Research ArticleTuberculosis

Exaggerated IL-17A activity in human in vivo recall responses discriminates active tuberculosis from latent infection and cured disease

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Science Translational Medicine  05 May 2021:
Vol. 13, Issue 592, eabg7673
DOI: 10.1126/scitranslmed.abg7673

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IL-luminating active tuberculosis disease

Immune responses at the site of Mycobacterium tuberculosis (Mtb) infection can dictate pathogenesis within the infected individual and likelihood of transmission to others. However, the understanding of immunological distinctions between active, latent, and cured tuberculosis disease has been limited to assessment of peripheral blood of patients. Here, Pollara et al. evaluated immune response gene signatures in individuals with active, latent, or cured Mtb infection at the site of a tuberculin skin test, which reflects the immune response at the site of infection. The authors found that active disease, but not latent or cured disease, was associated with exaggerated interleukin-17A (IL-17A) activity and neutrophil recruitment. Thus, IL-17A may represent a therapeutic target for active Mtb infection.

Abstract

Host immune responses at the site of Mycobacterium tuberculosis infection can mediate pathogenesis of tuberculosis (TB) and onward transmission of infection. We hypothesized that pathological immune responses would be enriched at the site of host-pathogen interactions modeled by a standardized tuberculin skin test (TST) challenge in patients with active TB compared to those without disease, and interrogated immune responses by genome-wide transcriptional profiling. We show exaggerated interleukin-17A (IL-17A) and T helper 17 (TH17) responses among 48 individuals with active TB compared to 191 with latent TB infection, associated with increased neutrophil recruitment and matrix metalloproteinase-1 expression, both involved in TB pathogenesis. Curative antimicrobial treatment reversed these observed changes. Increased IL-1β and IL-6 responses to mycobacterial stimulation were evident both in circulating monocytes and in molecular changes at the site of TST in individuals with active TB, supporting a model in which monocyte-derived IL-1β and IL-6 promote TH17 differentiation within tissues. Modulation of these cytokine pathways may provide a rational strategy for host-directed therapy in active TB.

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