Mycobacterial Infection Research Articles

50599 Reviewing the Risks of Medical Tourism: Atypical Mycobacterial Infections Associated with Cosmetic Procedures Abroad

50599 Reviewing the Risks of Medical Tourism: Atypical Mycobacterial Infections Associated with Cosmetic Procedures Abroad

The controversy of immune checkpoint inhibition and risk of mycobacterial infections: the need for further studies and continued discussions on this puzzling issue.

The controversy of immune checkpoint inhibition and risk of mycobacterial infections: the need for further studies and continued discussions on this puzzling issue.

Divergent downstream biosynthetic pathways are supported by L-cysteine synthases of Mycobacterium tuberculosis.

Mycobacterium tuberculosis's (Mtb) autarkic lifestyle within the host involves rewiring its transcriptional networks to combat host-induced stresses. With the help of RNA sequencing performed under various stress conditions, we identified that genes belonging to Mtb sulfur metabolism pathways are significantly upregulated during oxidative stress. Using an integrated approach of microbial genetics, transcriptomics, metabolomics, animal experiments, chemical inhibition, and rescue studies, we investigated the biological role of non-canonical L-cysteine synthases, CysM and CysK2. While transcriptome signatures of RvΔcysM and RvΔcysK2 appear similar under regular growth conditions, we observed unique transcriptional signatures when subjected to oxidative stress. We followed pool size and labelling (34S) of key downstream metabolites, viz. mycothiol and ergothioneine, to monitor L-cysteine biosynthesis and utilization. This revealed the significant role of distinct L-cysteine biosynthetic routes on redox stress and homeostasis. CysM and CysK2 independently facilitate Mtb survival by alleviating host-induced redox stress, suggesting they are not fully redundant during infection. With the help of genetic mutants and chemical inhibitors, we show that CysM and CysK2 serve as unique, attractive targets for adjunct therapy to combat mycobacterial infection.

The Canadian Bronchiectasis and Nontuberculous Mycobacteria Registry: A Study Protocol

BackgroundBronchiectasis is a complex, chronic disease with geographic and ethnic diversity. While the most substantial cohort studies have been conducted in Europe and the USA, Canada also faces considerable challenges. The Comprehensive Canadian Bronchiectasis and Nontuberculous Mycobacterial Infection Registry aims to: (1) outline the clinical characteristics and natural history of bronchiectasis in Canada; (2) identify risk factors contributing to disease progression within Canadians; (3) integrate comprehensive clinical information to better understand the phenotypes of bronchiectasis; (4) support the development of large-scale, randomized controlled trials in Canada.MethodsThe Canadian Bronchiectasis and Nontuberculous Mycobacterial Infection Registry is an ongoing prospective, longitudinal, multi-center, observational cohort study. It aims to enroll at least 2000 participants to collect data such as medical history, etiological assessments, lung function tests, microbiological profiles, radiographic evaluations, comorbidities and quality of life (QoL) metrics. Participants will undergo annual follow-ups to gather longitudinal information regarding outcomes, treatments and changes in QoL. The inclusion criteria are a diagnosis of bronchiectasis by clinical history and computed tomography and/or pulmonary nontuberculous mycobacterial (NTM) infection as defined by ATS/IDSA guidelines. The study's protocol received ethical approval from the lead site, the University of Calgary, with future additional approval from local ethics committees at all participating centers.DiscussionThe outcomes of the registry will be instrumental in uncovering the clinical traits and natural history of bronchiectasis. This longitudinal study will be used for analysis to form evidence-based clinical practices and serve as a resource in Canada to inform future studies in NTM and bronchiectasis.

