Virus-virus interactions influence the epidemiology of respiratory infections. However, the impact of viruses causing upper respiratory infections on SARS-CoV-2 replication and transmission is currently unknown. Human rhinoviruses cause the common cold and are the most prevalent respiratory viruses of humans. Interactions between rhinoviruses and co-circulating respiratory viruses have been shown to shape virus epidemiology at the individual host and population level. Here, we examined the replication kinetics of SARS-CoV-2 in the human respiratory epithelium in the presence or absence of rhinovirus. We show that human rhinovirus triggers an interferon response that blocks SARS-CoV-2 replication. Mathematical simulations show that this virus-virus interaction is likely to have a population-wide effect as an increasing prevalence of rhinovirus will reduce the number of new COVID-19 cases.

We have analyzed the ability of human gamma+/delta+ T cells to recognize a nominal antigen in association with MHC molecules. A TT-specific T cell line with approximately 40% gamma+/delta+ T cells was established from a hyperimmunized donor, D.F., by stimulation with antigen and autologous APC. Three DF-derived gamma+/delta+ clones were CD8+ as determined by immunofluorescence staining, and by Southern and Northern blotting with probes detecting delta chain rearrangement and delta and gamma chain transcripts, respectively. The gamma+/delta+ clones responded to stimulation with TT, but not TNP-BSA, and autologous APC by proliferation and IFN-gamma production. No proliferation or IFN-gamma production was detected when TT-specific T cell clones were stimulated with either TT or autologous APC only. The response to TT was enhanced by addition of exogenous IL-2. The use of allogeneic APC from 19 donors sharing one HLA-determinant with the autologous donor D.F., showed that the gamma+/delta+ T cells responded to TT with HLA-DR4-related restriction as measured by proliferation and IFN-gamma production. These results demonstrate that gamma/delta receptors can recognize non-MHC-encoded foreign antigen in a self-MHC-restricted fashion.

Identifying drivers of SARS-CoV-2 exposure and quantifying population immunity is crucial to prepare for future epidemics. We performed a serial cross-sectional serosurvey throughout the first pandemic wave among patients from the largest health board in Scotland. Screening of 7480 patient sera showed a weekly seroprevalence ranging from 0.10% to 8.23% in primary and 0.21% to 17.44% in secondary care, respectively. Neutralisation assays showed that around half of individuals who tested positive by ELISA assay, developed highly neutralising antibodies, mainly among secondary care patients. We estimated the individual probability of SARS-CoV-2 exposure and quantified associated risk factors. We show that secondary care patients, males and 45-64-year-olds exhibit a higher probability of being seropositive. The identification of risk factors and the differences in virus neutralisation activity between patient populations provided insights into the patterns of virus exposure during the first pandemic wave and shed light on what to expect in future waves.

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Human respiratory syncytial virus (RSV) causes severe respiratory illness in children and the elderly. Here, using cryogenic electron microscopy and tomography combined with computational image analysis and three-dimensional reconstruction, we show that there is extensive helical ordering of the envelope-associated proteins and glycoproteins of RSV filamentous virions. We calculated a 16 A resolution sub-tomogram average of the matrix protein (M) layer that forms an endoskeleton below the viral envelope. These data define a helical lattice of M-dimers, showing how M is oriented relative to the viral envelope. Glycoproteins that stud the viral envelope were also found to be helically ordered, a property that was coordinated by the M-layer. Furthermore, envelope glycoproteins clustered in pairs, a feature that may have implications for the conformation of fusion (F) glycoprotein epitopes that are the principal target for vaccine and monoclonal antibody development. We also report the presence, in authentic virus infections, of N-RNA rings packaged within RSV virions. These data provide molecular insight into the organisation of the virion and the mechanism of its assembly.

Background Multiple viruses cocirculate and contribute to the burden of respiratory disease. Virus-virus interactions can decrease susceptibility to infection and this interference can have an epidemiological impact. As humans are normally exposed to a community of cocirculating respiratory viruses, experimental coinfection studies are necessary to understand the disease mechanisms of multi-pathogen systems. We aimed to characterize interactions within the respiratory tract between severe acute respiratory syndrome virus 2 (SARS-CoV-2) and two major respiratory viruses: influenza A virus (IAV), and respiratory syncytial virus (RSV). Methods We performed single infections and coinfections with SARS-CoV-2 combined with IAV or RSV in cultures of human bronchial epithelial cells. We combined microscopy with quantification of viral replication in the presence or absence of an innate immune inhibitor to determine changes in virus-induced pathology, virus spread, and virus replication. Results SARS-CoV-2 replication is inhibited by both IAV and RSV. This inhibition is dependent on a functional antiviral response and the level of inhibition is proportional to the timing of secondary viral infection. Conclusions Infections by other respiratory viruses might provide transient resistance to SARS-CoV-2. It would therefore be expected that the incidence of COVID-19 may decrease during periods of high circulation of IAV and RSV. Virus-virus interactions impact the infection dynamics of respiratory viruses at multiple levels, from cells to populations. Using three-dimensional cultures of airway epithelium, we showed that SARS-CoV-2 replication is impaired in coinfections with either influenza A or respiratory syncytial virus.

Interactions between co-circulating respiratory viruses are recognized for their impact on viral transmission and clinical outcomes. However, the consequences of these virus-virus interactions at the cellular level are unclear. We coinfected human lung cells with influenza A virus (IAV) and respiratory syncytial virus (RSV). Super-resolution microscopy combined with live-cell imaging and scanning electron microscopy identified extracellular and membrane-associated filamentous structures, likely composed of elements of both IAV and RSV virions. Cryo-electron tomography confirmed the presence of chimeric virus particles exhibiting glycoproteins and ribonucleoproteins of both parental viruses. Functional assays revealed chimeric particles facilitate IAV infection in cells depleted of IAV receptors, demonstrating expanded tropism. Our observations define a previously unknown interaction that is likely to affect virus pathogenesis and have profound implications for infection biology.

Influenza A virus (IAV) and respiratory syncytial virus (RSV) are important respiratory pathogens that share common epidemiological features and cellular tropism within the respiratory tract. This gives rise to the potential for biological interactions between IAV and RSV during coinfection of hosts. Virus–virus interactions are increasingly recognised for their contribution to viral dynamics during infection, however, the molecular processes underpinning these interactions are unknown. Here, we developed an in vitro coinfection system to characterise the infection dynamics of IAV (A/Puerto Rico/8/34, H1N1) and RSV (A2) in single virus infection or coinfection in lung epithelial cells, with the aim to identify biological processes that drive virus–virus interactions during coinfection. We compared viral replication kinetics at different multiplicities of infection and observed that RSV replication was inhibited during coinfection with IAV, whilst IAV replication was facilitated by coinfection. To further characterise IAV/RSV interactions, we determined the relative proportions of single virus infected or coinfected cells during early and late timepoints post-infection and observed differences in expression of viral proteins between single and coinfected states. Additionally, cell viability was measured determine differences in viral-induced cytopathic effect. Compared with RSV infection, cell death is induced at earlier timepoints post IAV infection and coinfection, indicating that different cellular processes are initiated in response to infection. These studies highlight that both competitive and facilitative ecological interactions occur between IAV and RSV during coinfection and shed light on sources of potential interactions at the cellular and molecular level.