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Resistance and Susceptibility Immune Factors at Play during Mycobacterium tuberculosis Infection of Macrophages.

ABSTRACT: Tuberculosis (TB), caused by infection with Mycobacterium tuberculosis (M.tb), is responsible for >1.5 million deaths worldwide annually. Innate immune cells, especially macrophages, are the first to encounter M.tb, and their response dictates the course of infection. During infection, macrophages exert a variety of immune factors involved in either controlling or promoting the growth of M.tb. Research on this topic has been performed in both in vitro and in vivo animal models with discrepant results in some cases based on the model of study. Herein, we review macrophage resistance and susceptibility immune factors, focusing primarily on recent advances in the field. We include macrophage cellular pathways, bioeffector proteins and molecules, cytokines and chemokines, associated microbiological factors and bacterial strains, and host genetic factors in innate immune genes. Recent advances in mechanisms underlying macrophage resistance and susceptibility factors will aid in the successful development of host-directed therapeutics, a topic emphasized throughout this review.

SUBMITTER: Simper JD

PROVIDER: S-EPMC9611686 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Resistance and Susceptibility Immune Factors at Play during <i>Mycobacterium tuberculosis</i> Infection of Macrophages.

Simper Jan D JD Perez Esteban E Schlesinger Larry S LS Azad Abul K AK

Pathogens (Basel, Switzerland) 20221006 10

Tuberculosis (TB), caused by infection with Mycobacterium tuberculosis (M.tb), is responsible for >1.5 million deaths worldwide annually. Innate immune cells, especially macrophages, are the first to encounter M.tb, and their response dictates the course of infection. During infection, macrophages exert a variety of immune factors involved in either controlling or promoting the growth of M.tb. Research on this topic has been performed in both in vitro and in vivo animal models with discrepant re ...[more]

PMID: 36297211

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Project description:The immune control of tuberculosis (TB) infection could be influenced by pregnancy. To elucidate this, we longitudinally characterized Mycobacterium tuberculosis (Mtb)-specific and nonspecific immune responses in women during pregnancy and postpartum. HIV-uninfected women without past or current active TB, and with blood samples available from the 1st/2nd trimester, 3rd trimester, and 9 months postpartum, were identified at Ethiopian antenatal care clinics. Twenty-two TB+ women and 10 TB- women, defined according to Mtb-stimulated interferon-γ levels (≥0.35 and <0.20 IU/mL, respectively, in the Quantiferon-TB Gold-Plus assay), were included in the study. Longitudinal dynamics of six cytokines (IL-1ra, IL-2, IP-10, MCP-2, MCP-3, and TGF-β1) were analyzed in supernatants from Mtb-stimulated and unstimulated whole blood. In TB+ women, Mtb-specific expression of IL-2 and IP-10 was higher at 3rd compared to 1st/2nd trimester (median 139 pg/mL versus 62 pg/mL, P = 0.006; 4,999 pg/mL versus 2,310 pg/mL, P = 0.031, respectively), whereas level of Mtb-triggered TGF-β1 was lower at 3rd compared to 1st/2nd trimester (-6.8 ng/mL versus 2.3 ng/mL, P = 0.020). Unstimulated IL-2, IP-10, and MCP-2 levels were increased postpartum, compared with those noted during pregnancy, in TB+ women. Additionally, postpartum levels of proinflammatory cytokines in unstimulated blood were higher in TB+ women, than in TB- women. None of the women developed active TB during follow-up. Taken together, dynamic changes of Mtb-specific cytokine expression revealed during the 3rd trimester in TB+ women indicate increased Mtb-antigen stimulation at later stages of pregnancy. This could reflect elevated bacterial activity, albeit without transition to active TB, during pregnancy. IMPORTANCE Tuberculosis (TB) is globally one of the most common causes of death, and a quarter of the world's population is estimated to have TB infection. The risk of active TB is increased in connection to pregnancy, a phenomenon that could be due to physiological immune changes. Here, we studied the effect of pregnancy on immune responses triggered in HIV-uninfected women with TB infection, by analyzing blood samples obtained longitudinally during pregnancy and after childbirth. We found that the dynamics of Mtb-specific and nonspecific immune responses changed during pregnancy, especially in later stages of pregnancy, although none of the women followed in this study developed active TB. This suggests that incipient TB, with elevated bacterial activity, occurs during pregnancy, but progression of infection appears to be counteracted by Mtb-specific immune responses. Thus, this study sheds light on immune control of TB during pregnancy, which could be of importance for future intervention strategies.

Project description:Tuberculosis (TB) is a highly infectious bacterial disease that primarily attacks the lungs. TB is manifested either as latent TB infection (LTBI) or active TB disease, the latter posing a greater threat to life. The risk of developing active TB disease from LTBI is three times higher in individuals with type 2 diabetes mellitus (T2DM). The association between TB and T2DM is becoming more prominent as T2DM is rapidly increasing in settings where TB is endemic. T2DM is a chronic metabolic disorder characterized by elevated blood glucose, insulin resistance, and relative insulin deficiency. Insulin resistance and stress-induced hyperglycemia have been shown to be increased by TB and to return to normal upon treatment. Previously, we demonstrated that adipocytes (or fat tissue) regulate pulmonary pathology, inflammation, and Mycobacterium tuberculosis (Mtb) load in a murine model of TB. Metabolic disturbances of adipose tissue and/or adipocyte dysfunction contribute to the pathogenesis of T2DM. Thus, pathological adipocytes not only regulate pulmonary pathology, but also increase the risk for T2DM during TB infection. However, the cellular and molecular mechanisms driving the interaction between hyperglycemia, T2DM and TB remain poorly understood. Here, we report the impact of Mtb infection on the development of insulin resistance in mice fed on a regular diet (RD) versus high-fat diet (HFD) and, conversely, the effect of hyperglycemia on pulmonary pathogenesis in juvenile and adult mouse models. Overall, our study demonstrated that Mtb persists in adipose tissue and that Mtb infection induces irregular adipocyte lipolysis and loss of fat cells via different pathways in RD- and HFD-fed mice. In RD-fed mice, the levels of TNFα and HSL (hormone sensitive lipase) play an important role whereas in HFD-fed mice, ATGL (adipose triglyceride lipase) plays a major role in regulating adipocyte lipolysis and apoptosis during Mtb infection in adult mice. We also showed that Mtb infected adult mice that were fed an RD developed insulin resistance similar to infected adult mice that were overweight due to a HFD diet. Importantly, we found that a consequence of Mtb infection was increased lipid accumulation in the lungs, which altered cellular energy metabolism by inhibiting major energy signaling pathways such as insulin, AMPK and mToR. Thus, an altered balance between lipid metabolism and glucose metabolism in adipose tissue and other organs including the lungs may be an important component of the link between Mtb infection and subsequent metabolic syndrome.

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Resistance and Susceptibility Immune Factors at Play during Mycobacterium tuberculosis Infection of Macrophages.

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Resistance and Susceptibility Immune Factors at Play during <i>Mycobacterium tuberculosis</i> Infection of Macrophages.

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Resistance and Susceptibility Immune Factors at Play during Mycobacterium tuberculosis Infection of Macrophages.

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Resistance and Susceptibility Immune Factors at Play during &lt;i&gt;Mycobacterium tuberculosis&lt;/i&gt; Infection of Macrophages.

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Resistance and Susceptibility Immune Factors at Play during <i>Mycobacterium tuberculosis</i> Infection of Macrophages.