Visualisation of in vivo protein synthesis during mycobacterial infection through [68Ga]Ga-DOTA-puromycin µPET/MRI

Radiolabelled puromycin analogues will allow the quantification of protein synthesis through nuclear medicine-based imaging. A particularly useful application could be the non-invasive longitudinal visualisation of mycobacterial activity through direct quantification of puromycin binding. This study assesses the value of [68Ga]Ga-DOTA-puromycin in the visualisation of mycobacteria through positron emission tomography combined with magnetic resonance imaging (µPET/MRI). The radiopharmaceutical was produced by previously published and validated methods. [68Ga]Ga-DOTA-Puromycin imaging was performed on severe immunodeficient mice infected with Bacille Calmette-Guérin-derived M. Bovis (BCG). Acute and chronic infection stages were examined by µPET/MRI. A follow-up group of animals acted as controls (animals bearing S. aureus-derived infection and sterile inflammation) to assess tracer selectivity. [68Ga]Ga-DOTA-puromycin-µPET/MRI images revealed the acute, widespread infection within the right upper shoulder and armpit. Also, [68Ga]Ga-DOTA-puromycin signal sensitivity measured after a 12-week period was lower than that of [18F]FDG-PET in the same animals. A suitable correlation between normalised uptake values (NUV) and gold standard histopathological analysis confirms accurate tracer accumulation in viable bacteria. The radiopharmaceutical showed infection selectivity over inflammation but accumulated in both M. Bovis and S. Aureus, lacking pathogen specificity. Overall, [68Ga]Ga-DOTA-puromycin exhibits potential as a tool for non-invasive protein synthesis visualization, albeit without pathogen selectivity.

Value of bronchoalveolar lavage fluid metagenomic next-generation sequencing in acute exacerbation of fibrosing interstitial lung disease: an individualized treatment protocol based on microbiological evidence

BackgroundAcute exacerbation of fibrosing interstitial lung diseases (AE-ILD) is a serious life-threatening event per year. Methylprednisolone and/or immunosuppressive agents (ISA) are a mainstay in any regimen, under the premise that pulmonary infection has been promptly identified and controlled. We investigated the value of bronchoalveolar lavage fluid (BALF) metagenomic next-generation sequencing (mNGS) on the treatment adjustment of AE-ILD.MethodsWe conducted a cross-sectional observational study. All data were collected prospectively and retrospectively analyzed. We included fifty-six patients with AE-ILD and nineteen stable ILD who underwent BALF mNGS at the beginning of admission.ResultsPatients with a variety of ILD classification were included. Connective–tissue disease related ILD (CTD-ILD) occupy the most common underlying non-idiopathic pulmonary fibrosis (non-IPF). The infection-triggered AE accounted for 39.29%, with the majority of cases being mixed infections. The microorganisms load in the AE-ILD group was significantly higher. After adjusted by mNGS, the therapy coverage number of pathogens was significantly higher compared to the initial treatment (p < 0.001). After treatment, the GGO score and the consolidation score were significantly lower during follow up in survivors (1.57 ± 0.53 vs. 2.38 ± 0.83 with p < 0.001, 1.11 ± 0.24 vs. 1.49 ± 0.47 with p < 0.001, respectively). Some detected microorganisms, such as Tropheryma whipplei, Mycobacterium, Aspergillus, and mixed infections were difficult to be fully covered by empirical medication. BALF mNGS was also very helpful for excluding infections and early administration of methylprednisolone and/or ISA.ConclusionsmNGS has been shown to be a useful tool to determine pathogens in patients with AE-ILD, the results should be fully analyzed. The comprehensive treatment protocol based on mNGS has been shown crucial in AE-ILD patients.

Forecasting climate-associated non-tuberculous mycobacteria (NTM) infections in the UK using international surveillance data and machine learning.

Nontuberculous mycobacteria (NTM) cause skin and lung infections, have high mortality rates, and are resistant to a range of antibiotics and water treatment methods. As NTM reside in environmental reservoirs, they are sensitive to environmental conditions. The suitability of their environmental reservoirs can increase as a result of climate change, subsequently increasing environmental exposure and infection rates. NTM infections are not generally notifiable, including in the UK, but sustained increases have been observed in regions that report NTM infection rates. To assess the burden of NTM infections in the UK under projected climate change, we examined the relationship between climate variables and available NTM surveillance data internationally. Statistically significant increases were found in regions where NTM infections are notifiable, which were positively associated with increased precipitation and temperatures. A random forest regressor was trained using supervised learning from international NTM surveillance data and linked climate variables. The random forest model was applied to UK climate projections, projecting a 6.2% increase in NTM infection rates over the next 10 years, with notable regional variation. Our random forest model predicts that the forecasted impacts of climate change in the UK, including increasing temperatures and frequency of heavy rainfall, will lead to increases in NTM infection rates. Robust surveillance in the future is necessary to increase data available to train models, increasing our predictive power in forecasting climate-associated NTM trends. Our results highlight a novel aspect of how climate change will impact health outcomes in the UK.

