Comorbid illnesses are associated with altered adaptive immune responses to SARS-CoV-2

Krystle K Q Yu ,Chetan Seshadri,Deniz Cizmeci,Caroline Atyeo,Malisa T Smith,Melissa S Aguilar,Kiel Shuey,Galit Alter,Carolin Loos,Stephanie Fischinger,Jingyou Yu,Nicholas Franko,Dan H Barouch,Jennifer K Logue,Anna Wald,David M Koelle,Erik D Layton,Robert Y Choi,Helen Y Chu,Caitlin R Wolf ,Douglas A Lauffenburger

doi:10.1172/jci.insight.146242

Abstract

Comorbid medical illnesses, such as obesity and diabetes, are associated with more severe COVID-19, hospitalization, and death. However, the role of the immune system in mediating these clinical outcomes has not been determined. We used multiparameter flow cytometry and systems serology to comprehensively profile the functions of T cells and antibodies targeting spike, nucleocapsid, and envelope proteins in a convalescent cohort of COVID-19 subjects who were either hospitalized (n = 20) or not hospitalized (n = 40). To avoid confounding, subjects were matched by age, sex, ethnicity, and date of symptom onset. Surprisingly, we found that the magnitude and functional breadth of virus-specific CD4+ T cell and antibody responses were consistently higher among hospitalized subjects, particularly those with medical comorbidities. However, an integrated analysis identified more coordination between polyfunctional CD4+ T cells and antibodies targeting the S1 domain of spike among subjects who were not hospitalized. These data reveal a functionally diverse and coordinated response between T cells and antibodies targeting SARS-CoV-2, which is reduced in the presence of comorbid illnesses that are known risk factors for severe COVID-19.

Highlights

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causes Coronavirus Disease 2019 (COVID-19), which is responsible for over 2 million deaths since its discovery in 2019 [1, 2]
This resulted in a final set of COVID-19 subjects who were either hospitalized (n = 20) or not hospitalized (n = 40) and from whom plasma and peripheral blood mononuclear cells (PBMCs) were collected at a median of approximately 50 days after symptom onset (Table 1)
We consistently found the magnitude and functional breadth of measured responses to be higher among hospitalized subjects and in the presence of medical comorbidities

Summary

Introduction

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causes Coronavirus Disease 2019 (COVID-19), which is responsible for over 2 million deaths since its discovery in 2019 [1, 2]. The clinical course of COVID-19 is variable and ranges from asymptomatic or mild disease to acute respiratory distress syndrome (ARDS) and death [3]. Epidemiologic studies have revealed several factors, such as advanced age, male sex, and nonwhite ethnicity [4,5,6], that are associated with adverse clinical outcomes, including hospitalization. Several studies have investigated whether virus-specific T cell and antibody responses are associated with disease severity [24,25,26]. These studies have not comprehensively examined the functions of antigen-specific T cells and have not been designed to robustly examine associations with clinical risk factors. Some studies reported differences between acutely ill patients, healthy controls, and recovered donors, but the healthy controls were significantly younger and recovered donors had blood drawn much later in their illness course [19, 25]

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Results

Conclusion