Mycobacterium tuberculosis (Mtb) has latently infected over two billion people worldwide (LTBI) and caused ~1.6 million deaths in 2021. Human immunodeficiency virus (HIV) co-infection with Mtb will affect the Mtb progression and increase the risk of developing active tuberculosis by 10–20 times compared with HIV- LTBI+ patients. It is crucial to understand how HIV can dysregulate immune responses in LTBI+ individuals. Plasma samples collected from healthy and HIV-infected individuals were investigated using liquid chromatography–mass spectrometry (LC-MS), and the metabolic data were analyzed using the online platform Metabo-Analyst. ELISA, surface and intracellular staining, flow cytometry, and quantitative reverse-transcription PCR (qRT-PCR) were performed using standard procedures to determine the surface markers, cytokines, and other signaling molecule expressions. Seahorse extra-cellular flux assays were used to measure mitochondrial oxidative phosphorylation and glycolysis. Six metabolites were significantly less abundant, and two were significantly higher in abundance in HIV+ individuals compared with healthy donors. One of the HIV-upregulated metabolites, N-acetyl-L-alanine (ALA), inhibits pro-inflammatory cytokine IFN-γ production by the NK cells of LTBI+ individuals. ALA inhibits the glycolysis of LTBI+ individuals’ NK cells in response to Mtb. Our findings demonstrate that HIV infection enhances plasma ALA levels to inhibit NK-cell-mediated immune responses to Mtb infection, offering a new understanding of the HIV–Mtb interaction and providing insights into the implication of nutrition intervention and therapy for HIV–Mtb co-infected patients.

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...

Inflammation is the defense mechanism of the immune system against harmful stimuli such as pathogens, toxic compounds, damaged cells, radiation, etc., and is characterized by tissue redness, swelling, heat generation, pain, and loss of tissue functions. Inflammation is essential in the recruitment of immune cells at the site of infection, which not only aids in the elimination of the cause, but also initiates the healing process. However, prolonged inflammation often brings about several chronic inflammatory disorders; hence, a balance between the pro- and anti-inflammatory responses is essential in order to eliminate the cause while producing the least damage to the host. A growing body of evidence indicates that extracellular vesicles (EVs) play a major role in cell–cell communication via the transfer of bioactive molecules in the form of proteins, lipids, DNA, RNAs, miRNAs, etc., between the cells. The present review provides a brief classification of the EVs followed by a detailed description of how EVs contribute to the pathogenesis of various inflammation-associated diseases and their implications as a therapeutic measure. The latter part of the review also highlights how EVs act as a bridging entity in blood coagulation disorders and associated inflammation. The findings illustrated in the present review may open a new therapeutic window to target EV-associated inflammatory responses, thereby minimizing the negative outcomes.

BackgroundMycobacterium tuberculosis(Mtb) has latently infected over two billion people worldwide (LTBI) and causes 1.8 million deaths each year. Human immunodeficiency virus (HIV) co-infection with Mtb will affect the Mtb progression and increase the risk of developing active tuberculosis by 10-20 times compared to the HIV-LTBI+ patients. It is crucial to understand how HIV can dysregulate immune responses in LTBI+ individuals.MethodsPlasma samples collected from healthy and HIV-infected individuals were investigated by liquid chromatography-mass spectrometry (LC-MS), and the metabolic data were analyzed using an online platform Metabo-Analyst. ELISA, surface and intracellular staining, flow cytometry, quantitative reverse transcription PCR (qRT-PCR) were performed by standard procedure to determine the surface markers, cytokines and other signaling molecule expression. Seahorse extra cellular flux assays were used to measure the mitochondrial oxidative phosphorylation and glycolysis.ResultsSix metabolites were significantly less abundant, and two were significantly higher in abundance in HIV+ individuals compared to healthy donors. One of the HIV-upregulated metabolites, N-Acetyl-L-Alanine (ALA), inhibits pro-inflammatory cytokine IFN-□ production by NK cells of LTBI+ individuals. ALA inhibits glycolysis of LTBI+ individuals’ NK cells in response toMtb.ConclusionsOur findings demonstrate that HIV infection enhances plasma ALA levels to inhibit NK cell-mediated immune responses toMtbinfection, offering a new understanding of the HIV-Mtbinteraction and providing the implication of nutrition intervention and therapy for HIV-Mtbco-infected patients.