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Special Issue "Genetics and Immunity of Mycobacterial Infections: A Battle of Two Genomes"

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: 31 December 2021.

Special Issue Editors

Prof. Dr. Alexander S. Apt
E-Mail Website
Guest Editor
Professor and Head, Laboratory for Immunogenetics, Central Research Institute for Tuberculosis, Moscow, Russia
Interests: tuberculosis, host genetics, immune responses, lung pathology, inflammation, T cell populations
Prof. Dr. David N. McMurray
E-Mail Website
Guest Editor
Regents Professor Emeritus, Department of Microbial Pathogenesis and Immunology, Texas A&M College of Medicine, College Station, Texas, USA
Interests: tuberculosis, animal models, immunology, vaccination

Special Issue Information

Dear Colleagues,

Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), is one of most successful pathogens of mankind, currently infecting one-quarter of the global population and claiming about 1.5 million lives every year. Long adaptive co-evolution of mycobacterial offensive and human defensive mechanisms has resulted in a wide spectrum of TB susceptibility and severity, ranging from asymptomatic latency to progressive fatal disease. The ability of mycobacteria to persist in the immune host in a latent state is often considered central to the host-pathogen relationship. Recent advances in mycobacterial genetics and virulence mechanisms on the one hand, and host immunity and genetic susceptibility on the other hand, provide an opportunity for renewed investigation of this major threat to human health. Both a plethora of mycobacterial disease manifestations and a long history of research on TB (and leprosy) has made these infections a “gold standard” for investigating the pathogenesis of chronic infectious diseases and the elucidation of fundamental concepts of parasitism. TB, when viewed as an interaction between two co-evolving species each with their own survival strategies – a “battle of two genomes”, has emerged as a paradigm for intracellular parasitism.

Genetic investigation of TB infection susceptibility and disease severity has been ongoing for decades both in experimental and clinical settings, but has gained traction recently from functional studies, including microRNAs, transcriptomics, proteomics and epigenetics of the host and parasite. The previously unappreciated importance of innate host defense mechanisms has revolutionized the understanding of the host-pathogen relationship. Effective adaptive immune responses, including the key activity of mycobacteria-specific and bystander CD4+ and CD8+ effector and regulatory T cell populations, can control mycobacterial populations throughout the body, but can also promote the development of progressively destructive lesions in host tissues. The role of B cells and humoral immunity, long overlooked by mycobacterial researchers, has received renewed interest. Host and parasite genomics are most powerful when focusing on carefully selected immune/pathology phenotypes in specific host-pathogen combinations. Genetic and physiological manipulation of mycobacteria and the rational selection of genetically defined hosts in experimental settings provide useful information about how mycobacteria alter innate and acquired immune responses of the host, and what features of pathology underlie protective vs. pathogenic inflammatory responses. We believe that a series of articles within this framework will make a valuable contribution to a better understanding of these very important, rapidly developing and still highly controversial aspects of mycobacterial research.

Prof. Dr. Alexander S. Apt
Prof. Dr. David N. McMurray
Guest Editors

Manuscript Submission Information

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Keywords

  • tuberculosis
  • mycobacteria-host interactions
  • virulence factors
  • mycobacteria and host gene expression
  • lung inflammation
  • TB latency

Published Papers (6 papers)

