Nitric oxide prevents a pathogen-permissive granulocytic inflammation during tuberculosis

Abstract

Nitric oxide (NO) contributes to protection from tuberculosis (TB). It is generally assumed that this protection is due to direct inhibition of Mycobacterium tuberculosis (Mtb) growth, which prevents subsequent pathological inflammation. In contrast, we report NO primarily protects mice by repressing an interleukin-1 and 12/15-lipoxygenase dependent neutrophil recruitment cascade that promotes bacterial replication. Using Mtb mutants as indicators of the pathogen's environment, we inferred that granulocytic inflammation generates a nutrient-replete niche that supports Mtb growth. Parallel clinical studies indicate that a similar inflammatory pathway promotes TB in patients. The human 12/15 lipoxygenase ortholog, ALOX12, is expressed in cavitary TB lesions, the abundance of its products correlate with the number of airway neutrophils and bacterial burden, and a genetic polymorphism that increases ALOX12 expression is associated with TB risk. These data suggest that Mtb exploits neutrophilic inflammation to preferentially replicate at sites of tissue damage that promote contagion.

Nitric Oxide Modulates Macrophage Responses to Mycobacterium tuberculosis Infection through Activation of HIF-1α and Repression of NF-κB

“…It is possible that the aerosol infection model we use results in a hyperinflammation via multiple mechanisms, thereby masking a protective effect of neutrophil depletion. While this manuscript was under review, a new study highlighting the role of NO in suppressing damaging neutrophilic infiltration in M. tuberculosis infected mouse lungs was published (40). In their study, the authors demonstrate that depleting neutrophils using the 1A8 antibody decreases CFU in the lungs of Nos2 − / − mice.…”

Mechanisms of M. tuberculosis Immune Evasion as Challenges to TB Vaccine Design

“…Other mechanisms contribute to M. tuberculosis innate immunity, including pattern recognition molecules and adaptors (Stamm et al, 2015), neutrophils (Blomgran et al, 2012; Blom-gran and Ernst, 2011), reactive oxygen (Köister et al, 2017) and nitrogen (Mishra et al, 2017), autophagy (Ouimet et al, 2016), and apoptosis (Martin et al, 2012). For each of these, M. tuberculosis has evolved the ability to inhibit or resist these defense mechanisms (Cambier et al, 2014; Goldberg et al, 2014).…”

Evaluation of IL-1 blockade as an adjunct to linezolid therapy for tuberculosis in mice and macaques

“…The susceptibility of mice lacking critical mediators of IL-1 signaling indicates that some initial production of IL-1β upon Mtb infection is essential for priming downstream immune responses necessary for disease control (5-8). In contrast, IL-1 is also responsible for the accumulation of disease-promoting neutrophils in chronically-infected susceptible mice, and genetic variants that result in higher IL-1β production are associated with increased disease severity and neutrophil accumulation in humans (9-11). Given that HDT is designed to be administered to chronically-infected patients during treatment, when persistent IL-1 production appears to play a more pathological role, it could be beneficial to block the inflammation and disease promoting activities of this cytokine.…”