Metabolites enhance innate resistance to human Mycobacterium tuberculosis infection

Abstract

We characterized the phenotype and function of various immune cells in a large group of LTBI -HHCs (nonconverters) of patients with TB (a total of 452 individuals). We performed these measures at baseline (0 months) and follow-up (24 months) while monitoring the participants for conversion to LTBI. By following a large cohort of HHCs of patients with TB and performing transcriptional and metabolomic studies, we determined whether resistance to M. tuberculosis infection is preceded by specific changes in the transcriptional profile. We also determined whether metabolites regulate macrophage metabolism and function to restrict M. tuberculosis growth. ResultsPrevalence of nonconverters in the HHCs of patients with TB. At baseline, among 990 HHCs, 538 (54.3%) were positive and 452 (45.6%) were negative for LTBI by the IFN-γ release assay (IGRA) as described in the Methods (Supplemental Table 1; supplemental material available online with this article; https://doi.org/10.1172/ jci.insight.152357DS1). We followed these 452 LTBI -HHCs for 2 years at 4-month intervals (study plan is shown in Figure 1A). Exposure to index patients was determined following the criteria mentioned in previous studies (10-14) and in the Methods section. Among the 452 LTBI -HHCs, 96 (21.2%) became IGRA + (converters) over 2 years of follow-up. Despite similar exposure levels, 293 (64.8%) HHCs remained IGRA -(nonconverters) until the end of the study (Table 1 and Supplemental Data 1). As shown in Supplemental Data 1, all (n = 96) converters consistently produced IFN-γ in response to M. tuberculosis antigens. The demographic details of converters and nonconverters are shown in Table 1 and Supplemental Table 1.Immune cell phenotypes of converters and nonconverters. The innate immune response is critical to clear M. tuberculosis infection and may play an important role in preventing LTBI conversion (15-18). We determined various immune cell populations at baseline and during the follow-up visits (24 months) in freshly isolated peripheral blood mononuclear cells (PBMCs) of age-and sex-matched nonconverters (n = 293) and converters (n = 96). At baseline, in fresh PBMCs of nonconverters, the percentages of CD14 + and CD3 -CD56 + CD27 + CCR7 + memory-like NK cells were significantly higher than those of converters (Figure 1B and Supplemental Figure 1). No significant differences in CD4 + , CD16 + , CD14 + CD16 + , CD16 + CD56 + , or CD4 + CD25 + FoxP3 + cells were found in the PBMCs of nonconverters and converters (Figure 1B). As shown in Figure 1B, the percentage of memory-like NK cells significantly decreased in converters at follow-up. However, in nonconverters, the percentages of the cells remained the same throughout the study (Figure 1B).Cytokine and chemokine production by the PBMCs of converters and nonconverters in response to M. tuberculosis antigens. Various cytokines and chemokines produced following M. tuberculosis exposure are crucial to the outcome of infection (19,20). We determined cytokine and chemokine production by PBMCs of convert...

Loss of circulating CD8α+NK cells during humanMycobacterium tuberculosisinfection

“…The most extensively studied is an NK cell memory population co-expressing NKG2C and CD57 that expands in blood during human cytomegalovirus (CMV) infection ( 27, 46 ). Multiple putative markers of NK cell memory during Mtb infection have been suggested, including CD57, CD8α, CD161, and CD27 ( 28, 34, 45 ). We compared expression of these markers across clinical groups and found that household-associated LTBI (IGRA+ contacts) and active TB disease donors had progressively decreasing frequency of CD8α + CD56 dim NK cells ( Fig.…”

“…Prior work provides mechanistic evidence for NK cell recognition of intracellular and extracellular Mtb in vitro through natural cytotoxicity receptor engagement of Mtb cell wall components or stress-induced self-ligands ( 22–33 ). However, few published studies directly examine NK cell biology during natural Mtb transmission in humans ( 27, 28, 34 ).…”

“…Prior work provides mechanistic evidence for NK cell recognition of intracellular and extracellular Mtb in vitro through natural cytotoxicity receptor engagement of Mtb cell wall components or stress-induced self-ligands (22-33). However, few published studies directly examine NK cell biology during natural Mtb transmission in humans (27,28,34).In this study, we interrogate peripheral blood NK cells in a cohort of household TB contacts in an endemic region in Port-au-Prince, Haiti. We analyzed samples from active TB cases (n=50) and their contacts from the same households (n=50) in addition to interferon-gamma (IFNg) release assay (IGRA)-matched unrelated donors from the source community without household exposure (n=50).…”

“…Mtb cell wall components or stress-induced self-ligands (22-33). However, few published studies directly examine NK cell biology during natural Mtb transmission in humans (27,28,34).…”