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.

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The pandemic spread of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the etiological agent of Coronavirus Disease 2019 (COVID-19), represents an ongoing international health crisis. A key symptom of SARS-CoV-2 infection is the onset of fever, with a hyperthermic temperature range of 38 to 41°C. Fever is an evolutionarily conserved host response to microbial infection that can influence the outcome of viral pathogenicity and regulation of host innate and adaptive immune responses. However, it remains to be determined what effect elevated temperature has on SARS-CoV-2 replication. Utilizing a three-dimensional (3D) air–liquid interface (ALI) model that closely mimics the natural tissue physiology of SARS-CoV-2 infection in the respiratory airway, we identify tissue temperature to play an important role in the regulation of SARS-CoV-2 infection. Respiratory tissue incubated at 40°C remained permissive to SARS-CoV-2 entry but refractory to viral transcription, leading to significantly reduced levels of viral RNA replication and apical shedding of infectious virus. We identify tissue temperature to play an important role in the differential regulation of epithelial host responses to SARS-CoV-2 infection that impact upon multiple pathways, including intracellular immune regulation, without disruption to general transcription or epithelium integrity. We present the first evidence that febrile temperatures associated with COVID-19 inhibit SARS-CoV-2 replication in respiratory epithelia. Our data identify an important role for tissue temperature in the epithelial restriction of SARS-CoV-2 independently of canonical interferon (IFN)-mediated antiviral immune defenses.

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.