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Genetics and Immunity of Mycobacterial Infections: A Battle of Two Genomes

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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: closed (31 December 2021) | Viewed by 37456

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Prof. Dr. Alexander S. Apt

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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
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. David N. McMurray

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Regents Professor Emeritus, Department of Microbial Pathogenesis and Immunology, Texas A&M College of Medicine, College Station, TX, USA
Interests: tuberculosis; animal models; immunology; vaccination
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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

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Keywords

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

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Genetics and Immunity of Mycobacterial Infections: A Battle of Two Genomes 2.0 in International Journal of Molecular Sciences (3 articles)

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Research

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23 pages, 11316 KiB

Open AccessArticle

Progression and Dissemination of Pulmonary Mycobacterium Avium Infection in a Susceptible Immunocompetent Mouse Model

by Raymond Rosenbloom, Igor Gavrish, Anna E. Tseng, Kerstin Seidel, Shivraj M. Yabaji, Hans P. Gertje, Bertrand R. Huber, Igor Kramnik and Nicholas A. Crossland

Int. J. Mol. Sci. 2022, 23(11), 5999; https://doi.org/10.3390/ijms23115999 - 26 May 2022

Cited by 4 | Viewed by 2832

Abstract

Pulmonary infections caused by the group of nontuberculosis mycobacteria (NTM), Mycobacterium avium complex (MAC), are a growing public health concern with incidence and mortality steadily increasing globally. Granulomatous inflammation is the hallmark of MAC lung infection, yet reliable correlates of disease progression, susceptibility, and resolution are poorly defined. Unlike widely used inbred mouse strains, mice that carry the mutant allele at the genetic locus sst1 develop human-like pulmonary tuberculosis featuring well-organized caseating granulomas. We characterized pulmonary temporospatial outcomes of intranasal and left intrabronchial M. avium spp. hominissuis (M.av) induced pneumonia in B6.Sst1S mice, which carries the sst1 mutant allele. We utilized traditional semi-quantitative histomorphological evaluation, in combination with fluorescent multiplex immunohistochemistry (fmIHC), whole slide imaging, and quantitative digital image analysis. Followingintrabronchiolar infection with the laboratory M.av strain 101, the B6.Sst1S pulmonary lesions progressed 12–16 weeks post infection (wpi), with plateauing and/or resolving disease by 21 wpi. Caseating granulomas were not observed during the study. Disease progression from 12–16 wpi was associated with increased acid-fast bacilli, area of secondary granulomatous pneumonia lesions, and Arg1+ and double positive iNOS+/Arg1+ macrophages. Compared to B6 WT, at 16 wpi, B6.Sst1S lungs exhibited an increased area of acid-fast bacilli, larger secondary lesions with greater Arg1+ and double positive iNOS+/Arg1+ macrophages, and reduced T cell density. This morphomolecular analysis of histologic correlates of disease progression in B6.Sst1S could serve as a platform for assessment of medical countermeasures against NTM infection. Full article

(This article belongs to the Special Issue Genetics and Immunity of Mycobacterial Infections: A Battle of Two Genomes)

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17 pages, 2053 KiB

Open AccessArticle

An In Vivo Model of Separate M. tuberculosis Phagocytosis by Neutrophils and Macrophages: Gene Expression Profiles in the Parasite and Disease Development in the Mouse Host

by Elena Kondratieva, Konstantin Majorov, Artem Grigorov, Yulia Skvortsova, Tatiana Kondratieva, Elvira Rubakova, Irina Linge, Tatyana Azhikina and Alexander Apt

Int. J. Mol. Sci. 2022, 23(6), 2961; https://doi.org/10.3390/ijms23062961 - 9 Mar 2022

Cited by 3 | Viewed by 2920

Abstract

The role of neutrophils in tuberculosis infection remains less well studied compared to that of the CD4⁺ T-lymphocytes and macrophages. Thus, alterations in Mycobacterium tuberculosis transcription profile following phagocytosis by neutrophils and how these shifts differ from those caused by macrophage phagocytosis remain unknown. We developed a mouse model that allows obtaining large amounts of either neutrophils or macrophages infected in vivo with M. tuberculosis for mycobacteria isolation in quantities sufficient for the whole genome RNA sequencing and aerosol challenge of mice. Here, we present: (i) the differences in transcription profiles of mycobacteria isolated from liquid cultures, neutrophils and macrophages infected in vivo; (ii) phenotypes of infection and lung inflammation (life span, colony forming units (CFU) counts in organs, lung pathology, immune cells infiltration and cytokine production) in genetically TB-susceptible mice identically infected via respiratory tract with neutrophil-passaged (NP), macrophage-passaged (MP) and conventionally prepared (CP) mycobacteria. Two-hour residence within neutrophils caused transcriptome shifts consistent with mycobacterial transition to dormancy and diminished their capacity to attract immune cells to infected lung tissue. Mycobacterial multiplication in organs did not depend upon pre-phagocytosis, whilst survival time of infected mice was shorter in the group infected with NP bacilli. We also discuss possible reasons for these phenotypic divergences. Full article

(This article belongs to the Special Issue Genetics and Immunity of Mycobacterial Infections: A Battle of Two Genomes)

