediates HVP entry, indicating that in the context of a hybrid particle, IAV can use the glycoprotein of an unrelated virus as its functional envelope protein. This property may facilitate within-host dissemination to areas of the respiratory tract that are refractory to infection by one of the parental viruses, which is likely to impact pathogenesis and disease outcome.

For example, IAV predominantly infects the upper and middle respiratory tract causing uncomplicated influenza, while RSV spreads more readily to the middle and lower respiratory tract (LRT)29,30. HVPs could enable IAV to escape mucosal antibodies while spreading to the LRT, with subsequent potential complications, including viral pneumonia 30.

In addition, as IAVs exhibit high mutation rates, LRT infections by HVPs might favour the selection of IAVs with increased tropism for the LRT and, therefore, result in selection of more pathogenic viruses.

In recent years, a conceptual framework that incorporates social evolution theory has been developed to explain how virus–virus interactions can have a substantial effect on virus function and fitness 31. We show that HVP formation is maintained over multiple rounds of infection, and that HVPs facilitate the spread of IAV within a population of refractory cells.

This observation aligns with the concept that, like other pathogens and organisms, viruses can engage in social-like traits that are beneficial to virus fitness and function.

Using a lung-derived human cell line, we show that the generation of HVPs by coinfection is biologically feasible. The fact that IAV and RSV cocirculate in winter in the same populations1, have a shared tropism for ciliated epithelial cells 32,33, bud from the apical cellular surface 22,33,34 and coinfect cells within the respiratory epithelium (this work) suggest that HVPs have the potential to be generated in vivo.

The likelihood of a cell becoming coinfected during natural infection remains unknown but will vary depending on the timing of infection and the localization of infectious foci within the respiratory tract. Estimates of viral bursts show that as viral load increases, the effective MOI to susceptible cells surrounding an infectious focus increases 35, enhancing the probability of cellular coinfection and therefore the potential generation of HVPs.

The formation of HVPs raises questions about fundamental rules that govern viral assembly and budding. These processes, which are thought to be highly regulated, involve selective recruitment, trafficking 36,37 and multimerization of viral proteins 19,38,39,40 within specific compartments of the cell.

While we described the formation of HVPs as a consequence of coinfection by IAV and RSV, we hypothesize that coinfections involving other pleomorphic enveloped viruses are also likely to generate HVPs. However, we posit that formation of infectious HVPs requires more than structural compatibility, and includes similar tropism, absence of superinfection exclusion or interference, as well as seasonal and geographical co-circulation.

RSV is a pleomorphic enveloped virus with a broad tropism for different regions of the respiratory tract and is frequently observed in co-infections in winter 41,42,43, therefore RSV is a good candidate to form HVPs with other respiratory viruses. This might explain some of the mechanisms that lead to viral pneumonia 44.

One limitation of this study is that experiments were carried out in cell culture systems. While primary differentiated human airway cells provide the closest human-derived model of the upper respiratory tract available, they cannot fully capture the spatial and physiological complexity of the whole respiratory tract.

Therefore, further in vivo studies are required to determine the frequency of coinfection within respiratory tissues and the potential for HVP formation. Additionally, further studies will be required to address which virus combinations can generate infectious HVPs; which viral properties favour their formation; and how they impact on pathogenesis and virus transmission.

LEAVE A REPLY

Please enter your comment!
Please enter your name here

Questo sito usa Akismet per ridurre lo spam. Scopri come i tuoi dati vengono elaborati.