Interrogating immune protection against Mycobacterium tuberculosis through the lens of humoral immunity

Abstract

Nearly a century and a half after the discovery of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), TB remains the leading cause of death from a single bacterial infection globally. While treatable by antibiotics, the intensive drug regimen coupled with the emergence of antibiotic resistance has highlighted the need for an efficacious tuberculosis vaccine, as well as for the development of therapeutics robust to drug resistance. The majority of efforts to harness the immune system to control TB have focused on potentiating cell-mediated immunity, as T cells play a critical role in protection. Conversely, little work has focused on exploiting the diverse effector mechanisms of humoral immunity to combat infection, rendering antibodies an untapped immune effector in the fight against TB.

In the present work, we seek to uncover the humoral features that distinguish protective immunity, as well as the functional mechanisms antibodies may leverage to promote Mtb control. In Chapter 2, we take an antibody engineering approach to test the hypothesis that antibodies direct innate immunity to restrict Mtb growth. We demonstrate that antibody Fc engineering can augment antibody-mediated Mtb restriction, and further that Fc engineered antibodies deploy neutrophil function to promote control of Mtb. Beginning in Chapter 3, we seek to learn the defining features of a protective humoral immune response from nature. Leveraging samples from a recent vaccination study in non-human primates (NHPs) demonstrating the near-sterilizing protection afforded by intravenous (IV) BCG vaccination, we show that IV immunization with BCG uniquely induces a robust, lung-localized antibody response, and identify IgM responses as a strong marker of protection. In Chapter 4 we characterize antibody responses in the setting of human immunodeficiency virus (HIV)/TB co-infection. Beyond lower IgG responses to select Mtb antigens, we show that HIV infected individuals with uncontrolled ATB exhibited a broad defect in IgM responses, congruent with the protective IgM signature identified in the IV BCG model. In Chapter 5 we leverage Mtb proteome-wide microarray analyses to characterize protein-targeting antibody responses that evolve in subjects with a dynamic spectrum in infection outcome, ranging from pulmonary TB disease, to sterilizing protection from infection. We identify antigens selectively targeted by antibodies in distinct Mtb-exposed populations, as well as antigens associated with TB control across protected populations, pointing to a limited set of common proteins targeted by protective humoral immune responses. Ultimately, the collective of this work indicates that antibody quantity, quality, and biodistribution, are all critical parameters in antibody-mediated protection against Mtb, and highlights the unrealized value in harnessing humoral immunity to inform and to promote immunological control of TB. We conclude in Chapter 6 by outlining the unknowns and challenges that remain to guide and motivate future work in the field.