Immune Regulation of COVID-19 Infection in Cancer and Autoimmunity

点击翻译按钮获取中文摘要

1 Abstract 2 The negative impact of SARS-CoV-2 worldwide has been astronomical in many different ways, impacting on all 3 aspects of society. Up to date more than 13 million infections and over 600,000 deaths have already been 4 accounted for. The current lack of understanding of the modulation of the immune response by the virus is a 5 dominant factor in the absence of effective prophylactic, therapeutic approaches which can ameliorate virus 6 transmission and mortality. COVID-19 disease is greatly heterogeneous in incidence and clinical course, due in 7 part to ethnic background, age and pre-existing clinical conditions. Severe COVID19 and increased death rate 8 has been reported in cancer patients and in African-Americans (AA). One common feature among these 9 populations is the heightened basal level of inflammation that could synergize with the SARS-COV-2 driven 10 inflammation leading to poor clinical outcomes. This pro-inflammatory milieu will exacerbate the lymphopenia 11 already prevalent in COVID-19 disease and which could lead to disrupted T cell homeostasis, poor T cell help 12 and lack of survival of the memory T and B cell compartments. A central corollary of the current proposal is 13 that individuals with underlying immune dysregulation, such as in cancer, will have abnormal responses 14 to COVID-19, mediating poor short-term outcomes and impairment of long term immune memory. To 15 address this directly, we have access to well-powered cohorts of subjects, including high representation of AA, 16 with lung cancer and B cell lymphomas. Our strategy will generate precise quantification of the B cell response 17 at the functional (neutralization, effector function) and cellular level (deep phenotyping of B cell/plasmablasts, 18 diversity of BCR sequences). State-of-the-art assays including single cell RNAseq, CITEseq, ATACseq, high 19 density flow cytometry, cytokine array, circulating metabolites and microbiome will provide high dimensional 20 analysis of the inflammatory milieu in cancer subjects and its impact on innate and Tfh function as well as 21 longevity of B cell and T cell memory responses. Integration of these measures of B cell function (Aim 1) with 22 those generated from the OMICs data (Aim 2-3) will contribute to the identification of the mechanistic 23 underpinnings that enhance disease severity in the context of cancer. Specifically, we propose to: 24 1) Analyze the dynamics and durability of antigen-specific B cell responses after SARS-CoV-2 infection 25 in cancer patients compared to patients without cancer 26 2) identify the molecular and cellular mechanisms triggered by the inflammatory environment prevalent 27 in cancer patients during acute infection which impairs humoral responses during COVID-19 28 3) Identify the epigenetic and transcriptional mechanisms triggered by SARS-CoV-2 infection and/or 29 microbial translocation that will impede on the longevity of memory B and Tfh cells. 30 This collective effort aims to elucidate better paths for immune intervention and/or prevention in COVID-19. 31 32 33 Narrative 34 This proposal aims at understanding the mechanistic underpinnings of SARS-COV-2 infection in cancer patients 35 which lead to their worsened prognosis. We will dissect features of the innate and adaptive immune responses 36 using unbiased holistic approaches to define the impact of the cancer host milieu on qualitative and quantitative 37 features of the protective memory T and B cell response. Our major goal is to develop novel effective 38 interventions to treat this severely affected population. 39 40 41