Priming With Rhinovirus Protects Mice Against a Lethal Pulmonary Coronavirus Infection

Abstract

Rhinoviruses (RV) have been shown to inhibit subsequent infection by heterologous respiratory viruses, including influenza viruses and severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). To better understand the mechanisms whereby RV protects against pulmonary coronavirus infection, we used a native murine virus, mouse hepatitis virus strain 1 (MHV-1), that causes severe disease in the lungs of infected mice. We found that priming of the respiratory tract with RV completely prevented mortality and reduced morbidity of a lethal MHV-1 infection. Replication of MHV-1 was reduced in RV-primed mouse lungs although expression of antiviral type I interferon, IFN-β, was more robust in mice infected with MHV-1 alone. We further showed that signaling through the type I interferon receptor was required for survival of mice given a non-lethal dose of MHV-1. RV-primed mice had reduced pulmonary inflammation and hemorrhage and influx of leukocytes, especially neutrophils, in the airways upon MHV-1 infection. Although MHV-1 replication was reduced in RV-primed mice, RV did not inhibit MHV-1 replication in coinfected lung epithelial cells in vitro. In summary, RV-mediated priming in the respiratory tract reduces viral replication, inflammation, and tissue damage, and prevents mortality of a pulmonary coronavirus infection in mice. These results contribute to our understanding of how distinct respiratory viruses interact with the host to affect disease pathogenesis, which is a critical step in understanding how respiratory viral coinfections impact human health.

Influenza A and Respiratory Syncytial Virus Trigger a Cellular Response That Blocks Severe Acute Respiratory Syndrome Virus 2 Infection in the Respiratory Tract

“…Such challenges also apply to in vivo studies using animal models. For example, a mouse model study showed that coinfection with IAV and HRV caused milder influenza but did not reduce IAV shedding [8], whereas coinfection with IAV and mouse hepatitis virus strain 1, a murine coronavirus, attenuated disease presentation and reduced IAV replication [7,8], and this was associated with IFN upregulation. In contrast, other studies that investigated in vivo coinfections of IAV and SARS-CoV-2 showed that disease severity was increased in coinfections [34][35][36] and SARS-CoV-2 replication was reduced [34,37].…”

“…Clinical and experimental studies using air-liquid interface (ALI) cultures of respiratory epithelium support this hypothesis as they showed that some viruses trigger an interferon (IFN)-mediated response that can block a secondary viral infection [2][3][4]. Experimental coinfections using animal models supported the occurrence of virus-virus interactions in vivo [5][6][7][8].…”

Dermatologic Changes in Experimental Model of Long COVID

“…Investigations have delved into a clinical syndrome exhibiting similarities to severe acute respiratory syndrome (SARS) in mice infected with murine hepatitis virus-1 (MHV-1). This syndrome is distinguished by a markedly high mortality rate [ 8 , 9 , 10 , 11 , 12 , 13 ]. These mice exhibit pronounced lung injury with mortality rates ranging from 40% to 60% between days 7 and 12 post-infection [ 14 ].…”

Counterintuitive effect of antiviral therapy on influenza A-SARS-CoV-2 coinfection due to viral interference

“…One demonstrated mechanism of interference among respiratory viruses is induction of the interferon response, a broad antiviral defense mechanism that is induced by most respiratory viruses, and also suppresses replication of most viruses[5-8]. Within the airway epithelium, the replicating viral genome is the initiating trigger of the interferon response[9].…”