Virulence and pathogenesis of SARS-CoV-2 infection in rhesus macaques: A nonhuman primate model of COVID-19 progression

Author summary Understanding of the pathologic process caused by SARS-CoV-2 is critical for promoting vaccine evaluations and medical treatment. Prior to the development of this model, several animal models of SARS-CoV-2 infection focused on revealing the virus shedding period, the development of interstitial pneumonia, and virus dissemination in respiratory tract. However, data describing the kinetics of the T cell response and local immune response during SARS-CoV-2 infection are lacking. Here, in our rhesus macaque model, in addition to focusing on virus shedding and interstitial pneumonia similar with human cases, we observed the response of T cell subsets and local cytokine/chemokine changes in respiratory tract regarded as the important evaluation parameters for a successful animal model of COVID-19. The COVID-19 has emerged as an epidemic, causing severe pneumonia with a high infection rate globally. To better understand the pathogenesis caused by SARS-CoV-2, we developed a rhesus macaque model to mimic natural infection via the nasal route, resulting in the SARS-CoV-2 virus shedding in the nose and stool up to 27 days. Importantly, we observed the pathological progression of marked interstitial pneumonia in the infected animals on 5-7 dpi, with virus dissemination widely occurring in the lower respiratory tract and lymph nodes, and viral RNA was consistently detected from 5 to 21 dpi. During the infection period, the kinetics response of T cells was revealed to contribute to COVID-19 progression. Our findings implied that the antiviral response of T cells was suppressed after 3 days post infection, which might be related to increases in the Treg cell population in PBMCs. Moreover, two waves of the enhanced production of cytokines (TGF-alpha, IL-4, IL-6, GM-CSF, IL-10, IL-15, IL-1 beta), chemokines (MCP-1/CCL2, IL-8/CXCL8, and MIP-1 beta/CCL4) were detected in lung tissue. Our data collected from this model suggested that T cell response and cytokine/chemokine changes in lung should be considered as evaluation parameters for COVID-19 treatment and vaccine development, besides of observation of virus shedding and pathological analysis.