The Drug Susceptibility of Non-Tuberculous Mycobacteria (NTM) in a Referral Hospital in Rome from 2018 to 2023.

Background: The treatment of non-tuberculous mycobacterial (NTM) infections is challenging because of the difficulty in obtaining phenotypic (pDST) and/or molecular (mDST) drug susceptibility testing and the need of a multi-drug regimen. Objectives: The objective was to describe the in vitro susceptibility patterns of various NTM species through an analysis of susceptibility results obtained on isolates collected between 2018 and 2023. Methods: Species identification and mutations in rrs or rrl genes (mDST) were identified by a line probe assay, while the pDST was performed by broth microdilution and interpreted according to CLSI criteria. Results: We analysed 337 isolates of NTM belonging to 15 species/subspecies. The Mycobacterium avium complex (MAC) was the most common (62%); other species identified included M. gordonae (11%), M. kansasii (5%), the M. abscessus complex (8%), M. chelonae (6%), and M. fortuitum (2%). The results of pDST (claritromycin and amikacin) and mDST (rrl and rrs genes) on 66 NTM strains showed that while wild-type rrl and rrs occurred in 86.3% and 94% strains, respectively, the pDST showed 88% sensitivity for clarithromycin and 57.5% for amikacin. The main incongruity was observed for macrolides. Conclusions: Most NTM are likely to be susceptible to macrolides and aminoglycosides. The molecular identification of resistant genotypes is accurate and strongly recommended for optimal patient management.

A clinical comparison of glycol and water-based heater-cooler systems for cardiopulmonary bypass.

While newer heater-cooler technologies using ethylene glycol-based (GB) solutions during cardiothoracic surgery have become commercially available, there is a paucity of clinical data describing their effectiveness during cardiopulmonary bypass (CPB) support. This analysis aimed to compare clinical characteristics and procedural outcomes using water-based (WB) and GB heater-cooler systems. A retrospective analysis was performed on consecutive adult patients undergoing CPB from June to October 2022 comparing WB or GB groups. The primary outcome was a composite of operative death or major morbidity. Secondary endpoints included transfusion requirements on CPB, patient cooling and warming rates, and vasoactive-inotropic scores (VIS) at case completion. P-control charts were used to monitor the weekly incidence of the composite outcome. A sub-analysis was performed to evaluate the primary outcome for cardiac surgery cases indexed by the Society of Thoracic Surgeons (STS). There were 167 patients included for analysis; 87 (52.1%) underwent CPB with a WB system and 80 (47.9%) with a GB system. GB procedure subjects were younger (p = .01), experienced longer CPB times (p = .034), and were more likely to receive thoracic transplant or aortic surgery (p = 0.015). The composite outcome of operative mortality or major morbidity occurred in 29.9% and 24% of the WB and GB groups, respectively (p = .372). P-control charts indicated a weekly mean incidence of 30% during WB practice, which decreased to 24% with GB practice. Among 106 STS-indexed cardiac surgery cases, mean composite outcome incidence decreased from 19% to 6% following our GB transition. Additionally, cooling, and warming rates indexed to patient BSA and VIS at case completion were not significantly different. Our analysis demonstrated a safe transition from WB to GB heater-cooler technologies in our practice. This early analysis suggests that GB heater coolers may be safely adopted to mitigate the risks of nontuberculous mycobacterium infections for cardiac surgical patients.

