Exposure to lung-migrating helminth protects against murine SARS-CoV-2 infection through macrophage-dependent T cell activation

Helminth endemic regions report lower COVID-19 morbidity and mortality. Here, we show that lung remodeling from a prior infection with a lung-migrating helminth, Nippostrongylus brasiliensis, enhances viral clearance and survival of human-ACE2 transgenic mice challenged with SARS-CoV-2 (SCV2). This protection is associated with a lymphocytic infiltrate, including increased accumulation of pulmonary SCV2-specific CD8+ T cells, and anti-CD8 antibody depletion abrogated the N. brasiliensis–mediated reduction in viral loads. Pulmonary macrophages with a type 2 transcriptional and epigenetic signature persist in the lungs of N. brasiliensis–exposed mice after clearance of the parasite and establish a primed environment for increased CD8+ T cell recruitment and activation. Accordingly, depletion of macrophages ablated the augmented viral clearance and accumulation of CD8+ T cells driven by prior N. brasiliensis infection. Together, these findings support the concept that lung-migrating helminths can limit disease severity during SCV2 infection through macrophage-dependent enhancement of antiviral CD8+ T cell responses. Description Prior exposure to lung-migrating helminths leads to better outcomes upon SARS-CoV-2 challenge via a macrophage-CD8+ T cell circuit. Editor’s summary Parasitic helminths generate a type 2 immune response that can persist even after clearance of the infection, but how this affects subsequent immunity against viral infections remains unclear. Using a mouse model of roundworm infection with Nippostrongylus brasiliensis, Oyesola et al. found that prior exposure to lung-migrating helminths protects transgenic K18-hACE2 mice against SARS-CoV-2 infection. Pulmonary macrophages from N. brasiliensis–infected mice adopted a type 2 transcriptional and epigenetic signature that persisted after parasite clearance and at least 45 days after infection. SARS-CoV-2–specific CD8+ T cell responses were driven by alveolar macrophages and required for helminth-mediated protection. These results demonstrate that lung-migrating helminths reprogram lung immune homeostasis, leading to enhanced protection against subsequent SARS-CoV-2 infection. —Claire Olingy