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Research

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Article
Mycobacterium tuberculosis Load in Host Cells and the Antibacterial Activity of Alveolar Macrophages Are Linked and Differentially Regulated in Various Lung Lesions of Patients with Pulmonary Tuberculosis
Int. J. Mol. Sci. 2021, 22(7), 3452; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073452 - 26 Mar 2021
Cited by 2 | Viewed by 575
Abstract
Tuberculosis (TB) is a disease caused by Mycobacterium tuberculosis (Mtb) infection with the formation of a broad range of abnormal lung lesions within a single patient. Although host–pathogen interactions determine disease outcome, they are poorly understood within individual lesions at different [...] Read more.
Tuberculosis (TB) is a disease caused by Mycobacterium tuberculosis (Mtb) infection with the formation of a broad range of abnormal lung lesions within a single patient. Although host–pathogen interactions determine disease outcome, they are poorly understood within individual lesions at different stages of maturation. We compared Mtb load in a tuberculoma wall and the lung tissue distant from tuberculomas in TB patients. These data were combined with an analysis of activation and bactericidal statuses of alveolar macrophages and other cell subtypes examined both in ex vivo culture and on the histological sections obtained from the same lung lesions. The expression of pattern recognition receptors CD14, CD11b, and TLR-2, transcription factors HIF-1α, HIF-2α, and NF-κB p50 and p65, enzymes iNOS and COX-2, reactive oxygen species (ROS) biosynthesis, and lipid production were detected for various lung lesions, with individual Mtb loads in them. The walls of tuberculomas with insufficient inflammation and excessive fibrosis were identified as being the main niche for Mtb survival (single or as colonies) in non-foamy alveolar macrophages among various lung lesions examined. The identification of factors engaged in the control of Mtb infection and tissue pathology in local lung microenvironments, where host–pathogen relationships take place, is critical for the development of new therapeutic strategies. Full article
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Article
A Role for Mycobacterium tuberculosis Sigma Factor C in Copper Nutritional Immunity
Int. J. Mol. Sci. 2021, 22(4), 2118; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22042118 - 20 Feb 2021
Viewed by 600
Abstract
Sigma factor C (SigC) contributes to Mycobacterium tuberculosis virulence in various animal models, but the stress response coordinated by this transcription factor was undefined. The results presented here indicate that SigC prevents copper starvation. Whole genome expression studies demonstrate short-term (4-h) induction of [...] Read more.
Sigma factor C (SigC) contributes to Mycobacterium tuberculosis virulence in various animal models, but the stress response coordinated by this transcription factor was undefined. The results presented here indicate that SigC prevents copper starvation. Whole genome expression studies demonstrate short-term (4-h) induction of sigC, controlled from a tetracycline-inducible promoter, upregulates ctpB and genes in the nonribosomal peptide synthase (nrp) operon. These genes are expressed at higher levels after 48-h sigC induction, but also elevated are genes encoding copper-responsive regulator RicR and RicR-regulated copper toxicity response operon genes rv0846–rv0850, suggesting prolonged sigC induction results in excessive copper uptake. No growth and global transcriptional differences are observed between a sigC null mutant relative to its parent strain in 7H9 medium. In a copper-deficient medium, however, growth of the sigC deletion strain lags the parent, and 40 genes (including those in the nrp operon) are differentially expressed. Copper supplementation reverses the growth defect and silences most transcriptional differences. Together, these data support SigC as a transcriptional regulator of copper acquisition when the metal is scarce. Attenuation of sigC mutants in severe combined immunodeficient mice is consistent with an inability to overcome innate host defenses that sequester copper ions to deprive invading microbes of this essential micronutrient. Full article
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Article
Interaction of TLR4 and TLR8 in the Innate Immune Response against Mycobacterium Tuberculosis
Int. J. Mol. Sci. 2021, 22(4), 1560; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041560 - 04 Feb 2021
Viewed by 797
Abstract
The interaction and crosstalk of Toll-like receptors (TLRs) is an established pathway in which the innate immune system recognises and fights pathogens. In a single nucleotide polymorphisms (SNP) analysis of an Indian cohort, we found evidence for both TLR4-399T and TRL8-1A conveying increased [...] Read more.
The interaction and crosstalk of Toll-like receptors (TLRs) is an established pathway in which the innate immune system recognises and fights pathogens. In a single nucleotide polymorphisms (SNP) analysis of an Indian cohort, we found evidence for both TLR4-399T and TRL8-1A conveying increased susceptibility towards tuberculosis (TB) in an interdependent manner, even though there is no established TLR4 ligand present in Mycobacterium tuberculosis (Mtb), which is the causative pathogen of TB. Docking studies revealed that TLR4 and TLR8 can build a heterodimer, allowing interaction with TLR8 ligands. The conformational change of TLR4-399T might impair this interaction. With immunoprecipitation and mass spectrometry, we precipitated TLR4 with TLR8-targeted antibodies, indicating heterodimerisation. Confocal microscopy confirmed a high co-localisation frequency of TLR4 and TLR8 that further increased upon TLR8 stimulation. The heterodimerisation of TLR4 and TLR8 led to an induction of IL12p40, NF-κB, and IRF3. TLR4-399T in interaction with TLR8 induced an increased NF-κB response as compared to TLR4-399C, which was potentially caused by an alteration of subsequent immunological pathways involving type I IFNs. In summary, we present evidence that the heterodimerisation of TLR4 and TLR8 at the endosome is involved in Mtb recognition via TLR8 ligands, such as microbial RNA, which induces a Th1 response. These findings may lead to novel targets for therapeutic interventions and vaccine development regarding TB. Full article
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Article
Developing Tadpole Xenopus laevis as a Comparative Animal Model to Study Mycobacterium abscessus Pathogenicity
Int. J. Mol. Sci. 2021, 22(2), 806; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020806 - 15 Jan 2021
Viewed by 799
Abstract
Mycobacterium abscessus (Mab) is an emerging, nontuberculosis mycobacterium (NTM) that infects humans. Mab has two morphotypes, smooth (S) and rough (R), related to the production of glycopeptidolipid (GPL), that differ in pathogenesis. To further understand the pathogenicity of these morphotypes in vivo, the [...] Read more.
Mycobacterium abscessus (Mab) is an emerging, nontuberculosis mycobacterium (NTM) that infects humans. Mab has two morphotypes, smooth (S) and rough (R), related to the production of glycopeptidolipid (GPL), that differ in pathogenesis. To further understand the pathogenicity of these morphotypes in vivo, the amphibian Xenopus laevis was used as an alternative animal model. Mab infections have been previously modeled in zebrafish embryos and mice, but Mab are cleared early from immunocompetent mice, preventing the study of chronic infection, and the zebrafish model cannot be used to model a pulmonary infection and T cell involvement. Here, we show that X. laevis tadpoles, which have lungs and T cells, can be used as a complementary model for persistent Mab infection and pathogenesis. Intraperitoneal (IP) inoculation of S and R Mab morphotypes disseminated to tadpole tissues including liver and lungs, persisting for up to 40 days without significant mortality. Furthermore, the R morphotype was more persistent, maintaining a higher bacterial load at 40 days postinoculation. In contrast, the intracardiac (IC) inoculation with S Mab induced significantly greater mortality than inoculation with the R Mab form. These data suggest that X. laevis tadpoles can serve as a useful comparative experimental organism to investigate pathogenesis and host resistance to M. abscessus. Full article
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Review

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Review
Genetic Involvement of Mycobacterium avium Complex in the Regulation and Manipulation of Innate Immune Functions of Host Cells
Int. J. Mol. Sci. 2021, 22(6), 3011; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22063011 - 16 Mar 2021
Viewed by 793
Abstract
Mycobacterium avium complex (MAC), a collection of mycobacterial species representing nontuberculous mycobacteria, are characterized as ubiquitous and opportunistic pathogens. The incidence and prevalence of infectious diseases caused by MAC have been emerging globally due to complications in the treatment of MAC-pulmonary disease (PD) [...] Read more.
Mycobacterium avium complex (MAC), a collection of mycobacterial species representing nontuberculous mycobacteria, are characterized as ubiquitous and opportunistic pathogens. The incidence and prevalence of infectious diseases caused by MAC have been emerging globally due to complications in the treatment of MAC-pulmonary disease (PD) in humans and the lack of understating individual differences in genetic traits and pathogenesis of MAC species or subspecies. Despite genetically close one to another, mycobacteria species belonging to the MAC cause diseases to different host range along with a distinct spectrum of disease. In addition, unlike Mycobacterium tuberculosis, the underlying mechanisms for the pathogenesis of MAC infection from environmental sources of infection to their survival strategies within host cells have not been fully elucidated. In this review, we highlight unique genetic and genotypic differences in MAC species and the virulence factors conferring the ability to MAC for the tactics evading innate immune attacks of host cells based on the recent advances in genetic analysis by exemplifying M. avium subsp. hominissuis, a major representative pathogen causing MAC-PD in humans. Further understanding of the genetic link between host and MAC may contribute to enhance host anti-MAC immunity, but also provide novel therapeutic approaches targeting the pangenesis-associated genes of MAC. Full article
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Review
Mycobacteriophages as Potential Therapeutic Agents against Drug-Resistant Tuberculosis
Int. J. Mol. Sci. 2021, 22(2), 735; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020735 - 13 Jan 2021
Cited by 2 | Viewed by 1244
Abstract
The current emergence of multi-, extensively-, extremely-, and total-drug resistant strains of Mycobacterium tuberculosis poses a major health, social, and economic threat, and stresses the need to develop new therapeutic strategies. The notion of phage therapy against bacteria has been around for more [...] Read more.
The current emergence of multi-, extensively-, extremely-, and total-drug resistant strains of Mycobacterium tuberculosis poses a major health, social, and economic threat, and stresses the need to develop new therapeutic strategies. The notion of phage therapy against bacteria has been around for more than a century and, although its implementation was abandoned after the introduction of drugs, it is now making a comeback and gaining renewed interest in Western medicine as an alternative to treat drug-resistant pathogens. Mycobacteriophages are genetically diverse viruses that specifically infect mycobacterial hosts, including members of the M. tuberculosis complex. This review describes general features of mycobacteriophages and their mechanisms of killing M. tuberculosis, as well as their advantages and limitations as therapeutic and prophylactic agents against drug-resistant M. tuberculosis strains. This review also discusses the role of human lung micro-environments in shaping the availability of mycobacteriophage receptors on the M. tuberculosis cell envelope surface, the risk of potential development of bacterial resistance to mycobacteriophages, and the interactions with the mammalian host immune system. Finally, it summarizes the knowledge gaps and defines key questions to be addressed regarding the clinical application of phage therapy for the treatment of drug-resistant tuberculosis. Full article
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