International Journal of Molecular Sciences

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Open AccessEditorial

Cellular and Molecular Mechanisms in Mycobacterial Infection

by Natalie E. Nieuwenhuizen and Joanna C. Evans

Int. J. Mol. Sci. 2022, 23(13), 7205; https://doi.org/10.3390/ijms23137205 - 29 Jun 2022

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Abstract

Tuberculosis (TB), caused by the bacillus Mycobacterium tuberculosis (Mtb), remains a leading cause of death by infectious disease, overshadowed only recently by the COVID-19 pandemic [...] Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Mycobacterial Infection)

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21 pages, 3343 KiB

Open AccessArticle

Insight into Population Structure and Drug Resistance of Pediatric Tuberculosis Strains from China and Russia Gained through Whole-Genome Sequencing

by Svetlana Zhdanova, Wei-Wei Jiao, Viacheslav Sinkov, Polina Khromova, Natalia Solovieva, Alexander Mushkin, Igor Mokrousov, Olesya Belopolskaya, Aleksey Masharsky, Anna Vyazovaya, Lubov Rychkova, Lubov Kolesnikova, Viacheslav Zhuravlev, A-Dong Shen and Oleg Ogarkov

Int. J. Mol. Sci. 2023, 24(12), 10302; https://doi.org/10.3390/ijms241210302 - 18 Jun 2023

Cited by 1 | Viewed by 1765

Abstract

This study aimed to determine phenotypic and genotypic drug resistance patterns of Mycobacterium tuberculosis strains from children with tuberculosis (TB) in China and Russia, two high-burden countries for multi/extensively-drug resistant (MDR/XDR) TB. Whole-genome sequencing data of M. tuberculosis isolates from China (n [...] Read more.

This study aimed to determine phenotypic and genotypic drug resistance patterns of Mycobacterium tuberculosis strains from children with tuberculosis (TB) in China and Russia, two high-burden countries for multi/extensively-drug resistant (MDR/XDR) TB. Whole-genome sequencing data of M. tuberculosis isolates from China (n = 137) and Russia (n = 60) were analyzed for phylogenetic markers and drug-resistance mutations, followed by comparison with phenotypic susceptibility data. The Beijing genotype was detected in 126 Chinese and 50 Russian isolates. The Euro-American lineage was detected in 10 Russian and 11 Chinese isolates. In the Russian collection, the Beijing genotype and Beijing B0/W148-cluster were dominated by MDR strains (68% and 94%, respectively). Ninety percent of B0/W148 strains were phenotypically pre-XDR. In the Chinese collection, neither of the Beijing sublineages was associated with MDR/pre-XDR status. MDR was mostly caused by low fitness cost mutations (rpoB S450L, katG S315T, rpsL K43R). Chinese rifampicin-resistant strains demonstrated a higher diversity of resistance mutations than Russian isolates (p = 0.003). The rifampicin and isoniazid resistance compensatory mutations were detected in some MDR strains, but they were not widespread. The molecular mechanisms of M. tuberculosis adaptation to anti-TB treatment are not unique to the pediatric strains, but they reflect the general situation with TB in Russia and China. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Mycobacterial Infection 2.0)

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19 pages, 9169 KiB

Open AccessArticle

Human GBP1 Is Involved in the Repair of Damaged Phagosomes/Endolysosomes

by Hellen Buijze, Volker Brinkmann, Robert Hurwitz, Anca Dorhoi, Stefan H. E. Kaufmann and Gang Pei

Int. J. Mol. Sci. 2023, 24(11), 9701; https://doi.org/10.3390/ijms24119701 - 2 Jun 2023

Cited by 4 | Viewed by 2081

Abstract

Mouse guanylate-binding proteins (mGBPs) are recruited to various invasive pathogens, thereby conferring cell-autonomous immunity against these pathogens. However, whether and how human GBPs (hGBPs) target M. tuberculosis (Mtb) and L. monocytogenes (Lm) remains unclear. Here, we describe hGBPs association with intracellular Mtb and [...] Read more.

Mouse guanylate-binding proteins (mGBPs) are recruited to various invasive pathogens, thereby conferring cell-autonomous immunity against these pathogens. However, whether and how human GBPs (hGBPs) target M. tuberculosis (Mtb) and L. monocytogenes (Lm) remains unclear. Here, we describe hGBPs association with intracellular Mtb and Lm, which was dependent on the ability of bacteria to induce disruption of phagosomal membranes. hGBP1 formed puncta structures which were recruited to ruptured endolysosomes. Furthermore, both GTP-binding and isoprenylation of hGBP1 were required for its puncta formation. hGBP1 was required for the recovery of endolysosomal integrity. In vitro lipid-binding assays demonstrated direct binding of hGBP1 to PI4P. Upon endolysosomal damage, hGBP1 was targeted to PI4P and PI(3,4)P2-positive endolysosomes in cells. Finally, live-cell imaging demonstrated that hGBP1 was recruited to damaged endolysosomes, and consequently mediated endolysosomal repair. In summary, we uncover a novel interferon-inducible mechanism in which hGBP1 contributes to the repair of damaged phagosomes/endolysosomes. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Mycobacterial Infection 2.0)

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18 pages, 4453 KiB

Open AccessArticle

Mycobacterium leprae’s Infective Capacity Is Associated with Activation of Genes Involved in PGL-I Biosynthesis in a Schwann Cells Infection Model

by Bibiana Chavarro-Portillo, Carlos Y. Soto and Martha Inírida Guerrero

Int. J. Mol. Sci. 2023, 24(10), 8727; https://doi.org/10.3390/ijms24108727 - 13 May 2023

Cited by 1 | Viewed by 1965

Abstract

Peripheral nerves and Schwann cells (SCs) are privileged and protected sites for initial colonization, survival, and spread of leprosy bacillus. Mycobacterium leprae strains that survive multidrug therapy show a metabolic inactivation that subsequently induces the recurrence of typical clinical manifestations of leprosy. Furthermore, [...] Read more.

