Biology subjects

Anaya-Sanchez, A.

Publications and source records attributed to Anaya-Sanchez, A..

3 recordsLinked to original sources

bioRxiv2023

Disruption of Aldehyde Dehydrogenase 2 protects against 1 bacterial infection

The ALDH2*2 (rs671) variant present in >500 million individuals reduces ALDH2 function, impairing aldehyde detoxification. While aldehyde accumulation in these individuals is associated with numerous negative health consequences, a previous study showed a cohort of ALDH2*2 carriers are less likely to develop active pulmonary tuberculosis. Here, we present additional human data that support this finding and show ALDH2-deficiency in mice provides a fitness advantage during bacterial infections. We found aldehydes normally detoxified by ALDH2 killed the bacterial pathogens Mycobacterium tuberculosis and Francisella tularensis. Infected macrophages from Aldh2-/-mice had higher levels of formaldehyde and 4-hydroxynonenal, which enhanced their microbicidal capacity. Aldh2-/- mice were more resistant to infection with Mycobacterium tuberculosis and Francisella tularensis than parental mice and displayed elevated inflammatory cytokine and chemokine levels, accompanied by an increased accumulation of inflammatory monocytes and macrophages. These findings support a model in which host-derived aldehydes are robust innate immune effectors, limiting bacterial infection through both direct microbicidal activity and immune modulation. Collectively, this work may explain why the ALDH2*2 allele was selected for in humans.

microbiology↗

bioRxiv2023

Mycobacterial formation of intracellular lipid inclusions is a dynamic process associated with rapid replication

Intracellular lipid inclusions (ILI) are triacylglyceride rich organelles produced by mycobacteria thought to serve as energy reservoirs. It is believed that ILI are formed as a result of a dosR mediated transition from replicative growth to non-replicating persistence (NRP). ILI rich Mycobacterium tuberculosis (Mtb) bacilli have been reported during infection and in sputum, establishing their importance in Mtb pathogenesis. Studies conducted in mycobacteria such as Mycobacterium smegmatis, Mycobacterium abscessus, or lab Mtb strains have demonstrated ILI formation in the presence of hypoxic, nitric oxide, nutrient limitation, or low nitrogen stress, conditions believed to emulate the host environment within which Mtb resides. Here, we show that M. marinum and clinical Mtb isolates make ILI during active replication in axenic culture independent of environmental stressors. By tracking ILI formation dynamics we demonstrate that ILI are quickly formed in the presence of fresh media or exogenous fatty acids but are rapidly depleted while bacteria are still actively replicating. We also show that the cell envelope is an alternate site for neutral lipid accumulation observed during stationary phase. In addition, we screen a panel of 60 clinical isolates and observe variation in ILI production during early log phase growth between and among Mtb lineages. Finally, we show that dosR expression level does not strictly correlate with ILI accumulation in fresh clinical isolates. Taken together, our data provide evidence of an active ILI formation pathway in replicating mycobacteria cultured in the absence of stressors, suggesting a decoupling of ILI formation from NRP.

microbiology↗

bioRxiv2021

Listeria monocytogenes requires cellular respiration for NAD+ regeneration and pathogenesis

Cellular respiration is essential for multiple bacterial pathogens and a validated antibiotic target. In addition to driving oxidative phosphorylation, bacterial respiration has a variety of ancillary functions that obscure its contribution to pathogenesis. We find here that the intracellular pathogen Listeria monocytogenes encodes two respiratory pathways which are partially functionally redundant and indispensable for pathogenesis. Loss of respiration decreased NAD+ regeneration, but this could be specifically reversed by heterologous expression of a water-forming NADH oxidase (NOX). NOX expression fully rescued intracellular growth defects and increased L. monocytogenes loads >1,000-fold in a mouse infection model. Consistent with NAD+ regeneration maintaining L. monocytogenes viability and enabling immune evasion, a respiration-deficient strain exhibited elevated bacteriolysis within the host cytosol and NOX rescued this phenotype. These studies show that NAD+ regeneration, rather than oxidative phosphorylation, represents the primary role of L. monocytogenes respiration and highlight the nuanced relationship between bacterial metabolism, physiology, and pathogenesis.

microbiology↗