Human rhinovirus infection and susceptibility to SARS-CoV-2 infection and symptomatic disease

ABSTRACT Children tend to experience more frequent asymptomatic infections and milder illnesses associated with SARS-CoV-2 infections than adults, but the reasons for these age-associated differences are unclear. While typical patterns of respiratory syncytial virus, influenza, and other viruses were markedly disrupted during the early pandemic, human rhinoviruses (HRVs) remained prevalent. Unlike other respiratory viruses, HRVs, consisting of species A, B, and C, are detected frequently year-round, and HRV infection is often asymptomatic, especially in children, who frequently undergo frequent re-infections with new HRV strains. The immunological consequences of these frequent HRV reinfections are unclear. Studies have suggested a role for HRV infection in rendering individuals less susceptible to infection with heterologous respiratory viruses, including SARS-CoV-2, with recent studies reporting that infection with HRV may trigger interferon responses that block SARS-CoV-2 replication and reduce SARS-CoV-2 transmission. While insightful, many prior observations of HRV interference with SARS-CoV-2 or other viruses are derived from ecological studies or animal models of infection, in which the experimental conditions are closely controlled. Observations from individuals in real-world conditions with detailed information on the sequence of infections, specimen collection prior to development of symptoms, and clinical features of illness are scarce. We aim to overcome these limitations by leveraging an intensive case-based longitudinal SARS-CoV-2 household surveillance platform, with daily nasal sampling and symptom assessment for 14 days following a positive test of the index SARS-CoV-2 case, to test the innovative hypothesis that interactions between HRV and SARS-CoV-2 may reduce the risk of symptomatic SARS-CoV-2 infection, reduce clinical symptoms among symptomatic infected individuals, and reduce transmission of SARS-CoV-2 in humans. We further hypothesize that these interactions may be HRV species-specific. We propose to build upon supportive experimental and in vitro studies to evaluate the clinical relevance of HRV and SARS-CoV-2 interactions in real-world settings by studying two Specific Aims: 1) To test the hypothesis that prevalent HRV infections reduce susceptibility to SARS-CoV-2 infection among exposed household members, and 2) To test the hypothesis that prevalent HRV infection reduces the risk of symptomatic infection or reduces symptom intensity upon SARS-CoV-2 infection. By assessing the impact of HRV co-infection on the individual variability observed in SARS-CoV-2 susceptibility to infection and disease severity, findings from the proposed study may yield new insights into ARI pathogenesis and development of enhanced prevention strategies.