The Role of Group 3 Innate Lymphoid cells (ILC3) in Tuberculosis

Over the past three months, COVID-19 has emerged as a major pandemic with over ~ 1.9 million productiveinfections and ~100,000 deaths due to infection with the novel Coronavirus SARS-CoV-2, a viral pathogenwhich is highly infectious and pathogenic. This is particularly true in the elderly and people withimmunocompromising conditions who are exhibiting acute respiratory distress syndrome at a greaterfrequency. Unfortunately, no known cures and vaccines exist. Worse, there were no well-characterized animalmodels of SARS-CoV-2 infection and COVID-19 disease till recently. With the limited information on hostinnate immune responses, early reports implicate a role for inflammation in mediating COVID-19 disease. Asan logical extension of ongoing work on innate immune responses in the lung on the parent grant, wehypothesize that similar to tuberculosis (TB), control of SARS-CoV2 will correlate with accumulation of innatelymphoid cells including NK cells in the lung, while inflammation and increased disease will be associated withmyeloid cell accumulation. To test this hypothesis, we will utilize recently acquired banked lung samples from anovel rhesus macaque model of SARS-CoV-2 infection/COVID-19 disease developed at the SouthWestNational Primate Research Center (in collaboration with Deepak Kaushal Lab, Co-I on parent grant). Thesenew results from the NHP model indicate that rhesus macaques develop signs of human COVID-19 diseaseincluding pyrexia, dysregulation of complete blood cell counts indicative of viral infection, acute stress markers,and experience cough and weight-loss. This is accompanied by high viral loads in bronchoalveolar lavage(BAL) and lungs, and pneumonia is detected by CT scan as well as grossly at necropsy. Single cell RNAsequencing (scRNA-seq) is just beginning to be applied to the immune system in animal models and humansin both healthy and diseased states. The application of scRNA-seq to COVID-19 samples from macaques isparticularly well-suited, as the immune cells infiltrating the lung that may play roles in the disease are diverse,including virtually all types of lymphocytes (ILCs, CD4+ T cells, CD8+ T cells, γδ T cells, NK cells, B cells) andseveral myeloid cell types (monocytes, macrophages and potentially dendritic cells (DCs) and neutrophils(PMNs)). Within each of these subtypes, further heterogeneity exists in terms of cytokine production andtranscription factor expression, such that each subtype may demonstrate further heterogeneity. BecausescRNA-seq can define the transcriptomic heterogeneity of a complex community of cells and assign unbiasedidentity classifications to cell populations, it is optimally suited for application to the study of complexinflammatory disease such as TB and COVID-19. The data obtained and its computational analysis willdelineate the nature of inflammation, especially the role of innate cells such as NK cells and ILCs in COVID-19mediated inflammation. These studies will create new opportunities for identifying therapeutic targets forcontrol of pan-epidemics such as TB and COVID-19.