immune regulation by helminths and the microbiota with SARS-Cov2 infection

National Institute Of Allergy And Infectious Diseases

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Abstract

It is unclear why some individuals infected with Covid-19 are asymptomatic while others develop severe hyper-inflammation, severe acute respiratory distress syndrome (ARDS) and multi-organ failure that can be fatal. Additionally, there is considerable variation in the pathogenesis and severity of Covid-19 globally. The effect of parasitic helminths on the disease pathogenesis and immune response following exposure to SARS-CoV-2 (as well as SARS-CoV-2 vaccines) is unknown. We initiated a cross-sectional household study in Chennai, India, to study the immunological effects of helminth coinfection and the microbiota on CoV2 seropositive individuals. Since this study began as the study population started to get vaccinated, we could also investigate the effects of helminth infection on vaccination. We have enrolled approximately 200 households and 600 study participants. Epidemiological data indicates that after correcting for other factors, helminth infection status did not have a significant effect on SARS-CoV2 infection sero-prevalence status. In addition to these human epidemiological studies, we performed murine studies to assess the effect of helminth infection on COVID disease outcome and pathogenesis. We observed that K18 ACE2 transgenic mice previously infected with the rodent helminth, N. brasiliensis, had better survival outcomes with lower viral titres. 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.