Peripheral nerves and Schwann cells (SCs) are privileged and protected sites for initial colonization, survival, and spread of leprosy bacillus. Mycobacterium leprae strains that survive multidrug therapy show a metabolic inactivation that subsequently induces the recurrence of typical clinical manifestations of leprosy. Furthermore, the role of the cell wall phenolic glycolipid I (PGL-I) in the M. leprae internalization in SCs and the pathogenicity of M. leprae have been extensively known. This study assessed the infectivity in SCs of recurrent and non-recurrent M. leprae and their possible correlation with the genes involved in the PGL-I biosynthesis. The initial infectivity of non-recurrent strains in SCs was greater (27%) than a recurrent strain (6.5%). In addition, as the trials progressed, the infectivity of the recurrent and non-recurrent strains increased 2.5- and 2.0-fold, respectively; however, the maximum infectivity was displayed by non-recurrent strains at 12 days post-infection. On the other hand, qRT-PCR experiments showed that the transcription of key genes involved in PGL-I biosynthesis in non-recurrent strains was higher and faster (Day 3) than observed in the recurrent strain (Day 7). Thus, the results indicate that the capacity of PGL-I production is diminished in the recurrent strain, possibly affecting the infective capacity of these strains previously subjected to multidrug therapy. The present work opens the need to address more extensive and in-depth studies of the analysis of markers in the clinical isolates that indicate a possible future recurrence. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Mycobacterial Infection 2.0)

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25 pages, 4315 KiB

Open AccessArticle

Safety and Immunogenicity of Recombinant Bacille Calmette-Guérin Strain VPM1002 and Its Derivatives in a Goat Model

by Julia Figl, Heike Köhler, Nadine Wedlich, Elisabeth M. Liebler-Tenorio, Leander Grode, Gerald Parzmair, Gopinath Krishnamoorthy, Natalie E. Nieuwenhuizen, Stefan H. E. Kaufmann and Christian Menge

Int. J. Mol. Sci. 2023, 24(6), 5509; https://doi.org/10.3390/ijms24065509 - 14 Mar 2023

Cited by 4 | Viewed by 2142

Abstract

A more effective vaccine against tuberculosis than Bacille Calmette-Guérin (BCG) is urgently needed. BCG derived recombinant VPM1002 has been found to be more efficacious and safer than the parental strain in mice models. Newer candidates, such as VPM1002 Δpdx1 (PDX) and VPM1002 [...] Read more.

A more effective vaccine against tuberculosis than Bacille Calmette-Guérin (BCG) is urgently needed. BCG derived recombinant VPM1002 has been found to be more efficacious and safer than the parental strain in mice models. Newer candidates, such as VPM1002 Δpdx1 (PDX) and VPM1002 ΔnuoG (NUOG), were generated to further improve the safety profile or efficacy of the vaccine. Herein, we assessed the safety and immunogenicity of VPM1002 and its derivatives, PDX and NUOG, in juvenile goats. Vaccination did not affect the goats’ health in regards to clinical/hematological features. However, all three tested vaccine candidates and BCG induced granulomas at the site of injection, with some of the nodules developing ulcerations approximately one month post-vaccination. Viable vaccine strains were cultured from the injection site wounds in a few NUOG- and PDX- vaccinated animals. At necropsy (127 days post-vaccination), BCG, VPM1002, and NUOG, but not PDX, still persisted at the injection granulomas. All strains, apart from NUOG, induced granuloma formation only in the lymph nodes draining the injection site. In one animal, the administered BCG strain was recovered from the mediastinal lymph nodes. Interferon gamma (IFN-γ) release assay showed that VPM1002 and NUOG induced a strong antigen-specific response comparable to that elicited by BCG, while the response to PDX was delayed. Flow cytometry analysis of IFN-γ production by CD4⁺, CD8⁺, and γδ T cells showed that CD4⁺ T cells of VPM1002- and NUOG-vaccinated goats produced more IFN-γ compared to BCG-vaccinated and mock-treated animals. In summary, the subcutaneous application of VPM1002 and NUOG induced anti-tuberculous immunity, while exhibiting a comparable safety profile to BCG in goats. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Mycobacterial Infection 2.0)

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13 pages, 1675 KiB

Open AccessArticle

Mycobacterium tuberculosis Evasion of Guanylate Binding Protein-Mediated Host Defense in Mice Requires the ESX1 Secretion System

by Andrew J. Olive, Clare M. Smith, Christina E. Baer, Jörn Coers and Christopher M. Sassetti

Int. J. Mol. Sci. 2023, 24(3), 2861; https://doi.org/10.3390/ijms24032861 - 2 Feb 2023

Cited by 6 | Viewed by 2386

Abstract

Cell-intrinsic immune mechanisms control intracellular pathogens that infect eukaryotes. The intracellular pathogen Mycobacterium tuberculosis (Mtb) evolved to withstand cell-autonomous immunity to cause persistent infections and disease. A potent inducer of cell-autonomous immunity is the lymphocyte-derived cytokine IFNγ. While the production of [...] Read more.

Cell-intrinsic immune mechanisms control intracellular pathogens that infect eukaryotes. The intracellular pathogen Mycobacterium tuberculosis (Mtb) evolved to withstand cell-autonomous immunity to cause persistent infections and disease. A potent inducer of cell-autonomous immunity is the lymphocyte-derived cytokine IFNγ. While the production of IFNγ by T cells is essential to protect against Mtb, it is not capable of fully eradicating Mtb infection. This suggests that Mtb evades a subset of IFNγ-mediated antimicrobial responses, yet what mechanisms Mtb resists remains unclear. The IFNγ-inducible Guanylate binding proteins (GBPs) are key host defense proteins able to control infections with intracellular pathogens. GBPs were previously shown to directly restrict Mycobacterium bovis BCG yet their role during Mtb infection has remained unknown. Here, we examine the importance of a cluster of five GBPs on mouse chromosome 3 in controlling Mycobacterial infection. While M. bovis BCG is directly restricted by GBPs, we find that the GBPs on chromosome 3 do not contribute to the control of Mtb replication or the associated host response to infection. The differential effects of GBPs during Mtb versus M. bovis BCG infection is at least partially explained by the absence of the ESX1 secretion system from M. bovis BCG, since Mtb mutants lacking the ESX1 secretion system become similarly susceptible to GBP-mediated immune defense. Therefore, this specific genetic interaction between the murine host and Mycobacteria reveals a novel function for the ESX1 virulence system in the evasion of GBP-mediated immunity. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Mycobacterial Infection 2.0)

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15 pages, 2494 KiB

Open AccessArticle

Synthesis, Biological Evaluation and Computational Studies of New Hydrazide Derivatives Containing 1,3,4-Oxadiazole as Antitubercular Agents

by Daniele Zampieri, Sara Fortuna, Maurizio Romano, Alessandro De Logu, Gianluigi Cabiddu, Adriana Sanna and Maria Grazia Mamolo

Int. J. Mol. Sci. 2022, 23(23), 15295; https://doi.org/10.3390/ijms232315295 - 4 Dec 2022

Cited by 4 | Viewed by 1934

Abstract

To extend our screening for novel antimycobacterial molecules, we have designed, synthesized, and biologically evaluated a library of 14 new hydrazide derivatives containing 1,3,4-oxadiazole core. A variety of mycobacterial strains, including some drug-resistant strains, were tested for antimycobacterial activity. Among the compounds tested, [...] Read more.

To extend our screening for novel antimycobacterial molecules, we have designed, synthesized, and biologically evaluated a library of 14 new hydrazide derivatives containing 1,3,4-oxadiazole core. A variety of mycobacterial strains, including some drug-resistant strains, were tested for antimycobacterial activity. Among the compounds tested, five showed high antimycobacterial activity (MIC values of 8 μg/mL) against M. tuberculosis H37Ra attenuated strain, and two derivatives were effective (MIC of 4 µg/mL) against pyrazinamide-resistant strains. Furthermore, the novel compounds were tested against the fungal C. albicans strain, showing no antimycotic activity, and thus demonstrating a good selectivity profile. Notably, they also exhibited low cytotoxicity against human SH-SY5Y cells. The molecular modeling carried out suggested a plausible mechanism of action towards the active site of the InhA enzyme, which confirmed our hypothesis. In conclusion, the active compounds were predicted in silico for ADME properties, and all proved to be potentially orally absorbed in humans. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Mycobacterial Infection 2.0)

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25 pages, 6087 KiB

Open AccessArticle

Vaccine-Induced Subcutaneous Granulomas in Goats Reflect Differences in Host–Mycobacterium Interactions between BCG- and Recombinant BCG-Derivative Vaccines

by Elisabeth M. Liebler-Tenorio, Johannes Heyl, Nadine Wedlich, Julia Figl, Heike Köhler, Gopinath Krishnamoorthy, Natalie E. Nieuwenhuizen, Leander Grode, Stefan H. E. Kaufmann and Christian Menge

Int. J. Mol. Sci. 2022, 23(19), 10992; https://doi.org/10.3390/ijms231910992 - 20 Sep 2022

Cited by 5 | Viewed by 2822

Abstract

Tuberculous granulomas are highly dynamic structures reflecting the complex host–mycobacterium interactions. The objective of this study was to compare granuloma development at the site of vaccination with BCG and its recombinant derivatives in goats. To characterize the host response, epithelioid cells, multinucleated giant [...] Read more.

Tuberculous granulomas are highly dynamic structures reflecting the complex host–mycobacterium interactions. The objective of this study was to compare granuloma development at the site of vaccination with BCG and its recombinant derivatives in goats. To characterize the host response, epithelioid cells, multinucleated giant cells (MNGC), T cell subsets, B cells, plasma cells, dendritic cells and mycobacterial antigen were labelled by immunohistochemistry, and lipids and acid-fast bacteria (AFB) were labelled by specific staining. Granulomas with central caseous necrosis developed at the injection site of most goats though lesion size and extent of necrosis differed between vaccine strains. CD4⁺ T and B cells were more scarce and CD8⁺ cells were more numerous in granulomas induced by recombinant derivatives compared to their parental BCG strain. Further, the numbers of MNGCs and cells with lipid bodies were markedly lower in groups administered with recombinant BCG strains. Microscopic detection of AFB and mycobacterial antigen was rather frequent in the area of central necrosis, however, the isolation of bacteria in culture was rarely successful. In summary, BCG and its recombinant derivatives induced reproducibly subcutaneous caseous granulomas in goats that can be easily monitored and surgically removed for further studies. The granulomas reflected the genetic modifications of the recombinant BCG-derivatives and are therefore suitable models to compare reactions to different mycobacteria or TB vaccines. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Mycobacterial Infection 2.0)

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12 pages, 342 KiB

Open AccessArticle

Association between SNPs in microRNAs and microRNAs-Machinery Genes with Susceptibility of Leprosy in the Amazon Population

by Mayara Natália Santana da Silva, Diana Feio da Veiga Borges Leal, Camille Sena, Pablo Pinto, Angélica Rita Gobbo, Moises Batista da Silva, Claudio Guedes Salgado, Ney Pereira Carneiro dos Santos and Sidney Emanuel Batista dos Santos

Int. J. Mol. Sci. 2022, 23(18), 10628; https://doi.org/10.3390/ijms231810628 - 13 Sep 2022

Cited by 5 | Viewed by 2134

Abstract

Leprosy is a chronic neurodermatological disease caused by the bacillus Mycobacterium leprae. Recent studies show that SNPs in genes related to miRNAs have been associated with several diseases in different populations. This study aimed to evaluate the association of twenty-five SNPs in [...] Read more.

Leprosy is a chronic neurodermatological disease caused by the bacillus Mycobacterium leprae. Recent studies show that SNPs in genes related to miRNAs have been associated with several diseases in different populations. This study aimed to evaluate the association of twenty-five SNPs in genes encoding miRNAs related to biological processes and immune response with susceptibility to leprosy and its polar forms paucibacillary and multibacillary in the Brazilian Amazon. A total of 114 leprosy patients and 71 household contacts were included in this study. Genotyping was performed using TaqMan Open Array Genotyping. Ancestry-informative markers were used to estimate individual proportions of case and control groups. The SNP rs2505901 (pre-miR938) was associated with protection against the development of paucibacillary leprosy, while the SNPs rs639174 (DROSHA), rs636832 (AGO1), and rs4143815 (miR570) were associated with protection against the development of multibacillary leprosy. In contrast, the SNPs rs10739971 (pri-let-7a1), rs12904 (miR200C), and rs2168518 (miR4513) are associated with the development of the paucibacillary leprosy. The rs10739971 (pri-let-7a1) polymorphism was associated with the development of leprosy, while rs2910164 (miR146A) and rs10035440 (DROSHA) was significantly associated with an increased risk of developing multibacillary leprosy. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Mycobacterial Infection 2.0)

16 pages, 18495 KiB

Open AccessArticle

Replication-Deficient Lymphocytic Choriomeningitis Virus-Vectored Vaccine Candidate for the Induction of T Cell Immunity against Mycobacterium tuberculosis

by Elodie Belnoue, Alexis Vogelzang, Natalie E. Nieuwenhuizen, Magdalena A. Krzyzaniak, Stephanie Darbre, Mario Kreutzfeldt, Ingrid Wagner, Doron Merkler, Paul-Henri Lambert, Stefan H. E. Kaufmann, Claire-Anne Siegrist and Daniel D. Pinschewer

Int. J. Mol. Sci. 2022, 23(5), 2700; https://doi.org/10.3390/ijms23052700 - 28 Feb 2022

Cited by 6 | Viewed by 2830

Abstract

Mycobacterium tuberculosis (Mtb) represents a major burden to global health, and refined vaccines are needed. Replication-deficient lymphocytic choriomeningitis virus (rLCMV)-based vaccine vectors against cytomegalovirus have proven safe for human use and elicited robust T cell responses in a large proportion of [...] Read more.

Mycobacterium tuberculosis (Mtb) represents a major burden to global health, and refined vaccines are needed. Replication-deficient lymphocytic choriomeningitis virus (rLCMV)-based vaccine vectors against cytomegalovirus have proven safe for human use and elicited robust T cell responses in a large proportion of vaccine recipients. Here, we developed an rLCMV vaccine expressing the Mtb antigens TB10.4 and Ag85B. In mice, rLCMV elicited high frequencies of polyfunctional Mtb-specific CD8 and CD4 T cell responses. CD8 but not CD4 T cells were efficiently boosted upon vector re-vaccination. High-frequency responses were also observed in neonatally vaccinated mice, and co-administration of rLCMV with Expanded Program of Immunization (EPI) vaccines did not result in substantial reciprocal interference. Importantly, rLCMV immunization significantly reduced the lung Mtb burden upon aerosol challenge, resulting in improved lung ventilation. Protection was associated with increased CD8 T cell recruitment but reduced CD4 T cell infiltration upon Mtb challenge. When combining rLCMV with BCG vaccination in a heterologous prime-boost regimen, responses to the rLCMV-encoded Mtb antigens were further augmented, but protection was not significantly different from rLCMV or BCG vaccination alone. This work suggests that rLCMV may show utility for neonatal and/or adult vaccination efforts against pulmonary tuberculosis. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Mycobacterial Infection)

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18 pages, 4287 KiB

Open AccessArticle

Evaluation of Myeloperoxidase as Target for Host-Directed Therapy in Tuberculosis In Vivo

by Lara C. Linnemann, Ulrich E. Schaible and Tobias K. Dallenga

Int. J. Mol. Sci. 2022, 23(5), 2554; https://doi.org/10.3390/ijms23052554 - 25 Feb 2022

Cited by 5 | Viewed by 2531

Abstract

Due to the rise of tuberculosis cases infected with multi and extensively drug-resistant Mycobacterium tuberculosis strains and the emergence of isolates resistant to antibiotics newly in clinical use, host-directed therapies targeting pathogenesis-associated immune pathways adjunct to antibiotics may ameliorate disease and bacterial clearance. [...] Read more.

Due to the rise of tuberculosis cases infected with multi and extensively drug-resistant Mycobacterium tuberculosis strains and the emergence of isolates resistant to antibiotics newly in clinical use, host-directed therapies targeting pathogenesis-associated immune pathways adjunct to antibiotics may ameliorate disease and bacterial clearance. Active tuberculosis is characterized by neutrophil-mediated lung pathology and tissue destruction. Previously, we showed that preventing M. tuberculosis induced necrosis in human neutrophils by inhibition of myeloperoxidase (MPO) promoted default apoptosis and subsequent control of mycobacteria by macrophages taking up the mycobacteria-infected neutrophils. To translate our findings in an in vivo model, we tested the MPO inhibitor 4-aminobenzoic acid hydrazide (ABAH) in C3HeB/FeJ mice, which are highly susceptible to M. tuberculosis infection manifesting in neutrophil-associated necrotic granulomas. MPO inhibition alone or as co-treatment with isoniazid, a first-line antibiotic in tuberculosis treatment, did not result in reduced bacterial burden, improved pathology, or altered infiltrating immune cell compositions. MPO inhibition failed to prevent M. tuberculosis induced neutrophil necrosis in C3Heb/FeJ mice in vivo as well as in murine neutrophils in vitro. In contrast to human neutrophils, murine neutrophils do not respond to M. tuberculosis infection in an MPO-dependent manner. Thus, the murine C3HeB/FeJ model does not fully resemble the pathomechanisms in active human tuberculosis. Consequently, murine infection models of tuberculosis are not necessarily adequate to evaluate host-directed therapies targeting neutrophils in vivo. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Mycobacterial Infection)

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18 pages, 3381 KiB

Open AccessArticle

Mycobacterium tuberculosis H37Rv Strain Increases the Frequency of CD3⁺TCR⁺ Macrophages and Affects Their Phenotype, but Not Their Migration Ability

by Lucero A. Ramon-Luing, Claudia Carranza, Norma A. Téllez-Navarrete, Karen Medina-Quero, Yolanda Gonzalez, Martha Torres and Leslie Chavez-Galan

Int. J. Mol. Sci. 2022, 23(1), 329; https://doi.org/10.3390/ijms23010329 - 28 Dec 2021

Cited by 7 | Viewed by 3051

Abstract

In mycobacterial infections, the number of cells from two newly discovered subpopulations of CD3⁺ myeloid cells are increased at the infection site; one type expresses the T cell receptor (CD3⁺TCRαβ⁺) and the other does not (CD3⁺TCRαβ [...] Read more.

In mycobacterial infections, the number of cells from two newly discovered subpopulations of CD3⁺ myeloid cells are increased at the infection site; one type expresses the T cell receptor (CD3⁺TCRαβ⁺) and the other does not (CD3⁺TCRαβ⁻). The role of Mycobacterium tuberculosis (Mtb) virulence in generating these subpopulations and the ability of these cells to migrate remains unclear. In this study, monocyte-derived macrophages (MDMs) infected in vitro with either a virulent (H37Rv) or an avirulent (H37Ra) Mtb strain were phenotypically characterized based on three MDM phenotypes (CD3⁻, CD3⁺TCRαβ⁺, and CD3⁺TCRαβ⁻); then, their migration ability upon Mtb infection was evaluated. We found no differences in the frequency of CD3⁺ MDMs at 24 h of infection with either Mtb strain. However, H37Rv infection increased the frequency of CD3⁺TCRαβ⁺ MDMs at a multiplicity of infection of 1 and altered the expression of CD1b, CD1c, and TNF on the surface of cells from both the CD3⁺ MDM subpopulations; it also modified the expression of CCR2, CXCR1, and CCR7, thus affecting CCL2 and IL-8 levels. Moreover, H37Rv infection decreased the migration ability of the CD3⁻ MDMs, but not CD3⁺ MDMs. These results confirm that the CD3⁺ macrophage subpopulations express chemokine receptors that respond to chemoattractants, facilitating cell migration. Together, these data suggest that CD3⁺ MDMs are a functional subpopulation involved in the immune response against Mtb. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Mycobacterial Infection)

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18 pages, 3346 KiB

Open AccessArticle

PGRS Domain of Rv0297 of Mycobacterium tuberculosis Functions in A Calcium Dependent Manner

by Tarina Sharma, Jasdeep Singh, Sonam Grover, Manjunath P., Firdos Firdos, Anwar Alam, Nasreen Z. Ehtesham and Seyed E. Hasnain

Int. J. Mol. Sci. 2021, 22(17), 9390; https://doi.org/10.3390/ijms22179390 - 30 Aug 2021

Cited by 11 | Viewed by 2640

Abstract

Mycobacterium tuberculosis (M.tb), the pathogen causing tuberculosis, is a major threat to human health worldwide. Nearly 10% of M.tb genome encodes for a unique family of PE/PPE/PGRS proteins present exclusively in the genus Mycobacterium. The functions of most of these proteins are [...] Read more.

Mycobacterium tuberculosis (M.tb), the pathogen causing tuberculosis, is a major threat to human health worldwide. Nearly 10% of M.tb genome encodes for a unique family of PE/PPE/PGRS proteins present exclusively in the genus Mycobacterium. The functions of most of these proteins are yet unexplored. The PGRS domains of these proteins have been hypothesized to consist of Ca²⁺ binding motifs that help these intrinsically disordered proteins to modulate the host cellular responses. Ca²⁺ is an important secondary messenger that is involved in the pathogenesis of tuberculosis in diverse ways. This study presents the calcium-dependent function of the PGRS domain of Rv0297 (PE_PGRS5) in M.tb virulence and pathogenesis. Tandem repeat search revealed the presence of repetitive Ca²⁺ binding motifs in the PGRS domain of the Rv0297 protein (Rv0297PGRS). Molecular Dynamics simulations and fluorescence spectroscopy revealed Ca²⁺ dependent stabilization of the Rv0297PGRS protein. Calcium stabilized Rv0297PGRS enhances the interaction of Rv0297PGRS with surface localized Toll like receptor 4 (TLR4) of macrophages. The Ca²⁺ stabilized binding of Rv0297PGRS with the surface receptor of macrophages enhances its downstream consequences in terms of Nitric Oxide (NO) production and cytokine release. Thus, this study points to hitherto unidentified roles of calcium-modulated PE_PGRS proteins in the virulence of M.tb. Understanding the pathogenic potential of Ca²⁺ dependent PE_PGRS proteins can aid in targeting these proteins for therapeutic interventions. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Mycobacterial Infection)

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14 pages, 3592 KiB

Open AccessArticle

A Screening of the MMV Pandemic Response Box Reveals Epetraborole as A New Potent Inhibitor against Mycobacterium abscessus

by Taeho Kim, Bui-Thi-Bich Hanh, Boeun Heo, Nguyenthanh Quang, Yujin Park, Jihyeon Shin, Seunghyeon Jeon, June-Woo Park, Kirandeep Samby and Jichan Jang

Int. J. Mol. Sci. 2021, 22(11), 5936; https://doi.org/10.3390/ijms22115936 - 31 May 2021

Cited by 21 | Viewed by 3317

Abstract

Mycobacterium abscessus is the one of the most feared bacterial respiratory pathogens in the world. Unfortunately, there are many problems with the current M. abscessus therapies available. These problems include misdiagnoses, high drug resistance, poor long-term treatment outcomes, and high costs. Until now, [...] Read more.

Mycobacterium abscessus is the one of the most feared bacterial respiratory pathogens in the world. Unfortunately, there are many problems with the current M. abscessus therapies available. These problems include misdiagnoses, high drug resistance, poor long-term treatment outcomes, and high costs. Until now, there have only been a few new compounds or drug formulations which are active against M. abscessus, and these are present in preclinical and clinical development only. With that in mind, new and more powerful anti-M. abscessus medicines need to be discovered and developed. In this study, we conducted an in vitro-dual screen against M. abscessus rough (R) and smooth (S) variants using a Pandemic Response Box and identified epetraborole as a new effective candidate for M. abscessus therapy. For further validation, epetraborole showed significant activity against the growth of the M. abscessus wild-type strain, three subspecies, drug-resistant strains and clinical isolates in vitro, while also inhibiting the growth of M. abscessus that reside in macrophages without cytotoxicity. Furthermore, the in vivo efficacy of epetraborole in the zebrafish infection model was greater than that of tigecycline. Thus, we concluded that epetraborole is a potential anti-M. abscessus candidate in the M. abscessus drug search. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Mycobacterial Infection)

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16 pages, 1708 KiB

Open AccessArticle

Super-Resolution Microscopy Reveals a Direct Interaction of Intracellular Mycobacterium tuberculosis with the Antimicrobial Peptide LL-37

by Dhruva Deshpande, Mark Grieshober, Fanny Wondany, Fabian Gerbl, Reiner Noschka, Jens Michaelis and Steffen Stenger

Int. J. Mol. Sci. 2020, 21(18), 6741; https://doi.org/10.3390/ijms21186741 - 14 Sep 2020

Cited by 21 | Viewed by 5075

Abstract

The antimicrobial peptide LL-37 inhibits the growth of the major human pathogen Mycobacterium tuberculosis (Mtb), but the mechanism of the peptide–pathogen interaction inside human macrophages remains unclear. Super-resolution imaging techniques provide a novel opportunity to visualize these interactions on a molecular [...] Read more.

The antimicrobial peptide LL-37 inhibits the growth of the major human pathogen Mycobacterium tuberculosis (Mtb), but the mechanism of the peptide–pathogen interaction inside human macrophages remains unclear. Super-resolution imaging techniques provide a novel opportunity to visualize these interactions on a molecular level. Here, we adapt the super-resolution technique of stimulated emission depletion (STED) microscopy to study the uptake, intracellular localization and interaction of LL-37 with macrophages and virulent Mtb. We demonstrate that LL-37 is internalized by both uninfected and Mtb infected primary human macrophages. The peptide localizes in the membrane of early endosomes and lysosomes, the compartment in which mycobacteria reside. Functionally, LL-37 disrupts the cell wall of intra- and extracellular Mtb, resulting in the killing of the pathogen. In conclusion, we introduce STED microscopy as an innovative and informative tool for studying host–pathogen–peptide interactions, clearly extending the possibilities of conventional confocal microscopy. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Mycobacterial Infection)

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11 pages, 647 KiB

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MR1- and HLA-E-Dependent Antigen Presentation of Mycobacterium tuberculosis

by Se-Jin Kim and Elham Karamooz

Int. J. Mol. Sci. 2022, 23(22), 14412; https://doi.org/10.3390/ijms232214412 - 19 Nov 2022

Cited by 4 | Viewed by 2572

Abstract

MR1 and HLA-E are highly conserved nonclassical antigen-presenting molecules. They can present antigens derived from Mycobacterium tuberculosis to a distinct subset of MR1-restricted or HLA-restricted CD8+ T cells. MR1 presents small microbial metabolites, and HLA-E presents peptides and glycopeptides. In this review, we [...] Read more.

MR1 and HLA-E are highly conserved nonclassical antigen-presenting molecules. They can present antigens derived from Mycobacterium tuberculosis to a distinct subset of MR1-restricted or HLA-restricted CD8+ T cells. MR1 presents small microbial metabolites, and HLA-E presents peptides and glycopeptides. In this review, we will discuss the current understanding of MR1 and HLA-E antigen presentation in the context of Mycobacterium tuberculosis infection. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Mycobacterial Infection 2.0)

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12 pages, 729 KiB

Open AccessReview

Mitochondria in Mycobacterium Infection: From the Immune System to Mitochondrial Haplogroups

by Felipe Gouvea de Souza and Giovanna C. Cavalcante

Int. J. Mol. Sci. 2022, 23(17), 9511; https://doi.org/10.3390/ijms23179511 - 23 Aug 2022

Cited by 5 | Viewed by 2443

Abstract

In humans, mitochondria play key roles in the regulation of cellular functions, such as the regulation of the innate immune response and are targets of several pathogenic viruses and bacteria. Mycobacteria are intracellular pathogens that infect cells important to the immune system of [...] Read more.

In humans, mitochondria play key roles in the regulation of cellular functions, such as the regulation of the innate immune response and are targets of several pathogenic viruses and bacteria. Mycobacteria are intracellular pathogens that infect cells important to the immune system of organisms and target mitochondria to meet their energy demands. In this review, we discuss the main mechanisms by which mitochondria regulate the innate immune response of humans to mycobacterial infection, especially those that cause tuberculosis and leprosy. Notably, the importance of mitochondrial haplogroups and ancestry studies for mycobacterial diseases is also discussed. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Mycobacterial Infection 2.0)

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17 pages, 1993 KiB

Open AccessReview

The Mycobacterium tuberculosis PE_PGRS Protein Family Acts as an Immunological Decoy to Subvert Host Immune Response

by Tarina Sharma, Anwar Alam, Aquib Ehtram, Anshu Rani, Sonam Grover, Nasreen Z. Ehtesham and Seyed E. Hasnain

Int. J. Mol. Sci. 2022, 23(1), 525; https://doi.org/10.3390/ijms23010525 - 4 Jan 2022

Cited by 25 | Viewed by 8798

Abstract

Mycobacterium tuberculosis (M.tb) is a successful pathogen that can reside within the alveolar macrophages of the host and can survive in a latent stage. The pathogen has evolved and developed multiple strategies to resist the host immune responses. M.tb escapes from [...] Read more.

Mycobacterium tuberculosis (M.tb) is a successful pathogen that can reside within the alveolar macrophages of the host and can survive in a latent stage. The pathogen has evolved and developed multiple strategies to resist the host immune responses. M.tb escapes from host macrophage through evasion or subversion of immune effector functions. M.tb genome codes for PE/PPE/PE_PGRS proteins, which are intrinsically disordered, redundant and antigenic in nature. These proteins perform multiple functions that intensify the virulence competence of M.tb majorly by modulating immune responses, thereby affecting immune mediated clearance of the pathogen. The highly repetitive, redundant and antigenic nature of PE/PPE/PE_PGRS proteins provide a critical edge over other M.tb proteins in terms of imparting a higher level of virulence and also as a decoy molecule that masks the effect of effector molecules, thereby modulating immuno-surveillance. An understanding of how these proteins subvert the host immunological machinery may add to the current knowledge about M.tb virulence and pathogenesis. This can help in redirecting our strategies for tackling M.tb infections. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Mycobacterial Infection)

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20 pages, 3538 KiB

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Transmembrane TNF and Its Receptors TNFR1 and TNFR2 in Mycobacterial Infections

by Andy Ruiz, Yadira Palacios, Irene Garcia and Leslie Chavez-Galan

Int. J. Mol. Sci. 2021, 22(11), 5461; https://doi.org/10.3390/ijms22115461 - 22 May 2021

Cited by 26 | Viewed by 6163

Abstract

Tumor necrosis factor (TNF) is one of the main cytokines regulating a pro-inflammatory environment. It has been related to several cell functions, for instance, phagocytosis, apoptosis, proliferation, mitochondrial dynamic. Moreover, during mycobacterial infections, TNF plays an essential role to maintain granuloma formation. Several [...] Read more.