Atypical gouty tophus masquerading as a foreign body granuloma

Subcutaneous nodular lesions in a patient with significantly elevated inflammatory markers always raise the possibility of infectious diagnoses such as atypical infection, pyogenic abscess, mycobacterial infection, and malignancy. Definitive diagnosis requires tissue biopsy and histopathologic examination. The atypical presentation of a foreign body granuloma with concurrent intraoperative findings supports the diagnosis of gouty arthritis.We report a case of a 67-year-old man who presented with an inflammatory nodular lesion on the left elbow that was initially suspected to have an infectious cause. Histopathologic examination of the nodular tissue later revealed that the patient had a foreign body granuloma due to urate crystal deposition. The atypical appearance of the gouty arthritis, the low serum urate level, the negative crystal identification in the synovial fluid, and the markedly elevated inflammatory markers, which did not respond to the previous antibiotic and steroid therapy, raised the suspicion of atypical infection in this case.

Mycobacterium genavense detection in a blood smear from a domestic ferret

AbstractThe domestic ferret is sensitive to mycobacterial infections, which are likely underdiagnosed. There are limited reports of therapy for mycobacteriosis in ferrets and most have failed. A ferret in poor body condition revealed marked organomegaly on diagnostic imaging. The complete blood count revealed a mild pseudoeosinophilia, which might be attributed to negatively stained bacilli phagocytised by monocytes observed in the blood smear. Ziehl–Neelsen stain was performed and showed acid‐fast bacilli within monocytes. Fine‐needle aspirates of the spleen and liver revealed the same finding. Mycobacterium genavense was identified by PCR and DNA sequencing from peripheral blood. Treatment with rifampicin, clarithromycin and enrofloxacin was initiated. The disseminated mycobacteriosis was suspected from the observation of bacilli on the blood smear. After 16 months, the ferret is still undergoing treatment. To prevent recurrence, continued monitoring of drug toxicity and effective therapy will be maintained even after the resolution of clinical signs (mostly organomegaly).

Long-term successfull management of recurrent episodes of nontuberculous mycobacterial infection in an apparently healthy Chinese woman

BackgroundDisseminated non-tuberculous mycobacteria (dNTM) infections are mostly reported among individuals with an underlying congenital or acquired immunodeficiency or receiving immunosuppressive treatment, but are rarely documented in otherwise healthy subjects.Case presentationWe describe a case of recurrent disseminated mycobacterial infection in an apparently immunocompetent Chinese woman. Mycobacterium szulgai and Mycobacterium avium-complex were identified in distinct episodes. Long-term antimycobacterial therapy was administered given the occurrence of recurrent events when off-treatment. Successful management over more than 10 years and immunologic data are reported.ConclusionsThis case-report highlights that dNTM should be suspected also among apparently immunocompetent hosts and that thorough assessment of underling immune-impairments is helpful to define patients’ management. Long-term antimycobacterial therapy and close monitoring is required to grant successful outcomes in case of recurrent dNTM infections.

Insights into mycobacteriome composition in Mycobacterium bovis-infected African buffalo (Syncerus caffer) tissue samples

Animal tuberculosis significantly challenges global health, agriculture, and wildlife conservation efforts. Mycobacterial cultures are resource-intensive, time-consuming, and challenged by heterogeneous populations. In this study, we employed a culture-independent approach, using targeted long-read-based next-generation sequencing (tNGS), to investigate the mycobacterial composition in 60 DNA samples extracted from Mycobacterium bovis infected culture-confirmed African buffalo tissue. We detected mycobacterial DNA in 93.3% of the samples and the sensitivity for detecting Mycobacterium tuberculosis complex (MTBC) was 91.7%, demonstrating a high concordance of our culture-independent tNGS approach with mycobacterial culture results. In five samples, we identified heterogenous mycobacterial populations with various non-tuberculous mycobacteria, including members of the Mycobacterium avium complex (MAC), M. smegmatis, and M. komaniense. The latter Mycobacterium species was described in South Africa from bovine nasal swabs and environmental samples from the Hluhluwe-iMfolozi Park, which was the origin of the buffalo samples in the present study. This finding suggests that exposure to environmental mycobacteria may confound detection of MTBC in wildlife. In conclusion, our approach represents a promising alternative to conventional methods for detecting mycobacterial DNA. This high-throughput technique enables rapid differentiation of heterogeneous mycobacterial populations, which will contribute valuable insights into the epidemiology, pathogenesis, and microbial synergy during mycobacterial infections.

