Mechanisms of vitamin A-dependent risk for tuberculosis progression and prevention - Project Summary Mycobacterium tuberculosis, the causative agent of Tuberculosis (TB), is the leading cause of human mortality due to an infectious disease, outside of the COVID-19 pandemic. The limited knowledge on risk factors and comorbidities for TB progression and the mechanisms by which these promote susceptibility limits the ability to develop new prevention and treatment approaches. Recently, we published data showing a causal relationship between vitamin A deficiency and progression to clinical active TB disease, carrying up to a 10-fold higher risk for human TB progression. The substantial TB risk associated with vitamin A deficiency highlights the need to understand the mechanisms by which this molecule contributes to TB pathogenesis, particularly in the context of malnutrition among TB-affected communities, which are often the same communities affected by vitamin A deficiency. Vitamin A has been shown to have an impact on both innate and cell-mediated immunity, where diverse roles in immunity convolute the potential contributions of this molecule to TB immunity. We hypothesize that vitamin A is required for effective cell-mediated immunity to control infection after exposure, and respond properly to vaccination, requiring production within the lung for development of effective immunity. The goals of this research are to better understand the contribution of vitamin A bioavailability to the development of the immune response, the metabolic perturbations of vitamin A during infection that may limit bioavailability, and how vitamin A status impacts efficacies of BCG vaccination practices. These goals will be achieved through three Aims using a guinea pig model of vitamin A deficiency developed in our laboratory. We will first determine the contribution of vitamin A bioavailability to the development of the coordinated granuloma immune response using single cell and spatial transcriptomic approaches on infected guinea pig lung tissues. Next, we will evaluate cellular, organ-level, and systemic vitamin A metabolic patterns during infection using stable heavy isotope tracing methods in the guinea pig model throughout the course of infection. Finally, the impact of vitamin A on protective efficacy of BCG vaccination, the only vaccine available for TB, will be assessed under conditions of physiologic and pathologic neonatal vitamin A deficiencies. Upon completing these experiments, we will have determined the role of vitamin A in the development of the granuloma and cell mediated immunity, the requirements for, and availability of, vitamin A at the site of infection in the lung, and the impact of existing and proposed human vitamin A supplementation programs on the efficacy of BCG vaccination. These results will elucidate mechanisms of TB disease progression, identify the role of vitamin A in TB immunity and propose informed options for preventive or therapeutic intervention on vitamin A deficiency.
