SARS-CoV-2 infection of non-human primates

National Institute Of Allergy And Infectious Diseases

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Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has a spectrum of clinical outcomes, ranging from asymptomatic to fatal. There is a need to parse out the role of individual immune cell types and molecular pathways that contribute to effective control of viral infection in asymptomatic/mild disease and those leading to organ failure during severe coronavirus disease 2019 (COVID-19). Increased proinflammatory cytokines, deficient type I interferon (IFN) responses, and activation of inflammasomes, neutrophils, and monocytes/macrophages have all been associated with severe COVID-19. Coordinated activation of CD8+ and CD4+ T cells, T cell activation state, and antigen (Ag) specificity have all been linked to favorable outcomes of SARS-CoV-2 infection. Whereas neutralizing antibodies are clearly protective in immune hosts, T cell responses may also contribute to the protection provided by vaccination and natural infection. Most studies of immune correlates of COVID-19 disease severity in humans have focused on sampling of peripheral blood. Nevertheless, some studies have observed infiltration of immune cells into the bronchoalveolar lavage (BAL) fluid, into postmortem lung tissue acquired from fatal COVID-19 cases, or from individuals undergoing medically necessary procedures. On autopsy, several reports have observed an unexpected lack of immune cells infiltrating into extrapulmonary tissues despite the presence of high levels of virus. These data highlight the importance of understanding the early host response in pulmonary and extrapulmonary tissues in the first few days after SARS-CoV-2 infection. Animal models can be used to obtain a detailed understanding of the host response in infected tissues. Studies in SARS-CoV-2susceptible species provide insights into COVID-19 disease pathogenesis. For example, transgenic mouse strains expressing human angiotensin converting enzyme 2 (ACE2) (K18-hACE2), and mice induced to express hACE2 with viral vectors, are highly susceptible to SARS-CoV-2 infection. Syrian hamsters and ferrets are also moderately susceptible and shed infectious virus. On the other hand, species more resistant to SARS-CoV-2 induced disease are useful tools in examining mechanisms of efficient control of viral replication. Several nonhuman primate (NHP) species can be experimentally infected with SARS-CoV-2. Rhesus macaques, cynomolgus macaques, and African green monkeys typically develop mild symptoms after SARS-CoV-2 infection. SARS-CoV-2immune and SARS-CoV-2vaccinated rhesus macaques are protected from reinfection primarily by neutralizing antibodies and, to a lesser extent, anamnestic T cell responses. Thus, current NHP models are suitable for the study of protective host immune responses associated with mild SARS-CoV-2 infection, but not the mechanisms of pathogenesis during severe disease. In this reporting period, we used the rhesus macaque model of mild COVID-19 to examine the (i) kinetics of lung inflammation using 18F-fluorodeoxyglucose (18FDG) positron emission tomography/computed tomography (PET/CT) imaging, (ii) innate immune responses using single-cell RNA sequencing (scRNAseq), and (iii) the tissue distribution of SARS-CoV-2specific T cell responses by flow cytometry. Our findings suggest that mild SARS-CoV-2 disease and efficient control of the infection are temporally correlated with activation of myeloid cells by type I IFN before the induction of Ag-specific T and B cell responses. Moreover, they reveal a strong propensity for Ag-specific T cell migration into the pulmonary compartment compared with other mucosal sites of infection.