Complications After Exosome Treatment for Aesthetic Skin Rejuvenation

ABSTRACTBackgroundExosomes have gained significant attention in aesthetic dermatology for their potential in skin rejuvenation. Despite numerous studies investigating the use of exosomes in aesthetic applications, no adverse events have been reported thus far. This case series presents patients with noticeable adverse effects following the application of exosomes to the skin for aesthetic purposes in South Korea.MethodsA consortium of concerned aesthetic dermatologists from South Korea provided a case series of patients who developed complications after receiving exosome treatments for skin rejuvenation. The case series included eight female patients, ranging in age from 26 to 52 years old, who developed delayed‐onset granulomatous lesions at the treatment sites.ResultsAll patients in the case series developed erythematous, indurated papules or nodules at the sites of exosome injections, with onset ranging from 2 weeks to 3 months posttreatment. Histopathological examination of biopsied lesions revealed necrotizing granulomas not related to mycobacterial infections. The patients' response to topical and oral steroids, as well as other treatments, varied.ConclusionAlthough exosome‐based therapies hold great promise in aesthetic dermatology, this case series highlights the potential for delayed‐onset granulomatous complications following exosome treatments for skin rejuvenation. Standardized protocols for exosome isolation and purification, as well as rigorous safety and efficacy standards, are needed to ensure the successful implementation of exosome‐based products in clinical settings.

New genetic biomarkers from transcriptome RNA-sequencing for Mycobacterium tuberculosis complex and Mycobacterium avium complex infections by bioinformatics analysis

The study aims to accurately identify differentially expressed genes (DEGs) and biological pathways in mycobacterial infections through bioinformatics for deeper disease understanding. Differentially expressed genes (DEGs) was explored by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Unique DEGs were submitted on least absolute shrinkage and selection operator (LASSO) regression analysis. 1,057 DEGs from two GSE datasets were identified, which were closely connected with NTM/ latent TB infection (LTBI)/active TB disease (ATB). It was demonstrated that these DEGs are mainly associated with detoxification processes, and virus and bacterial infections. Moreover, the METTL7B gene was the most informative marker for distinguishing LTBI and ATB with an area under the curve (AUC) of 0.983 (95%CI: 0.964 to 1). The significantly upregulated HBA1/2 genes were the most informative marker for distinguishing between individuals of IGRA-HC/NTM and LTBI (P < 0.001). Moreover, the upregulated HBD gene was also differ between IGRA-HC/NTM and ATB (P < 0.001). We have identified gene signatures associated with Mycobacterium infection in whole blood, which could be significant for understanding the molecular mechanisms and diagnosis of NTM, LTBI, or ATB.

Clinical Characteristics and Outcomes of Extrapulmonary Nontuberculous Mycobacterial Infections in a Tertiary-Care Hospital: A Retrospective Study.

Background/Objectives: The incidence of nontuberculous mycobacterial (NTM) infections has increased globally; however, the clinical manifestations and optimal treatment strategies for extrapulmonary NTM infections remain poorly defined. This study assessed the clinical manifestations and treatment outcomes of extrapulmonary NTM infections. Methods: Data from adult patients with suspected extrapulmonary NTM infections at a tertiary-care hospital from 2009-2022 were categorized into NTM disease and isolation groups. Diagnosis of NTM disease relied on stringent criteria, whereas isolation required NTM isolation without meeting the criteria for infection. Results: Among 75 patients evaluated, 32 (42%) were diagnosed with NTM disease and 43 (57%) with NTM isolation. History of immunosuppressant use within the past 3 months (p = 0.070) and injection (p = 0.001) were more frequent in the disease group. The median interval from symptom onset to evaluation was 106.6 and 20 days in the disease and isolation groups, respectively. The prevalence of positive NTM polymerase chain reaction results (36.4%, p = 0.003) and acid-fast bacillus staining (39.1%, p < 0.001) was significantly higher in the disease group than in the isolation group. Mycobacterium intracellulare (21.9%), M. abscessus (15.6%), M. chelonae (9.4%), and M. fortuitum complex (9.4%) were the most frequently identified species. Of the 27 patients in the disease group who received treatment, 13 improved, four experienced treatment failure, seven were lost to follow-up, and three died during treatment, with one death directly attributable to NTM disease. Conclusions: NTM disease exhibits a spectrum of clinical manifestations. Accurate diagnosis is crucial for initiating effective treatment.

