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Infection and Immunity Jul 2021Although nontuberculous mycobacteria (NTM) are considered opportunistic infections, incidence and prevalence of NTM infection are increasing worldwide becoming a major... (Review)
Review
Although nontuberculous mycobacteria (NTM) are considered opportunistic infections, incidence and prevalence of NTM infection are increasing worldwide becoming a major public health threat. Innate immunity plays an essential role in mediating the initial host response against these intracellular bacteria. Specifically, macrophages phagocytose and eliminate NTM and act as antigen-presenting cells, which trigger downstream activation of cellular and humoral adaptive immune responses. Identification of macrophage receptors, mycobacterial ligands, phagosome maturation, autophagy/necrosis, and escape mechanisms are important components of this immunity network. The role of the macrophage in mycobacterial disease has mainly been studied in tuberculosis (TB), but limited information exists on its role in NTM. In this review, we focus on NTM immunity, the role of macrophages, and host interaction in NTM infection.
Topics: Adaptive Immunity; Host-Pathogen Interactions; Humans; Immunity, Innate; Macrophages; Microbial Viability; Mycobacterium Infections, Nontuberculous; Nontuberculous Mycobacteria; Phagocytosis
PubMed: 34097459
DOI: 10.1128/IAI.00812-20 -
American Journal of Respiratory Cell... Aug 2020The incidence and prevalence of nontuberculous mycobacteria (NTM) lung disease is rising worldwide and accounts for most clinical cases of NTM disease. NTM infections... (Review)
Review
The incidence and prevalence of nontuberculous mycobacteria (NTM) lung disease is rising worldwide and accounts for most clinical cases of NTM disease. NTM infections occur in both immunocompetent and immunocompromised hosts. Macrophages are the primary host cells that initiate an immune response to NTM. Defining the molecular events that govern the control of infection within macrophages is fundamental to understanding the pathogenesis of NTM disease. Here, we review key macrophage host signaling pathways that contribute to the host immune response to pulmonary NTM infections. In this review, we focus primarily on NTM that are known to cause lung disease, including , , and .
Topics: Animals; Humans; Lung Diseases; Macrophages; Mycobacterium Infections, Nontuberculous; Nontuberculous Mycobacteria; Signal Transduction
PubMed: 32160017
DOI: 10.1165/rcmb.2019-0241TR -
Scientific Reports Aug 2021To describe the clinical features and the risk factors for nontuberculous mycobacteria (NTM) and Talaromyces marneffei (TM) co-infections in HIV-negative patients. A... (Observational Study)
Observational Study
To describe the clinical features and the risk factors for nontuberculous mycobacteria (NTM) and Talaromyces marneffei (TM) co-infections in HIV-negative patients. A multicenter retrospective study in 13 hospitals, and a systematic literature review were performed of original articles published in English related to TM/NTM co-infections. HIV-negative patients with TM and NTM co-infections comprised Group 1; TM-only infection Group 2; NTM-only infection Group 3; and healthy volunteers Group 4. Univariate logistic analysis was used to estimate the potential risk factors of TM/NTM co-infections. A total of 22 cases of TM and NTM co-infections were enrolled. Of these, 17 patients (77.3%) had a missed diagnosis of one of the TM or NTM pathogens. The anti-IFN-γ autoantibodies (AIGAs) titer, white blood cell (WBC), neutrophil counts (N), erythrocyte sedimentation rate (ESR), C reactive protein (CRP), globulin, and immunoglobulin G (IgG) levels of Group 1 were higher than those of the other groups, whereas the levels of CD4T cells was lower than those of other groups. There was a significant negative correlation between the AIGA titers and the number of CD4T cells (P < 0.05). Factors including the ratio of the actual values to the cut-off values of AIGAs, WBC, N, HGB, CD4T cells, IgG, IgM, IgA, serum globulin, ESR, and CRP were taken as potential risk factors for TM and NTM co-infection. Most patients with TM and NTM co-infection had a missed diagnosis of one of the TM or NTM pathogens. The levels of AIGAs, WBC, N, ESR, and CRP in TM and NTM co-infections were remarkably higher than in mono-infection. High-titer AIGAs may be a potential risk factor and susceptibility factor for co-infection of TM and NTM in HIV-negative hosts.
