Details

Autor(en) / Beteiligte

• Ishida, Elise

Titel

Antibodies Associated with Control of Mycobacterium tuberculosis Infection

Ort / Verlag

ProQuest Dissertations & Theses

Erscheinungsjahr

2022

Quelle

ProQuest Dissertations & Theses A&I

Beschreibungen/Notizen

• The disease active tuberculosis (TB) annually claims 1.5 million lives worldwide and was the deadliest infectious disease caused by a single pathogen prior to COVID- 19. Moreover, 2 billion people are infected with Mycobacterium tuberculosis (Mtb) and are at risk to develop TB. The incidence in some TB endemic regions is very high and remains a global health crisis as around 10 million people developed TB in 2020. About 90% of all people who are infected with Mtb will naturally control it and remain asymptomatic, whereas 10% develop TB in their lifetimes. Therefore, we study the immune responses of individuals who control Mtb infection (termed latent Mtb infection [LTBI]) to better understand correlates of protection against TB and how to ultimately induce protective immune responses. Cell-mediated immunity is the one of the hallmark immune responses protecting against Mtb and other intracellular infections. Importantly, the immune responses observed in individuals who control Mtb infection are extremely heterogeneous and different arms of the immune system, in combination with cellmediated immunity, can play different roles during Mtb infection and protect from TB. Most TB research has overlooked the role of antibodies because of the assumption that intracellularly located Mtb is out of reach of extracellularly located antibodies. However, we and others have demonstrated that Mtb-specific antibodies are involved in controlling Mtb infection. My goals were to further explore the breadth of these antibodies to Mtb, especially those to the Mtb surface glycans, arabinomannan (AM) and related lipoarabinomannan (LAM), and to identify potentially new antigens and characteristics of antibodies during controlled Mtb infection by applying novel tools and analysis. After a review of the literature on what is currently known about control of Mtb infection and heterogeneity of the immune response to Mtb, I provide a background and hypothesis of how these antibodies against Mtb are induced and support all arms of the iii immune system. My first objective was to generate and characterize mAbs to the Mtb capsular polysaccharide AM from asymptomatic subjects exposed to or latently infected with Mtb. Using a targeted flow cytometry-based strategy, I generated two high-affinity mAbs to AM and characterized their distinct glycan epitopes. These mAbs are critical tools to study the mechanisms of action of antibodies against Mtb and the relevance of glycan epitope recognition for antibody functions and protection from TB. In addition, I characterized the binding properties of these mAbs and discussed their potential to also improve TB diagnostics. My second objective was to identify antibodies associated with protection against TB in nonhuman primates (NHPs). In contrast to other animal models, the NHPs investigated develop LTBI and TB in about equal proportions after low-dose Mtb airway infection and are thus the best model to study immune responses resembling those in humans. I applied an antigen-unbiased approach to screen NHPs for antibodies against the Mtb proteome and glycan motifs of major mycobacterial glycan classes. Using pre- and post Mtb-infection longitudinal airway and plasma samples from NHPs, we identified antibody signatures in NHPs that were associated with controlled Mtb infection/LTBI compared to uncontrolled Mtb infection/TB. I further compared the NHP antibody signatures to results from our human studies and discussed the relevance of both pre-existing lung mucosal and systemic IgA responses to specific mycobacterial AM epitopes and antigen-specific systemic IgG responses during early Mtb infection. Taken together, these projects contributed to teasing apart the heterogeneity of the antibody responses against Mtb, leading to new potential vaccination targets, and highlighting qualities of mAbs that are potentially important for the next generation of TB diagnostics. The results presented here are critical for future Mtb studies, particularly providing a foundation for more in-depth characterization of the antibodies induced by different TB vaccination strategies.