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

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.

Understanding the tuberculosis granuloma: the matrix revolutions

“…A separate RNAseq study suggested that neuroendocrine signalling was downregulated at the air–caseum interface in drug-resistant TB, whereas the complement pathway was upregulated [ 61 ]. Although MMP regulation was not directly noted, the oncostatin M (OSM) pathway was upregulated, similar to observations in the skin tuberculin study [ 54 ], and OSM can induce MMP1 secretion [ 62 ].…”

“…Using a similar transcriptomic approach, analysis of gene expression was compared in skin stimulated by tuberculin in patients with TB versus healthy controls [ 54 ]. Again, MMP1 emerged as a top divergently upregulated gene, and ingenuity pathway analysis suggested that an excessive IL-17 response was a key regulator.…”

“…The IL-17/MMP1 profile resolved with treatment of infection, implying that Mtb actively primes an excessive, matrix-destructive immune response that can be replicated by a distal antigenic challenge. The authors highlighted the double-edged sword of IL-17 in TB, with data supporting a protective role [ 55 , 56 ] and a pathological role when present in excess [ 54 , 57 ]. These two recent studies have the limitation of analysing a distal compartment (mediastinal lymph node and skin), and an identical gene expression profile cannot be assumed in the lung.…”

Advancing Adjuvants for Mycobacterium tuberculosis Therapeutics

“…Other studies have also found that CCR6 + CXCR3 + Th 1 /Th 17 cells responses were present in latently-infected individuals (compared to active infection) and were important for protection in an NHP model of TB ( 54 , 55 ). But while Th 17 responses are beneficial, excessive Th 17 responses are detrimental to the host ( 56 , 57 ). Therefore, adjuvants for TB vaccines should strive to induce early and balanced Th 1 /Th 17 as these are more likely to be necessary for protection.…”

Personalised Medicine for Tuberculosis and Non-Tuberculous Mycobacterial Pulmonary Disease

“…Impaired IL-17 responses have been reported in patients with MAC-PD [49] and MAB-PD [50], while transcriptional studies have demonstrated that downstream targets of the IL-17 pathway appear to be upregulated in NTM-PD even though IL-17 itself is not [51]. Exaggerated IL-17A and Th17 responses however have been observed in active TB compared to latent TB infection (LTBI) [52].…”