Animal models for investigating coronavirus heterotypic immunity
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Citation
Abstract
Endemic coronaviruses (CoVs) such as OC43 circulate seasonally and, while usually mild, represent the 6th leading cause of viral pneumonia. Additionally, multiple zoonotic spillovers of CoVs have occurred in the last 25 years to cause severe pneumonia, most recently the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome (SARS)-CoV-2. Coronaviruses therefore continue to pose significant public health burdens, and although significant advances have been made in understanding SARS-CoV-2, the immune response to endemic CoVs remains poorly understood. While most studies of immune memory are focused on defense against a subsequent infection with the same pathogen, this memory can cross-react with related pathogens in a phenomenon termed heterotypic immunity. Studies with other respiratory pathogens have implicated memory lymphocytes that establish long-term residency in the lung as critical in heterotypic immunity. Accumulating observational evidence from human studies suggests that remodeling of the immune landscape induced by prior endemic CoV infection influences outcomes of subsequent SARS-CoV-2 infection. Prior to 2020 no animal models existed for any of the four endemic CoVs, so the degree to which endemic CoVs produce lung-resident memory and the potential contributions of this to heterotypic immunity is unknown. In these studies, we utilized both rodents and non-human primates to model sequential infection of OC43 followed by SARS-CoV-2. In the mouse we focus on developing an OC43 model and how OC43 remodels the lung-resident environment, while in the macaque we focus on systemic and local inflammation generated during the subsequent SARS-CoV-2 infection.
In the mouse, OC43 was rapidly cleared but produced significant weight loss, leukocyte influx, and a robust type I interferon (IFN)-dependent production of IFN-γ. After two OC43 infections, lungs contained antigen-specific resident memory T and B lymphocytes and specific IgG and IgA. The addition of the immunostimulatory molecule cyclic-di-GMP (CDG) significantly increased generation of resident memory in lymphoid aggregates around lung vasculature and promoted Th1/Th17 polarization. The T cells and antibodies, with or without CDG, were specific to OC43 and did not cross-react with structural proteins of SARS-CoV-2.
In the macaque, OC43 infection produced no clinical signs of disease and was cleared by 3 days post-infection. Despite this asymptomatic (or at most mild) infection, prior OC43 decreased SARS-CoV-2 viral load and was sufficient to abrogate the serum inflammatory cytokine signature (IFN-β, IL-6, IL-8, IL-17, GM-CSF, and CCL2) that was observed in both naïve macaques. OC43-experienced macaques also had evidence of quicker pulmonary inflammation, more lung T cells, and decreased germinal center activity in draining lymph nodes compared to naïve counterparts after SARS-CoV-2.
Together, these studies demonstrate that OC43 infection remodels the lung immune landscape, including generation of lung-resident memory lymphocytes, and this can be boosted by immunostimulants. In the Balb/c inbred mouse line, the T cells and antibodies generated do not cross-react with SARS-CoV-2 structural proteins and experienced mice are not protected from SARS-CoV-2. In contrast, naïve macaques have greater markers of systemic and local inflammation after a mild SARS-CoV-2 compared to experienced macaques. The contrasting results underscore the need for human-like models to accomplish relevant host-pathogen interactions in the study of heterotypic adaptive immunity. These studies contribute to our understanding of CoV immune responses by establishing a mouse model of OC43 homotypic immunity and a primate model of CoV heterotypic immunity for future mechanistic investigations.
Description
2025