Editors' ChoiceTuberculosis

Neutrophils: Double agents for TB

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Science Translational Medicine  14 Jun 2017:
Vol. 9, Issue 394, eaan6195
DOI: 10.1126/scitranslmed.aan6195


Nitric oxide restricts growth of Mycobacterium tuberculosis by repressing neutrophilic inflammation.

In most people, infection with Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), results in stalemate. The immune system controls the tubercle bacilli but fails to eradicate them. However, in 10% of infected individuals, the balance shifts in favor of the pathogen. In these cases, the bacteria replicate to high numbers, and inflammatory mediators call in neutrophils to reinforce the defenses. Now, Mishra and colleagues add to mounting evidence that in the context of TB, rather than helping, these recruited neutrophils are aiding and abetting the enemy.

The investigators began their studies by challenging the assumption that nitric oxide controls M. tuberculosis by direct antibacterial action. Previous work from these authors demonstrated that nitric oxide inhibits production of interleukin-1 (IL-1), which drives neutrophil recruitment. Mice lacking nitric oxide synthase 2 (NOS2) succumb to M. tuberculosis infection with an exuberant neutrophilic infiltrate, as well as a high bacterial burden. Here, Mishra and colleagues used a variety of chemical and genetic perturbations to reduce the number of lung neutrophils in these mice. These treatments not only reversed lung pathology and clinical wasting but also resulted in a lower bacterial burden. This suggests that nitric oxide actually restricts mycobacterial replication by blunting neutrophil infiltration. The authors went on to examine why a neutrophil-rich environment promotes mycobacterial growth. They found that mycobacterial mutants deficient in iron scavenging and lipid metabolism grew better in the setting of extensive neutrophilic infiltration than when there were few neutrophils. Thus, neutrophils appear to create a nutrient-rich environment that supports M. tuberculosis proliferation. It will be interesting to determine whether specific neutrophil subsets are to blame and, if so, their role in other pulmonary infections.

Mishra and colleagues extended their findings to human disease by establishing which mediators act downstream of IL-1 to recruit neutrophils in mice, identifying ALOX15, a 12/15-lipoxygenase that produces 12-hydroxyeicosatetraenoic acid (12-HETE). In humans, 12-HETE is produced by ALOX12, which was expressed in cavitary lung lesions. In addition, the amount of 12-HETE in patients’ bronchoalveolar lavage correlated with neutrophil abundance. Moreover, a single nucleotide polymorphism that enhances ALOX12 expression was associated with TB disease. These studies suggest that in M. tuberculosis–infected humans, as in mice, 12-lipoxygenase metabolites recruit neutrophils that harbor the enemy and drive disease pathogenesis. This raises the possibility that therapies directed at reducing neutrophil recruitment might reduce lung pathology and deny M. tuberculosis a safe haven.

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