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Molecular and Immune Mechanisms in Pathogenic Mycobacteria Infections

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Microbiology".

Deadline for manuscript submissions: 20 July 2026 | Viewed by 3790

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Dr. Fabiana Bigi

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Guest Editor

Instituto Nacional de Tecnología Agropecuaria Buenos Aires, Buenos Aires, Argentina
Interests: transcriptional analysis; cattle immune cell; Mycobacteria infection

Dr. Federico Carlos Blanco

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Co-Guest Editor

Instituto de Agrobiotecnología y Biología Molecular (IABIMO), INTA-CONICET, Instituto de Biotecnología, CICVyA, Instituto Nacional de Tecnología Agropecuaria (INTA), N. Repetto y de Los Reseros, Hurlingham 1686, Argentina
Interests: bovine TB
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Special Issue Information

Dear Colleagues,

Pathogenic mycobacteria cause various diseases in a wide range of animals. Among these mycobacteria, the most relevant species belong to the Mycobacterium tuberculosis complex, which causes tuberculosis in mammals, including humans. The bacteria within this complex employ different mechanisms to evade the immune response and establish an active infection or persist in their hosts in a latent state for many years. In recent years, there have been significant advances in our understanding of the molecular and immune mechanisms governing how mycobacteria interact with their hosts. However, numerous aspects of these interactions remain unresolved. This Special Issue focused on "Molecular and immune mechanisms in infections by pathogenic mycobacteria" will include original research on the following: (1) advances in the knowledge of virulence factors and their mechanisms of action; (2) strategies employed by pathogenic mycobacteria to survive and/or replicate within their hosts; (3) immune responses to mycobacterial infection; and (4) cellular mechanisms in response to mycobacterial infection.

Dr. Fabiana Bigi
Dr. Federico Carlos Blanco
Guest Editors

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Keywords

Mycobacterium tuberculosis
virulence
pathogens

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Published Papers (5 papers)

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Research

18 pages, 2997 KB

Open AccessArticle

Mycobacterium bovis Strain-Dependent Effects of ESAT-6 and CFP-10 on Inflammasome Activation in Bovine Macrophages

by Federico Carlos Blanco, Cristina Lourdes Vazquez, María Mercedes Bigi, Rosana Valeria Rocha, Elizabeth Andrea García and Fabiana Bigi

Int. J. Mol. Sci. 2026, 27(9), 4099; https://doi.org/10.3390/ijms27094099 - 3 May 2026

Viewed by 133

Abstract

Mycobacterium bovis, the causative agent of bovine tuberculosis, infects and persists within macrophages, triggering pro-inflammatory responses. While these mechanisms are well characterized for Mycobacterium tuberculosis, less is known about host responses to M. bovis. Inflammasome activation and IL-1β production have been linked to ESAT-6, a substrate of the ESX-1 secretion system present in both species. Here, we examined inflammasome activation in bovine macrophages infected with the virulent M. bovis strain Mb04-303. M. bovis AF2122/97 and NCTC10772 upregulated IL-1β transcription, whereas Mb04-303 and BCG did not. Unexpectedly, deletion of the genes encoding ESAT-6 and CFP-10 from Mb04-303 enhanced inflammasome activation, as evidenced by increased NLRP3 and IL-1β transcription. Complementation with either wild-type ESAT-6/CFP-10 or the T63A ESAT-6 variant restored downregulation of the response, indicating that this substitution does not alter inflammasome modulation. In contrast, deletion of ESAT-6/CFP-10 from an attenuated M. bovis vaccine candidate reduced IL-1β transcription. No differences were observed between M. tuberculosis H37Rv and its ESAT-6-deficient mutant in bovine macrophages. Together, these findings demonstrate that ESAT-6/CFP-10-mediated modulation of inflammasome activation in bovine macrophages is highly dependent on the mycobacterial genetic background. Full article

(This article belongs to the Special Issue Molecular and Immune Mechanisms in Pathogenic Mycobacteria Infections)

