. Since TB remains an infection that results in extensive mortality, efficacious vaccines against Mtb infection are urgently sought. Recently, it has been proposed that mycobacteria attenuated in the regulation of redox-stress may be effective vaccine candidates, since these could interfere with the production of several microbial antioxidants. We have recently shown that an isogenic Mtb mutant in stress-response factor SigH significantly and impressively protects against homologous Mtb infection if used to immunize macaques via the aerosol route. As part of this application we propose to better understand correlates of protective immunity upon mucosal vaccination with ?sigH, using a set of three specific aims that are not inter-dependent. In addition we will study if such vaccination can also protect against infection with highly infectious heterologous strains of Mtb (Specific Aim 1). In a series of mechanistic experiments, we will deplete B-cells recruited to the lung iBALT follicles in great numbers following vaccination with the ?sigH mutant, using a recently developed and optimized macaque-specific reagent. These animals will be concurrently challenged with a high-dose homologous Mtb challenge to assess if the protective efficacy of ?sigH is eviscerated in the absence of B-cells (Specific Aim 2). Finally, we will study if inducible bronchus associated tissue (iBALT) provides a sanctuary where SIV can persist, or whether iBALT protects Tfh cells from depletion by SIV during co-infection (Specific Aim 3). Together the results obtained as part of these three aims will i) have the potential to establish ?sigH as a leading live-mycobacterium anti-TB vaccine vehicle; ii) provide defining correlates of protection from TB in a model system which would provide immediate applicability in human trials; and iii) define the controversial role of B-cells in protection from TB.
. This project seeks to better define correlates of protection from Mtb infection in macaques via vaccination with an attenuated Mycobacterium that has exhibited impressive protection in the aforementioned model system. In addition, we will also study the ability of the strain to vaccinate against heterologous clades. We will perform specific experiments to study if lung B-cells play a role in protecting from TB and assess if the B-cell containing follicles induced in the lung by vaccination can provide a niche for HIV to persist during co- infection.
|Gautam, Uma S; Foreman, Taylor W; Bucsan, Allison N et al. (2018) In vivo inhibition of tryptophan catabolism reorganizes the tuberculoma and augments immune-mediated control of Mycobacterium tuberculosis. Proc Natl Acad Sci U S A 115:E62-E71|
|Veatch, Ashley V; Kaushal, Deepak (2018) Opening Pandora's Box: Mechanisms of Mycobacterium tuberculosis Resuscitation. Trends Microbiol 26:145-157|