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22 pages, 4814 KiB

Open AccessArticle

Dual RNA Sequencing of Mycobacterium tuberculosis-Infected Human Splenic Macrophages Reveals a Strain-Dependent Host–Pathogen Response to Infection

by Víctor A. López-Agudelo, Andres Baena, Vianey Barrera, Felipe Cabarcas, Juan F. Alzate, Dany J. V. Beste, Rigoberto Ríos-Estepa and Luis F. Barrera

Int. J. Mol. Sci. 2022, 23(3), 1803; https://doi.org/10.3390/ijms23031803 - 4 Feb 2022

Cited by 12 | Viewed by 4164

Abstract

Tuberculosis (TB) is caused by Mycobacterium tuberculosis (Mtb), leading to pulmonary and extrapulmonary TB, whereby Mtb is disseminated to many other organs and tissues. Dissemination occurs early during the disease, and bacteria can be found first in the lymph nodes adjacent to the lungs and then later in the extrapulmonary organs, including the spleen. The early global gene expression response of human tissue macrophages and intracellular clinical isolates of Mtb has been poorly studied. Using dual RNA-seq, we have explored the mRNA profiles of two closely related clinical strains of the Latin American and Mediterranean (LAM) family of Mtb in infected human splenic macrophages (hSMs). This work shows that these pathogens mediate a distinct host response despite their genetic similarity. Using a genome-scale host–pathogen metabolic reconstruction to analyze the data further, we highlight that the infecting Mtb strain also determines the metabolic response of both the host and pathogen. Thus, macrophage ontogeny and the genetic-derived program of Mtb direct the host–pathogen interaction. Full article

(This article belongs to the Special Issue Genetics and Immunity of Mycobacterial Infections: A Battle of Two Genomes)

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23 pages, 3604 KiB

Open AccessArticle

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

by Elena G. Ufimtseva, Natalya I. Eremeeva, Tatiana V. Umpeleva, Diana V. Vakhrusheva and Sergey N. Skornyakov

Int. J. Mol. Sci. 2021, 22(7), 3452; https://doi.org/10.3390/ijms22073452 - 26 Mar 2021

Cited by 11 | Viewed by 2663

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 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

(This article belongs to the Special Issue Genetics and Immunity of Mycobacterial Infections: A Battle of Two Genomes)

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18 pages, 3179 KiB

Open AccessArticle

A Role for Mycobacterium tuberculosis Sigma Factor C in Copper Nutritional Immunity

by Benjamin T. Grosse-Siestrup, Tuhina Gupta, Shelly Helms, Samantha L. Tucker, Martin I. Voskuil, Frederick D. Quinn and Russell K. Karls

Int. J. Mol. Sci. 2021, 22(4), 2118; https://doi.org/10.3390/ijms22042118 - 20 Feb 2021

Cited by 11 | Viewed by 2665

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 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

(This article belongs to the Special Issue Genetics and Immunity of Mycobacterial Infections: A Battle of Two Genomes)

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23 pages, 2976 KiB

Open AccessArticle

Interaction of TLR4 and TLR8 in the Innate Immune Response against Mycobacterium Tuberculosis

by Shruthi Thada, Gabor L. Horvath, Mario M. Müller, Nickel Dittrich, Melanie L. Conrad, Saubashya Sur, Abid Hussain, Karin Pelka, Suman Latha Gaddam, Eicke Latz, Hortense Slevogt, Ralf R. Schumann and Sanne Burkert

Int. J. Mol. Sci. 2021, 22(4), 1560; https://doi.org/10.3390/ijms22041560 - 4 Feb 2021

Cited by 20 | Viewed by 4235

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 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

(This article belongs to the Special Issue Genetics and Immunity of Mycobacterial Infections: A Battle of Two Genomes)

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12 pages, 1104 KiB

Open AccessArticle

Developing Tadpole Xenopus laevis as a Comparative Animal Model to Study Mycobacterium abscessus Pathogenicity

by Arianna Lopez, Carolyn Shoen, Michael Cynamon, Dionysia Dimitrakopoulou, Matthieu Paiola, Martin S. Pavelka, Jr. and Jacques Robert

Int. J. Mol. Sci. 2021, 22(2), 806; https://doi.org/10.3390/ijms22020806 - 15 Jan 2021

Cited by 6 | Viewed by 2739

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 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

(This article belongs to the Special Issue Genetics and Immunity of Mycobacterial Infections: A Battle of Two Genomes)

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Review

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25 pages, 1545 KiB

Open AccessReview

Genetic Involvement of Mycobacterium avium Complex in the Regulation and Manipulation of Innate Immune Functions of Host Cells

by Min-Kyoung Shin and Sung Jae Shin

Int. J. Mol. Sci. 2021, 22(6), 3011; https://doi.org/10.3390/ijms22063011 - 16 Mar 2021

Cited by 12 | Viewed by 7508

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) 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

(This article belongs to the Special Issue Genetics and Immunity of Mycobacterial Infections: A Battle of Two Genomes)

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28 pages, 1461 KiB

Open AccessReview

Mycobacteriophages as Potential Therapeutic Agents against Drug-Resistant Tuberculosis

by Anna Allué-Guardia, Rajagopalan Saranathan, John Chan and Jordi B. Torrelles

Int. J. Mol. Sci. 2021, 22(2), 735; https://doi.org/10.3390/ijms22020735 - 13 Jan 2021

Cited by 28 | Viewed by 6788

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 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

(This article belongs to the Special Issue Genetics and Immunity of Mycobacterial Infections: A Battle of Two Genomes)

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