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23 pages, 1396 KB

Open AccessArticle

The Potassium-Uptake Systems, Trk and Kdp, Coordinately Contribute to Growth Regulation and Survival of M. tuberculosis in Ion-Depleted and Acidic Environments

by Ayman G. E. Osman, Maborwa T. Matjokotja, Mushal Allam, Arshad Ismail, Ronald Anderson and Moloko C. Cholo

Int. J. Mol. Sci. 2026, 27(9), 3962; https://doi.org/10.3390/ijms27093962 - 29 Apr 2026

Viewed by 153

Abstract

The Mycobacterium tuberculosis bacterium encodes two active potassium (K⁺)-uptake transport systems, the Trk and the Kdp. The Trk is the low-affinity K⁺ transporter, consisting of two TrkA proteins, while the Kdp consists of the high-affinity K⁺ transporter KdpFABC and the two-component system KdpDE. Both transporters are utilised by the bacteria for growth and survival. During growth, the bacteria utilise the constitutively expressed Trk and suppress the Kdp, but upregulate both transporters during survival. In the current study, we investigated the interactive effects of these systems on bacterial growth and survival. This was achieved by first constructing a M. tuberculosis mutant strain in which both the Trk and Kdp systems were inactivated by homologous recombination. The mutant was evaluated for its growth kinetics in planktonic cultures, as well as survival in biofilm and macrophage cultures. The constructed M. tuberculosis mutant showed faster growth rates in planktonic cultures, but was attenuated for both biofilm formation and intracellular survival in isolated human monocyte-derived macrophages. These results illustrate that both K⁺-uptake systems are essential to sustain slow rates of bacterial growth, as well as for bacterial persistence in hostile environments via optimisation of biofilm formation, and intracellular survival in macrophages. (Words: 194) Full article

(This article belongs to the Special Issue Molecular and Immune Mechanisms in Pathogenic Mycobacteria Infections)

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17 pages, 5883 KB

Open AccessArticle

Mycobacterium tuberculosis H37Rv Short Linear PDZ-Binding Motif Proteins at the Host–Pathogen Interface

by Edgar Sevilla-Reyes, Jorge Rosas-García, Luis Horacio Gutiérrez-González and Teresa Santos-Mendoza

Int. J. Mol. Sci. 2026, 27(7), 3153; https://doi.org/10.3390/ijms27073153 - 31 Mar 2026

Viewed by 562

Abstract

Short linear motifs (SLiMs), such as PDZ-binding motifs (PDZbms), are compact interaction modules that mediate transient, specific protein–protein interactions. While PDZbms are well characterized in viral pathogenesis, subverting host protein functions, their role in bacterial systems requires further study. Mycobacterium tuberculosis (Mtb) is an intracellular pathogen that mainly infects macrophages. The type VII secretion system (T7SS) of Mtb secretes a subset of effector proteins (Esx) involved in virulence. By using molecular docking and support vector machine-based prediction, we analyzed PDZbm occurrence in T7SS Esx effector proteins and their ability to bind human PDZ domain-containing proteins. We identified PDZbms in most of the Esx proteins studied, with EsxA and EsxG showing the best PDZ-dependent interaction with syntenin-1, a host scaffold protein involved in vesicular trafficking and immune signaling. Additional Esx proteins were predicted to engage other host PDZ proteins. Proteome-wide analysis of Mtb H37Rv revealed that 23.1% of expressed proteins with ≥50 amino acids contained a C-terminal PDZbm. Gene Ontology and Reactome pathway enrichment revealed their involvement in processes related to bacterial and bacterial–host interactions, including redox balance, immunomodulation, and membrane localization, at various stages of infection. Our results support the existence of a PDZbm-mediated interface between Mtb and the human host, extending the PDZbm mimicry hypothesis beyond viruses to bacterial systems as an immune evasion strategy. This work may open multiple research lines focused on experimental validation and the development of a comparative PDZbm catalogue to uncover conserved virulence mechanisms that may guide the design of host-directed therapeutics. Full article

(This article belongs to the Special Issue Molecular and Immune Mechanisms in Pathogenic Mycobacteria Infections)

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15 pages, 3633 KB

Open AccessArticle

Phagocytosis of Mycobacterium fortuitum by Caprine Alveolar Macrophages Is Associated with iNOS and Pro-Inflammatory Markers Expression

by Miriam Blay-Benach, Patricia Cuenca-Lara, Joan Repullés, Zoraida Cervera and Bernat Pérez de Val

Int. J. Mol. Sci. 2026, 27(3), 1529; https://doi.org/10.3390/ijms27031529 - 4 Feb 2026

Viewed by 622

Abstract

Mycobacterial diseases, including tuberculosis (TB), remain the major health and economic challenges in livestock, underscoring the need to characterise the innate immune mechanisms involved in early bacterial containment. Alveolar macrophages (AMs) are the first line of defence against inhaled mycobacteria, yet the functional links between activation, polarisation, and phagocytic capacity in caprine AMs remain poorly defined. In this study, we compared a pH-dependent live-cell fluorescence assay with a culture-based method to evaluate phagocytosis and clearance of Mycobacterium fortuitum under different immunostimulatory conditions. AMs were stimulated in vitro with LPS or heat-inactivated Mycobacterium bovis (HIMB), and phagocytosis was assessed alongside activation and pro-inflammatory markers. Both approaches showed that LPS stimulation significantly enhanced mycobacterial clearance, despite reduced initial bacterial uptake. Moreover, this improved phagocytic capacity was associated with increased expression of the inducible Nitric Oxide Synthase (iNOS), MHCII, CD80, and CD86, as well as an elevated production of some pro-inflammatory cytokines. In contrast, HIMB induced cytokine secretion but failed to enhance activation markers or bacterial clearance. Collectively, these results establish the first association between pro-inflammatory activation and functional mycobacterial phagocytosis in caprine AMs and validate a robust methodological framework for studying innate immune responses relevant to TB and vaccine development in goats. Full article

(This article belongs to the Special Issue Molecular and Immune Mechanisms in Pathogenic Mycobacteria Infections)

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22 pages, 3499 KB

Open AccessArticle

Zinc Promotes Mitochondrial Health Through PGC-1alpha Enhancing Bacterial Clearance in Macrophages Infected with Mycobacterium avium Complex

by Ruxana T. Sadikot, Prabagaran Narayanasamy, Zhihong Yuan, Deandra Smith and Daren L. Knoell

Int. J. Mol. Sci. 2025, 26(19), 9270; https://doi.org/10.3390/ijms26199270 - 23 Sep 2025

Cited by 1 | Viewed by 1502

Abstract

Mitochondria are increasingly recognized as important contributors to immune function, in addition to energy production. They exert this influence through modulation of various signaling pathways that regulate cellular metabolism and immune function in response to pathogens. Peroxisome proliferator-activated receptor (PPAR) coactivator 1 alpha (PGC-1α) is the primary transcription factor and regulator involved in mitochondrial biogenesis. Long known to be involved in immune function, zinc (Zn) is also required for proper mitochondrial function. It is increasingly recognized that many cellular immunometabolic activities are also Zn-dependent. Taken together, we investigated the role of Zn deficiency, both dietary and genetically induced, and Zn supplementation in PGC-1α-mediated macrophage mitochondrial biogenesis and immune function following infection with Mycobacterium avium complex (MAC). Our novel findings show that Zn is an important regulator of PGC-1α, TFAM and mitochondrial biogenesis, leading to enhanced bacterial phagocytosis and bacterial killing in macrophages. Mechanistically, we show that the Zn importer ZIP8 (Zrt/Irt-like protein) orchestrates Zn-mediated effects on PGC-1α and mitochondrial function. Taken together, defective Zn biodistribution may increase susceptibility to infection, whereas Zn supplementation may provide a tractable host-directed therapy to enhance the innate immune response in patients vulnerable to MAC infection. Full article

(This article belongs to the Special Issue Molecular and Immune Mechanisms in Pathogenic Mycobacteria Infections)

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