Title: Investigating aberrant B cell responses in a clinically diverse cohort of COVID-19 patients
Funder: The Academy of Medical Sciences

Abstract: COVID-19 is a heterogeneous disease with a wide spectrum of symptoms, ranging from asymptomatic spread to respiratory failure and death. Patients with severe disease generate a dysfunctional immune response resulting in immune-mediated lung pathology, and systemic hyperinflammation. The cause for this aberrant immune response to SARS-CoV-2 infection in a subset of patients remains unknown. B cells play a critical role in the immune response to viral infections by producing neutralizing antibodies to virus-specific antigens, secreting cytokines and via antigen presentation. In addition, a subset of B cells exhibit immunosuppressive functions via diverse regulatory mechanisms. This subset of regulatory B cells (Bregs) prevent uncontrolled inflammation and restore immune homeostasis in healthy individuals after an infection. I hypothesize that the uncontrolled inflammation in COVID-19 patients with severe disease is partly due to a lack of functional Bregs, and a preferential expansion of pro-inflammatory B effector cell (Beff) subsets. To test this, I propose to screen a longitudinal cohort of COVID-19 patients with varying disease severity for Breg/Beff frequency, cytokine profile and SARS-CoV-2-specific antibody responses. Using a combination of B cell repertoire and transcriptomic analysis, I will identify the molecular signature of ‘pathogenic’ B cell subsets in severe COVID-19 compared to mild disease. Furthermore, I aim to investigate B cell responses to SARS-CoV-2 infection in patients with rheumatic diseases, including those on existing biological therapies. This work will transform our understanding of aberrant B cell responses in severe COVID-19 and identify novel biological pathways to modulate B cell function in disease.

Lay abstract: B cells are a type of white blood cells that play a key role in killing invading viruses by producing virus-specific antibodies and inflammatory chemical mediators known as cytokines. Regulatory B cells (Bregs) are a type of B cell that suppress the immune response in order to prevent potentially harmful excessive inflammation during an infection. Thus, Bregs are important to generate a balanced immune response and restore immune homeostasis after an infection. COVID-19 is a highly heterogeneous disease with a wide clinical spectrum of symptoms, ranging from asymptomatic spread to respiratory failure and death. Patients with severe disease display hyperinflammation and immune-mediated lung pathology caused by a ‘cytokine storm’. The cause for this dysregulated immune response to the SARS-CoV-2 virus in a subset of patients remains unknown. My previous work has identified numerical and functional defects in Bregs in patients with chronic inflammatory disorders. I hypothesize that it is the loss of functional Bregs that results in the dysregulated immune response in COVID-19 patients with severe disease. It is likely that the reduction in Bregs is mirrored by an expansion of inflammatory B cells, that exacerbate ongoing inflammation in critically ill patients. Here, I aim to understand how aberrant B cells responses influence the clinical course of COVID-19 and how patients on existing immunotherapies respond to infection. This study will provide a more effective way of guiding clinicians about the choice and timing of treatment for their patients and could provide novel therapeutic avenues.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION