Identification of lung resident innate lymphocytes that specifically protect neonates from SARS-CoV-2 infections

Summary Immunological regulation of mucosal barrier development and maintenance is a critical process for infant health, as imbalances in immune sentinel activity can lead to lung, skin and gut inflammatory diseases. Central to the mucosal tissue homeostasis are Type 3 cytokine producing lymphocytes (T3L). In mice, fetal-origin γδTCR+ T3L called Tγδ17 cells dominantly regulate skin homeostasis and mediate protective immunity to influenza infections soon after birth. Tγδ17 cells are classified as innate lymphocytes as their effector function is programmed in the thymus before they migrate to populate the lung and skin. There, Tγδ17 cells respond rapidly to environmental cues to fortify the tissue barriers and coordinate pathogen clearance. Tγδ17 cells are representative of the class of innate T3L (iT3L) that include multiple cell types, whose major distinctions are how they recognize environmental cues and at what age of tissues they functionally dominate. SARS-CoV-2 infections are particularly dangerous for the elderly, while children are resistant to severe COVID-19. This exploratory proposal will test the hypothesis that neonatal lung Tγδ17 cells, or other iT3L, confer protection against SARS-CoV-2. Rationale for the hypothesis is built on four foundational observations: 1. SARS-CoV-2 infected children generate T3 responses while the aged only show muted responses, if at all; 2. Murine lung Tγδ17 cells protect against sepsis, a disease with similarity to severe COVID-19; 3. Neonatal Tγδ17 cells protect lung tissues against Influenza in mice; and 4. Attrition of Tγδ17 cells occurs with aging. It follows that the severe COVID-19 in elderly are in part caused by compromised lung iT3L protection with age. This project will establish T3L composition and activation status pre- and post- SARS-CoV-2 infection in neonates and adults, identify lung iT3L subset(s) that dominantly confer resistance to SARS-CoV-2 infections in neonates, and determine how diet and infection history impacts Tγδ17 cell-mediated lung protective responses to respiratory infections. By understanding how the young successfully respond to SARS-CoV-2 new insights into why the aged succumb to COVID-19 can be obtained. This in turn will provide leads into novel therapeutics against COVID-19.