Disruption of Aldehyde Dehydrogenase 2 protects against bacterial infection

Abstract

AbstractTheALDH2*2(rs671) allele is one of the most common genetic mutations in humans, yet the positive evolutionary selective pressure to maintain this mutation is unknown, despite its association with adverse health outcomes. ALDH2 is responsible for the detoxification of metabolically produced aldehydes, including lipid-peroxidation end products derived from inflammation. Here, we demonstrate that host-derived aldehydes 4-hydroxynonenal (4HNE), malondialdehyde (MDA), and formaldehyde (FA), all of which are metabolized by ALDH2, are directly toxic to the bacterial pathogensMycobacterium tuberculosisandFrancisella tularensisat physiological levels. We find thatAldh2expression in macrophages is decreased upon immune stimulation, and that bone marrow-derived macrophages fromAldh2–/–mice contain elevated aldehydes relative to wild-type mice. Macrophages deficient forAldh2exhibited enhanced control ofFrancisellainfection.Finally, mice lackingAldh2demonstrated increased resistance to pulmonary infection byM. tuberculosis, including in a hypersusceptible model of tuberculosis, and were also resistant toFrancisellainfection. We hypothesize that the absence of ALDH2 contributes to the host’s ability to control infection by pathogens such asM. tuberculosisandF. tularensis, and that host-derived aldehydes act as antimicrobial factors during intracellular bacterial infections.One sentence summaryAldehydes produced by host cells contribute to the control of bacterial infections.