Elaboration of nitric oxide (NO) is necessary for control of Mycobacterium tuberculosis infection, yet it remains unclear how NO mediates protection. Bacterial counts are higher in hosts deficient in NO production, and severe disease ensues. In Nature Microbiology, Mishra et al. show that NO prevents exuberant neutrophilic responses to mycobacterial infection by suppressing the production of interleukin 1 (IL-1) and 12/15-lipoxygenase. Loss of NO production does not alter the control of intracellular bacteria in Nos2−/− macrophages, which suggests that the defective control is not cell autonomous. Instead, sustained influx of neutrophils leads to enhanced host-cell death and the release of iron and lipid nutrients that favor bacterial growth. Inhibition or deletion of inflammasome NLRP3, the IL-1 receptor or 12/15-lipoxygenase (ALOX12 in humans) diminishes the influx of neutrophils into infected lungs and lessens disease severity in mice, whereas increased ALOX12 activity in humans is correlated with more-severe disease. Thus, targeting this regulatory pathway might be beneficial in treating infection with M. tuberculosis.

Nat. Micro. 2, 17072 (2017)