Functional host immunity to Mycobacterium tuberculosis: connecting innate and adaptive responses

Abstract

Tuberculosis, caused by Mycobacterium tuberculosis, remains a global health challenge. Improved vaccines and biomarkers require a better understanding of the immune mechanisms involved in mycobacterial control. This thesis investigated the functional contribution of innate and adaptive immune responses to the control of mycobacterial growth.

The findings demonstrate that immune function, rather than the magnitude of individual immune responses, is a key determinant of mycobacterial control. Functional antibody responses were shown to enhance Fc-receptor-mediated phagocytosis and contribute to in vitro control of mycobacterial growth. In parallel, active tuberculosis was associated with a dysfunctional circulating B-cell compartment that normalized following successful treatment.

Using mycobacterial growth inhibition assays, this thesis identified a role for trained innate immunity in mycobacterial growth control. Enhanced growth inhibition was associated with a CXCL10-producing CD14dim monocyte subset and CXCR3-dependent cellular interactions. Longitudinal studies demonstrated that the capacity to control mycobacterial growth is highly heterogeneous between individuals but remains relatively stable during tuberculosis treatment. Studies of BCG vaccination in humans and non-human primates further revealed that vaccine-induced growth control involves mechanisms distinct from those associated with natural immunity. Together, these findings highlight the complex interplay between trained immunity, cellular immunity, and functional antibody responses in host defense against tuberculosis.