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Cellular and Molecular Mechanisms of Pathogenesis and Drug Effects in Tuberculosis

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (20 December 2024) | Viewed by 6691

Special Issue Editor

Dr. Selvakumar Subbian

E-Mail Website
Guest Editor
New Jersey Medical School, Rutgers University, Newark, NJ 07103, USA
Interests: vaccines; innate immunity; macrophages; neutrophils; inflammation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Tuberculosis (TB) is a bacterial infectious disease caused by Mycobacterium tuberculosis complex organisms that caused nearly 1.3 million deaths and 10 million new cases among humans worldwide in 2022. In addition, about a fourth of the global human population has been estimated to have latent Mtb infections (LTBIs), which are largely asymptomatic. However, under immunocompromising conditions, LTBI can be reactive to symptomatic TB, fueling the burden of global TB cases. Since currently available anti-TB drug regimens and vaccines are inadequate, improved intervention strategies are urgently needed to control the global TB crisis. After successful implantation into the lungs, Mtb enters the host cells, mainly the phagocytes, which try to eliminate the infecting bacteria. The secretion of cytokines and effector molecules by the infected cells leads to the recruitment and activation of additional immune cells from circulation. This organized accumulation of immune cells surrounding Mtb-infected phagocytes is called the granuloma, a hallmark in TB pathogenesis. Within the granuloma, intricate host–pathogen interactions and signaling events direct the course and outcome of Mtb infection. However, the host- and pathogen-derived molecules and their signaling mechanisms that contribute to differential clinical outcomes, such as active and latent TB, remain largely unknown. Similarly, the molecular and cellular events of how Mtb evades host defense, including vaccine-induced protective immunity, as well as the activities of anti-TB drugs are not fully understood. In this Special Issue, we invite high-quality original articles and reviews pertaining to the molecular and cellular signaling aspects of TB pathogenesis, mechanisms of host evasion by Mtb, including anti-TB drug resistance mechanisms, as well as host-directed therapy. The suggested topics include but are not limited to the following:

  • Host–pathogen interaction studies using in vitro and/or in vivo model systems;
  • Mtb- and/or vaccine-induced host immune responses;
  • Systems approach to evaluate host and/or Mtb components of active TB, and LTBI with or without co-occurrence with other infections and diseases;
  • Host- and/or pathogen-mediated drug-resistance pathways;
  • Evaluation of novel vaccines, drugs, and host-directed therapies for TB in animal models;
  • Development and evaluation of novel model systems to study the spectrum of TB pathogenesis.

This Special Issue is supervised by Dr. Selvakumar Subbian and assisted by our Assistant Guest Editor Dr. Shivraj Yabaji (National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA 02215, USA).

Dr. Selvakumar Subbian
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • tuberculosis
  • mycobacterium
  • vaccines

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Published Papers (3 papers)