Topics: Adult; Aged; Case-Control Studies; China; Coinfection; Cytokines; Female; Follow-Up Studies; HIV Infections; Humans; Male; Middle Aged; Mycobacterium Infections, Nontuberculous; Nontuberculous Mycobacteria; Prognosis; Retrospective Studies; Risk Factors; Talaromyces
PubMed: 34376749
DOI: 10.1038/s41598-021-95686-0 -
European Respiratory Review : An... Jun 2021Nontuberculous mycobacteria (NTM) are diverse microbial species encompassing commensals and pathogens with the ability to cause pulmonary disease in both immunocompetent... (Review)
Review
Nontuberculous mycobacteria (NTM) are diverse microbial species encompassing commensals and pathogens with the ability to cause pulmonary disease in both immunocompetent and immunocompromised individuals. In contrast to , which has seen a reduction in disease rates in developed countries, the incidence and prevalence of NTM disease is increasing. NTM are difficult to treat with standard antimicrobial regimens and may contain both virulence and antibiotic-resistance genes with potential for pathogenicity. With the advent of molecular techniques, it has been elucidated that these organisms do not reside in isolation and are rather part of a complex milieu of microorganisms within the host lung microbiome. Over the last decade, studies have highlighted the impact of the microbiome on host immunity, metabolism and cell-cell communication. This recognition of a broader community raises the possibility that the microbiome may disrupt the balance between infection and disease. Additionally, NTM disease progression and antimicrobial therapy may affect the healthy steady state of the host and function of the microbiome, contributing to further dysbiosis and clinical deterioration. There have been limited studies assessing how NTM may influence the relationship between microbiome and host. In this review, we highlight available studies about NTM and the microbiome, postulate on virulence mechanisms by which these microorganisms communicate and discuss implications for treatment.
Topics: Humans; Lung Diseases; Microbiota; Mycobacterium Infections, Nontuberculous; Mycobacterium tuberculosis; Nontuberculous Mycobacteria
PubMed: 34039671
DOI: 10.1183/16000617.0299-2020 -
Frontiers in Immunology 2021Autophagy is critically involved in host defense pathways through targeting and elimination of numerous pathogens autophagic machinery. Nontuberculous mycobacteria... (Review)
Review
Autophagy is critically involved in host defense pathways through targeting and elimination of numerous pathogens autophagic machinery. Nontuberculous mycobacteria (NTMs) are ubiquitous microbes, have become increasingly prevalent, and are emerging as clinically important strains due to drug-resistant issues. Compared to (Mtb), the causal pathogen for human tuberculosis, the roles of autophagy remain largely uncharacterized in the context of a variety of NTM infections. Compelling evidence suggests that host autophagy activation plays an essential role in the enhancement of antimicrobial immune responses and controlling pathological inflammation against various NTM infections. As similar to Mtb, it is believed that NTM bacteria evolve multiple strategies to manipulate and hijack host autophagy pathways. Despite this, we are just beginning to understand the molecular mechanisms underlying the crosstalk between pathogen and the host autophagy system in a battle with NTM bacteria. In this review, we will explore the function of autophagy, which is involved in shaping host-pathogen interaction and disease outcomes during NTM infections. These efforts will lead to the development of autophagy-based host-directed therapeutics against NTM infection.
Topics: Animals; Anti-Bacterial Agents; Autophagy; Biological Evolution; Drug Resistance, Bacterial; Host-Pathogen Interactions; Humans; Immunity, Innate; Mycobacterium Infections, Nontuberculous; Nontuberculous Mycobacteria
PubMed: 34552591
DOI: 10.3389/fimmu.2021.728742 -
Frontiers in Cellular and Infection... 2021Genome scale mutagenesis identifies many genes required for mycobacterial infectivity and survival, but their contributions and mechanisms of action within the host are...
Genome scale mutagenesis identifies many genes required for mycobacterial infectivity and survival, but their contributions and mechanisms of action within the host are poorly understood. Using CRISPR interference, we created a knockdown of gene in (), which reduced the resistance to acid medium. To further explore the function of PPE31, the mutant strain was generated in and (), respectively. Macrophages infected with the mutant strain caused a reduced inflammatory mediator expressions. In addition, macrophages infected with Δ had decreased host cell death dependent on JNK signaling. Consistent with these results, deletion of from increased the sensitivity to acid medium and reduced cell death in macrophages. Furthermore, we demonstrate that both mutants from and resulted in reduced survival in macrophages, and the survivability of was deceased in zebrafish due to loss of . Our findings confirm that PPE31 as a virulence associated factor that modulates innate immune responses to mycobacterial infection.
Topics: Animals; Cell Death; Mycobacterium Infections, Nontuberculous; Mycobacterium marinum; Mycobacterium tuberculosis; Virulence; Zebrafish
PubMed: 33928042
DOI: 10.3389/fcimb.2021.629836 -
International Journal of Molecular... Sep 2020is a non-tuberculous mycobacterium notoriously known for causing severe, chronic infections. Treatment of these infections is challenging due to either intrinsic or... (Review)
Review
is a non-tuberculous mycobacterium notoriously known for causing severe, chronic infections. Treatment of these infections is challenging due to either intrinsic or acquired resistance of to multiple antibiotics. Despite prolonged poly-antimicrobial therapy, treatment of infections often fails, leading to progressive morbidity and eventual mortality. Great research efforts are invested in finding new therapeutic options for Clofazimine and rifabutin are known anti-mycobacterial antibiotics, repurposed for use against . Novel antimicrobials active against include delamanid, pretomanid and PIPD1 and the recently approved beta-lactamase inhibitors avibactam, relebactam and vaborbactam. Previously unused antimicrobial combinations, e.g. vancomycin-clarithromycin and dual beta-lactam therapy, have been shown to have synergistic effect against in experimental models, suggesting their possible use in multiple-drug regimens. Finally, engineered phage therapy has been reported to be clinically successful in a severe case of disseminated infection. While many of these experimental therapeutics have shown activity against in vitro, as well as in intracellular and/or animal models, most have little if any evidence of effect in human infections. Clinical studies of treatments are needed to reliably determine the value of their incorporation in therapeutic regimens.
