Sequential inflammatory processes define human progression from M. tuberculosis infection to tuberculosis disease

Abstract

Our understanding of mechanisms underlying progression from Mycobacterium tuberculosis infection to pulmonary tuberculosis disease in humans remains limited. To define such mechanisms, we followed M. tuberculosis-infected adolescents longitudinally. Blood samples from forty-four adolescents who ultimately developed tuberculosis disease (“progressors”) were compared with those from 106 matched controls, who remained healthy during two years of follow up. We performed longitudinal whole blood transcriptomic analyses by RNA sequencing and plasma proteome analyses using multiplexed slow off-rate modified DNA aptamers. Tuberculosis progression was associated with sequential modulation of immunological processes. Type I/II interferon signalling and complement cascade were elevated 18 months before tuberculosis disease diagnosis, while changes in myeloid inflammation, lymphoid, monocyte and neutrophil gene modules occurred more proximally to tuberculosis disease. Analysis of gene expression in purified T cells also revealed early suppression of Th17 responses in progressors, relative to M. tuberculosis-infected controls. This was confirmed in an independent adult cohort who received BCG re-vaccination; transcript expression of interferon response genes in blood prior to BCG administration was associated with suppression of IL-17 expression by BCG-specific CD4 T cells 3 weeks post-vaccination. Our findings provide a timeline to the different immunological stages of disease progression which comprise sequential inflammatory dynamics and immune alterations that precede disease manifestations and diagnosis of tuberculosis disease. These findings have important implications for developing diagnostics, vaccination and host-directed therapies for tuberculosis.Trial registrationClincialtrials.gov, NCT01119521

Four-Gene Pan-African Blood Signature Predicts Progression to Tuberculosis

“…The SEPT4 protein has antiapoptotic functions, and its deletion improved wound healing in mice (39), suggesting a possible association with lung healing during TB progression. BLK is a B-cell receptor kinase, and its downregulation is consistent with reduced B-cell proportions in blood during TB (19,40). The most generalizable pair defined in our metaanalysis showed upregulation of C1QC and downregulation of TRVAV27.…”

“…Interestingly, complement pathway genes are markedly upregulated after Mtb infection of nonhuman primates (41), consistent with the upregulation of C1QC/TRAV27 at baseline in the HHCs. Complement activation is also observed early during human progression to TB (40), whereas C1q is downregulated early after starting TB treatment (22), suggesting that C1q may be a proxy of early TB pathology. Conversely, downregulation of TRAV27 and several other T-cell genes (Table E18) is likely associated with the overall decrease in peripheral T-cell frequencies and their associated gene expression modules during TB progression, potentially due to migration of T cells to the disease site (19,21,40).…”

“…Complement activation is also observed early during human progression to TB (40), whereas C1q is downregulated early after starting TB treatment (22), suggesting that C1q may be a proxy of early TB pathology. Conversely, downregulation of TRAV27 and several other T-cell genes (Table E18) is likely associated with the overall decrease in peripheral T-cell frequencies and their associated gene expression modules during TB progression, potentially due to migration of T cells to the disease site (19,21,40). The simple C1QC/TRAV27 signal may thus be a readout of TB risk after initial exposure to an individual with pulmonary TB, which is more synchronized in an HHC study design, even though prior exposure to Mtb cannot be ruled out in our GC6-74 study and individuals with progression to TB disease within the first three months of the observation period were excluded from the analysis.…”

An evolutionary recent IFN-IL-6-CEBP axis is linked to monocyte expansion and tuberculosis severity in humans

“…More specifically, several "interferon-stimulated genes" (ISGs) are modulated in circulating mature neutrophils and monocytes in active TB patients, which calls forth a possible role of such genes in TB pathogenesis (Berry et al, 2010;Dos Santos et al, 2018;Zak et al, 2016). In contrast, lymphocyte compartments were recently demonstrated to be contracted during progression from latent to active TB in humans (Scriba et al, 2017). Therefore, the observed changes in blood leukocytes could be a consequence of the interactions between Mtb and the bone marrow cellular environment.…”

Friends and foes of tuberculosis: modulation of protective immunity

“…Longitudinal follow-up of Mtb-infected adolescents revealed that TB disease development was associated with sequential modulation of immunological processes [86]. Early changes involved alterations in Type I/II interferon signalling and complement proteins and repression of Th17 cells [86]. This illustrates the importance of kinetics and sequential events in the immune response against TB.…”