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Research

17 pages, 4026 KiB  
Article
Rv0687 a Putative Short-Chain Dehydrogenase Is Required for In Vitro and In Vivo Survival of Mycobacterium tuberculosis
by Gunapati Bhargavi, Mohan Krishna Mallakuntla, Deepa Kale and Sangeeta Tiwari
Int. J. Mol. Sci. 2024, 25(14), 7862; https://doi.org/10.3390/ijms25147862 - 18 Jul 2024
Cited by 1 | Viewed by 1439
Abstract
Mycobacterium tuberculosis (Mtb), a successful human pathogen, resides in host sentinel cells and combats the stressful intracellular environment induced by reactive oxygen and nitrogen species during infection. Mtb employs several evasion mechanisms in the face of the host as a survival [...] Read more.
Mycobacterium tuberculosis (Mtb), a successful human pathogen, resides in host sentinel cells and combats the stressful intracellular environment induced by reactive oxygen and nitrogen species during infection. Mtb employs several evasion mechanisms in the face of the host as a survival strategy, including detoxifying enzymes as short-chain dehydrogenases/reductases (SDRs) to withstand host-generated insults. In this study, using specialized transduction, we have generated a Rv0687 deletion mutant and its complemented strain and investigated the functional role of Rv0687, a member of SDRs family genes in Mtb pathogenesis. A wildtype (WT) and a mutant Mtb strain lacking Rv0687 (RvΔ0687) were tested for the in vitro stress response and in vivo survival in macrophages and mice models of infection. The study demonstrates that the deletion of Rv0687 elevated the sensitivity of Mtb to oxidative and nitrosative stress-inducing agents. Furthermore, the lack of Rv0687 compromised the survival of Mtb in primary bone marrow macrophages and led to an increase in the levels of the secreted proinflammatory cytokines TNF-α and MIP-1α. Interestingly, the growth of WT and RvΔ0687 was similar in the lungs of infected immunocompromised mice; however, a significant reduction in RvΔ0687 growth was observed in the spleen of immunocompromised Rag−/− mice at 4 weeks post-infection. Moreover, Rag−/− mice infected with RvΔ0687 survived longer compared to those infected with the WT Mtb strain. Additionally, we observed a significant reduction in the bacterial burden in the spleens and lungs of immunocompetent C57BL/6 mice infected with RvΔ0687 compared to those infected with complemented and WT Mtb strains. Collectively, this study reveals that Rv0687 plays a role in Mtb pathogenesis. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Pathogenesis and Drug Effects in Tuberculosis)
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24 pages, 4470 KiB  
Article
The Influence of Body Fat Dynamics on Pulmonary Immune Responses in Murine Tuberculosis: Unraveling Sex-Specific Insights
by Dhanya Dhanyalayam, Hariprasad Thangavel, Tabinda Sidrat, Neelam Oswal, Kezia Lizardo, Michael Mauro, Xin Zhao, Hai-Hui Xue, Jigar V. Desai and Jyothi F. Nagajyothi
Int. J. Mol. Sci. 2024, 25(13), 6823; https://doi.org/10.3390/ijms25136823 - 21 Jun 2024
Viewed by 1515
Abstract
The World Health Organization (WHO) highlights a greater susceptibility of males to tuberculosis (TB), a vulnerability attributed to sex-specific variations in body fat and dietary factors. Our study delves into the unexplored terrain of how alterations in body fat influence Mycobacterium tuberculosis ( [...] Read more.
The World Health Organization (WHO) highlights a greater susceptibility of males to tuberculosis (TB), a vulnerability attributed to sex-specific variations in body fat and dietary factors. Our study delves into the unexplored terrain of how alterations in body fat influence Mycobacterium tuberculosis (Mtb) burden, lung pathology, immune responses, and gene expression, with a focus on sex-specific dynamics. Utilizing a low-dose Mtb-HN878 clinical strain infection model, we employ transgenic FAT-ATTAC mice with modulable body fat to explore the impact of fat loss (via fat ablation) and fat gain (via a medium-fat diet, MFD). Firstly, our investigation unveils that Mtb infection triggers severe pulmonary pathology in males, marked by shifts in metabolic signaling involving heightened lipid hydrolysis and proinflammatory signaling driven by IL-6 and localized pro-inflammatory CD8+ cells. This stands in stark contrast to females on a control regular diet (RD). Secondly, our findings indicate that both fat loss and fat gain in males lead to significantly elevated (1.6-fold (p ≤ 0.01) and 1.7-fold (p ≤ 0.001), respectively) Mtb burden in the lungs compared to females during Mtb infection (where fat loss and gain did not alter Mtb load in the lungs). This upsurge is associated with impaired lung lipid metabolism and intensified mitochondrial oxidative phosphorylation-regulated activity in lung CD8+ cells during Mtb infection. Additionally, our research brings to light that females exhibit a more robust systemic IFNγ (p ≤ 0.001) response than males during Mtb infection. This heightened response may either prevent active disease or contribute to latency in females during Mtb infection. In summary, our comprehensive analysis of the interplay between body fat changes and sex bias in Mtb infection reveals that alterations in body fat critically impact pulmonary pathology in males. Specifically, these changes significantly reduce the levels of pulmonary CD8+ T-cells and increase the Mtb burden in the lungs compared to females. The reduction in CD8+ cells in males is linked to an increase in mitochondrial oxidative phosphorylation and a decrease in TNFα, which are essential for CD8+ cell activation. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Pathogenesis and Drug Effects in Tuberculosis)
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17 pages, 8283 KiB  
Article
Immunopathology of Pulmonary Mycobacterium tuberculosis Infection in a Humanized Mouse Model
by Afsal Kolloli, Ranjeet Kumar, Vishwanath Venketaraman and Selvakumar Subbian
Int. J. Mol. Sci. 2024, 25(3), 1656; https://doi.org/10.3390/ijms25031656 - 29 Jan 2024
Cited by 3 | Viewed by 2990
Abstract
Despite the availability of antibiotic therapy, tuberculosis (TB) is prevailing as a leading killer among human infectious diseases, which highlights the need for better intervention strategies to control TB. Several animal model systems, including mice, guinea pigs, rabbits, and non-human primates have been [...] Read more.
Despite the availability of antibiotic therapy, tuberculosis (TB) is prevailing as a leading killer among human infectious diseases, which highlights the need for better intervention strategies to control TB. Several animal model systems, including mice, guinea pigs, rabbits, and non-human primates have been developed and explored to understand TB pathogenesis. Although each of these models contributes to our current understanding of host-Mycobacterium tuberculosis (Mtb) interactions, none of these models fully recapitulate the pathological spectrum of clinical TB seen in human patients. Recently, humanized mouse models are being developed to improvise the limitations associated with the standard mouse model of TB, including lack of necrotic caseation of granulomas, a pathological hallmark of TB in humans. However, the spatial immunopathology of pulmonary TB in humanized mice is not fully understood. In this study, using a novel humanized mouse model, we evaluated the spatial immunopathology of pulmonary Mtb infection with a low-dose inoculum. Humanized NOD/LtSscidIL2Rγ null mice containing human fetal liver, thymus, and hematopoietic CD34+ cells and treated with human cytokines were aerosol challenged to implant <50 pathogenic Mtb (low dose) in the lungs. At 2 and 4 weeks post infection, the tissue bacterial load, disease pathology, and spatial immunohistology were determined in the lungs, liver, spleen, and adipose tissue using bacteriological, histopathological, and immunohistochemical techniques. The results indicate that implantation of <50 bacteria can establish a progressive disease in the lungs that transmits to other tissues over time. The disease pathology in organs correspondingly increased with the bacterial load. A distinct spatial distribution of T cells, macrophages, and natural killer cells were noted in the lung granulomas. The kinetics of spatial immune cell distribution were consistent with the disease pathology in the lungs. Thus, the novel humanized model recapitulates several key features of human pulmonary TB granulomatous response and can be a useful preclinical tool to evaluate potential anti-TB drugs and vaccines. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Pathogenesis and Drug Effects in Tuberculosis)
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