Human Rhinovirus Infection Blocks Severe Acute Respiratory Syndrome Coronavirus 2 Replication Within the Respiratory Epithelium: Implications for COVID-19 Epidemiology

Abstract

Virus-virus interactions influence the epidemiology of respiratory infections. However, the impact of viruses causing upper respiratory infections on severe acute respiratory syndrome coronavirus 2 (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 cocirculating 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 coronavirus disease 2019 cases.

Keywords: SARS-CoV-2; rhinovirus; virus-virus interactions.

Figure 1.

Replication kinetics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and human rhinovirus (HRV) in air-liquid interface cultures of human bronchial epithelial cells. A, SARS-CoV-2 titers in single SARS-CoV-2 infections (solid red line) and simultaneous SARS-CoV-2/HRV coinfections (dashed red line). B, HRV titers in single HRV infections (solid cyan line) and simultaneous SARS-CoV-2/HRV coinfections (dashed cyan line). C, D, SARS-CoV-2 (red) and HRV (cyan) titers in single infections (solid lines) and staggered SARS-CoV-2/HRV coinfections (dashed lines). The order of infections is described below each graph. SARS-CoV-2 is shown in red, and HRV in cyan. Abbreviation: TCID₅₀, 50% tissue culture infectious dose.

Figure 2.

Myxovirus resistance protein A (MxA) expression in air-liquid interface (ALI) cultures of human bronchial epithelial cells, shown in representative images obtained with fluorescence microscopy at various times after infection. ALI cultures were mock-infected, infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) only or human rhinovirus (HRV) only, or coinfected with SARS-CoV-2 and HRV. Nuclei are colored in blue, and MxA in magenta. Scale bar represents 50 μm.

Figure 3.

Detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in air-liquid interface cultures of human bronchial epithelial cells. Representative images show SARS-CoV-2 nucleocapsid detection by immunofluorescence in cells infected with SARS-CoV-2 (A); coinfected with SARS-CoV-2 and human rhinovirus (B); or mock-infected (C). Nuclei are colored in blue, and SARS-CoV-2 nucleocapsid protein in red. Scale bar represents 50 μm.

Figure 4.

Replication kinetics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and human rhinovirus (HRV) in air-liquid interface cultures of human bronchial epithelial cells coinfected simultaneously with SARS-CoV-2 and HRV in the presence or absence of BX795. A, SARS-CoV-2 titers. B, HRV titers. SARS-CoV-2 is shown in red, and HRV in cyan. Solid and dotted lines show infections in the presence or absence of BX795, respectively. Abbreviations: DMSO, dimethyl sulfoxide; TCID₅₀, 50% tissue culture infectious dose.

Figure 5.

Reduction in coronavirus disease 2019 growth rate for varying prevalence of human rhinovirus (HRV) infections in a given population and different assumptions for the duration of the refractory period. The growth rate in the absence of rhinovirus is assumed to be a 5% increase per day. Colors show reductions in growth rate expressed as percentages.