Topics: Administration, Inhalation; Animals; Anti-Bacterial Agents; Clinical Trials as Topic; Drug Evaluation, Preclinical; Drugs, Investigational; Humans; Mice; Mycobacterium Infections, Nontuberculous; Mycobacterium abscessus; Nitric Oxide; Phage Therapy; Therapies, Investigational; Zebrafish
PubMed: 32948001
DOI: 10.3390/ijms21186793 -
Antimicrobial Agents and Chemotherapy Sep 2021Benzoxaboroles are a new class of leucyl-tRNA synthetase inhibitors. We recently reported that the antitubercular 4-halogenated benzoxaboroles are active against...
Benzoxaboroles are a new class of leucyl-tRNA synthetase inhibitors. We recently reported that the antitubercular 4-halogenated benzoxaboroles are active against Mycobacterium abscessus. Here, we find that the nonhalogenated benzoxaborole epetraborole, a clinical candidate developed for Gram-negative infections, is also active against M. abscessus and in a mouse model of infection. This expands the repertoire of advanced lead compounds for the discovery of a benzoxaborole-based candidate to treat M. abscessus lung disease.
Topics: Animals; Anti-Bacterial Agents; Antitubercular Agents; Lung Diseases; Mice; Microbial Sensitivity Tests; Mycobacterium Infections, Nontuberculous; Mycobacterium abscessus; Nontuberculous Mycobacteria
PubMed: 34280020
DOI: 10.1128/AAC.01156-21 -
Stem Cell Reports Sep 2022Human macrophages are a natural host of many mycobacterium species, including Mycobacterium abscessus (M. abscessus), an emerging pathogen affecting immunocompromised...
Human macrophages are a natural host of many mycobacterium species, including Mycobacterium abscessus (M. abscessus), an emerging pathogen affecting immunocompromised and cystic fibrosis patients with few available treatments. The search for an effective treatment is hindered by the lack of a tractable in vitro intracellular infection model. Here, we established a reliable model for M. abscessus infection using human pluripotent stem cell-derived macrophages (hPSC-macrophages). hPSC differentiation permitted reproducible generation of functional macrophages that were highly susceptible to M. abscessus infection. Electron microscopy demonstrated that M. abscessus was present in the hPSC-macrophage vacuoles. RNA sequencing analysis revealed a time-dependent host cell response, with differing gene and protein expression patterns post-infection. Engineered tdTOMATO-expressing hPSC-macrophages with GFP-expressing mycobacteria enabled rapid image-based high-throughput analysis of intracellular infection and quantitative assessment of antibiotic efficacy. Our study describes the first to our knowledge hPSC-based model for M. abscessus infection, representing a novel and accessible system for studying pathogen-host interaction and drug discovery.
Topics: Humans; Macrophages; Mycobacterium; Mycobacterium Infections, Nontuberculous; Mycobacterium abscessus; Pluripotent Stem Cells
PubMed: 35985333
DOI: 10.1016/j.stemcr.2022.07.013 -
Lung Feb 2021E-cigarette or vaping product use associated lung injury (EVALI) has been an important health risk in both children and adults. The pathophysiology of EVALI is not well...
INTRODUCTION
E-cigarette or vaping product use associated lung injury (EVALI) has been an important health risk in both children and adults. The pathophysiology of EVALI is not well understood. However, it is speculated that certain substances such as Vitamin E Acetate (VEA), particularly in marijuana containing vape cartridges may result in lung injury and lead to respiratory dysfunction. EVALI is often seen in the absence of infections, but it has been found to be associated with both fungal and bacterial infections. Like EVALI, nontuberculous mycobacteria (NTM) pulmonary disease is also on the rise, but is primarily reported in immunocompromised individuals. Here, we present three immunocompetent individuals wherein pulmonary NTM infection co-occurred with vaping.
METHODS
Medical information including patient history, laboratory, and radiograph reports were abstracted from electronic medical records from participating institutions located in the Bronx, NY, Philadelphia, PA, and Lexington, KY.
RESULTS
All three cases were otherwise immunocompetent individuals with a significant history of vaping either nicotine and/or marijuana containing products. The pathogens isolated include Mycobacterium avium complex, M. xenopi, and M. gordonae. All three patients were treated for NTM.
CONCLUSION
There is little reported on the association between vaping and NTM. It is possible that vaping may have rendered these individuals to be more susceptible to NTM colonization and infection. The possible mechanisms of vaping lung injury and pulmonary NTM are discussed.
Topics: Adolescent; Adult; Antitubercular Agents; Asthma; Electronic Nicotine Delivery Systems; Female; Humans; Immunocompetence; Lung; Lung Diseases; Male; Mycobacterium Infections, Nontuberculous; Nontuberculous Mycobacteria; Retrospective Studies; Tomography, X-Ray Computed; Vaping; Young Adult
PubMed: 33423072
DOI: 10.1007/s00408-020-00414-6