Pollara, G;
Turner, CT;
Rosenheim, J;
Chandran, A;
Bell, LCK;
Khan, A;
Patel, A;
... Noursadeghi, M; + view all
(2021)
Exaggerated IL-17A activity in human in vivo recall responses discriminates active tuberculosis from latent infection and cured disease.
Science Translational Medicine
, 13
(592)
, Article eabg7673. 10.1126/scitranslmed.abg7673.
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Exaggerated IL-17A activity in human in vivo recall responses discriminates active tuberculosis from latent infection and cu.pdf - Accepted Version Download (2MB) | Preview |
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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