Tumor necrosis factor (TNF) is one of the main cytokines regulating a pro-inflammatory environment. It has been related to several cell functions, for instance, phagocytosis, apoptosis, proliferation, mitochondrial dynamic. Moreover, during mycobacterial infections, TNF plays an essential role to maintain granuloma formation. Several effector mechanisms have been implicated according to the interactions of the two active forms, soluble TNF (solTNF) and transmembrane TNF (tmTNF), with their receptors TNFR1 and TNFR2. We review the impact of these interactions in the context of mycobacterial infections. TNF is tightly regulated by binding to receptors, however, during mycobacterial infections, upstream activation signalling pathways may be influenced by key regulatory factors either at the membrane or cytosol level. Detailing the structure and activation pathways used by TNF and its receptors, such as its interaction with solTNF/TNFRs versus tmTNF/TNFRs, may bring a better understanding of the molecular mechanisms involved in activation pathways which can be helpful for the development of new therapies aimed at being more efficient against mycobacterial infections. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Mycobacterial Infection)

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24 pages, 923 KiB

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Neutrophils in Tuberculosis: Cell Biology, Cellular Networking and Multitasking in Host Defense

by Rachana R. Borkute, Sören Woelke, Gang Pei and Anca Dorhoi

Int. J. Mol. Sci. 2021, 22(9), 4801; https://doi.org/10.3390/ijms22094801 - 30 Apr 2021

Cited by 30 | Viewed by 6928

Abstract

Neutrophils readily infiltrate infection foci, phagocytose and usually destroy microbes. In tuberculosis (TB), a chronic pulmonary infection caused by Mycobacterium tuberculosis (Mtb), neutrophils harbor bacilli, are abundant in tissue lesions, and their abundances in blood correlate with poor disease outcomes in [...] Read more.

Neutrophils readily infiltrate infection foci, phagocytose and usually destroy microbes. In tuberculosis (TB), a chronic pulmonary infection caused by Mycobacterium tuberculosis (Mtb), neutrophils harbor bacilli, are abundant in tissue lesions, and their abundances in blood correlate with poor disease outcomes in patients. The biology of these innate immune cells in TB is complex. Neutrophils have been assigned host-beneficial as well as deleterious roles. The short lifespan of neutrophils purified from blood poses challenges to cell biology studies, leaving intracellular biological processes and the precise consequences of Mtb–neutrophil interactions ill-defined. The phenotypic heterogeneity of neutrophils, and their propensity to engage in cellular cross-talk and to exert various functions during homeostasis and disease, have recently been reported, and such observations are newly emerging in TB. Here, we review the interactions of neutrophils with Mtb, including subcellular events and cell fate upon infection, and summarize the cross-talks between neutrophils and lung-residing and -recruited cells. We highlight the roles of neutrophils in TB pathophysiology, discussing recent findings from distinct models of pulmonary TB, and emphasize technical advances that could facilitate the discovery of novel neutrophil-related disease mechanisms and enrich our knowledge of TB pathogenesis. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Mycobacterial Infection)

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26 pages, 4930 KiB

Open AccessReview

Addressing Latent Tuberculosis: New Advances in Mimicking the Disease, Discovering Key Targets, and Designing Hit Compounds

by André Campaniço, Shrika G. Harjivan, Digby F. Warner, Rui Moreira and Francisca Lopes

Int. J. Mol. Sci. 2020, 21(22), 8854; https://doi.org/10.3390/ijms21228854 - 23 Nov 2020

Cited by 12 | Viewed by 4144

Abstract

Despite being discovered and isolated more than one hundred years ago, tuberculosis (TB) remains a global public health concern arch. Our inability to eradicate this bacillus is strongly related with the growing resistance, low compliance to current drugs, and the capacity of the [...] Read more.

Despite being discovered and isolated more than one hundred years ago, tuberculosis (TB) remains a global public health concern arch. Our inability to eradicate this bacillus is strongly related with the growing resistance, low compliance to current drugs, and the capacity of the bacteria to coexist in a state of asymptomatic latency. This last state can be sustained for years or even decades, waiting for a breach in the immune system to become active again. Furthermore, most current therapies are not efficacious against this state, failing to completely clear the infection. Over the years, a series of experimental methods have been developed to mimic the latent state, currently used in drug discovery, both in vitro and in vivo. Most of these methods focus in one specific latency inducing factor, with only a few taking into consideration the complexity of the granuloma and the genomic and proteomic consequences of each physiological factor. A series of targets specifically involved in latency have been studied over the years with promising scaffolds being discovered and explored. Taking in account that solving the latency problem is one of the keys to eradicate the disease, herein we compile current therapies and diagnosis techniques, methods to mimic latency and new targets and compounds in the pipeline of drug discovery. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Mycobacterial Infection)

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