Delayed engagement of host defenses enables SARS-CoV-2 viremia and productive infection of distal organs

ABSTRACT: Clinical presentations that develop in response to infection are the culmination of interactions that occur between the pathogen and the ensuing defenses of the host. SARS-CoV-2, the aetiologic agent of COVID-19, directly antagonizes these defenses, resulting in a delay of immune engagement in the lungs that materializes only as cells succumb to infection and are phagocytosed. Leveraging the golden hamster model of COVID-19, we sought to understand the dynamics between SARS-CoV2 infection in the airways and the systemic host response that ensues. We find that early SARS-CoV-2 replication is largely confined to the respiratory tract and olfaction system, and, to a lesser extent, the heart and GI tract­­­, but generates a host antiviral response that can be observed in every organ as a result of circulating type I and III interferons (IFN-I/-III). Moreover, we show that diminishing the response in the airways by immunosuppression or administration of SARS-CoV-2 intravenously, results in a loss of immune priming, viremia, and an increase in viral tropism, including productive infection of the liver, kidney, spleen, and brain. Finally, we show that productive infection of the airways is required for mounting an effective and system-wide antiviral response. Together, these data illustrate how COVID-19 can result in diverse clinical presentations where disease outcomes can be a byproduct of the speed and strength of immune engagement. These studies provide additional evidence to the mechanistic insights of the diverse clinical presentations of COVID-19 and highlight the unique ability of the respiratory tract to generate a systemic immune defense following pathogen recognition.

ORGANISM(S): Mesocricetus auratus

PROVIDER: GSE232204 | GEO | 2026/07/31

REPOSITORIES: GEO