Clinical Management and Outcomes of Nontuberculous Mycobacterial Infections in Solid Organ Transplant Recipients: A Multinational Case-control Study.

The management and outcomes of nontuberculous mycobacterial (NTM) infections in solid organ transplant (SOT) recipients are poorly characterized. We aimed to describe the management and 1-y mortality of these patients. Retrospective, multinational, 1:2 matched case-control study included SOT recipients aged 12 y old or older diagnosed with NTM infection between January 1, 2008, and December 31, 2018. Controls were matched on transplanted organs, NTM treatment center, and posttransplant survival at least equal to the time to NTM diagnosis. The primary aim was 1-y mortality after NTM diagnosis. Differences between cases and controls were compared using the log-rank test, and Cox regression models were used to identify factors associated with mortality at 12 mo among cases. In 85 patients and 169 controls, the median age at the time of SOT was 54 y (interquartile range, 40-62 y), 59% were men, and the lungs were the most common site of infection after SOT (57.6%). One-year mortality was significantly higher in cases than in controls (20% versus 3%; P < 0.001), and higher mortality was associated with lung transplantation (hazard ratio 3.27; 95% confidence interval [1.1-9.77]; P = 0.034). Median time (interquartile range) from diagnosis to treatment initiation (20 [4-42] versus 11 [3-21] d) or the reduction of net immunosuppression (36% versus 45%, hazard ratio 1.35 [95% CI, 0.41-4.43], P = 0.618) did not differ between survivors and those who died. NTM disease in SOT recipients is associated with a higher mortality risk, especially among lung transplant recipients. Time to NTM treatment and reduction in net immunosuppression were not associated with mortality.

Histopathologic changes in different organs during mycobacteriosis in guppy (Poecilia reticulata) and japanese medaka (Oryzias latipes)

Total histological sections of laboratory fish Poecilia reticulata and Oryzias latipes with pronounced multiple organ failure caused by Mycobacterium infection (Mycobacterium sp.) were analyzed. The pathogenesis of the disease in question is expressed in the occurrence, in various tissues, of foci of inflammation, subsequently forming a connective tissue capsule — granuloma. These lesions were observed in almost all organs of the abdominal cavity of the fish. The largest and most common lesions were found in the pancreas, kidneys and liver (from 478.6 microns to 858.4 microns), significantly disrupting organ functions, which is a clinical picture characteristic of mycobacteriosis. The occurrence of granulomas and their average sizes in organs such as the intestine and gills were significantly lower and amounted to 328.3 and 468.9 microns, respectively. Data on the stages of granuloma development in different organs of fish are presented. The initial stage of granuloma development consists of clusters of macrophage-like cells, lymphocytes, granulocytes and a small number of cellular residues. At the final stage of development, it is a focus, including an eosinophilic-stained caseous-necrotic nucleus and a shell consisting of epithelioid macrophages. It is shown that there is a relationship between the size parameters of granulomas, the frequency of their occurrence and the degree of organ damage. The localization of granulomas and the degree of their development in guppies and medaka were similar, indicating the absence of species-specific virulence. It follows from this that any warm-water fish species cultivated under controlled conditions are at risk. This requires monitoring for signs of disease and regular preventive measures.

Pharmacokinetics of anti-Mycobacterium avium-intracellulare disease drugs in silkworms

Pulmonary Mycobacterium avium-intracellulare complex (MAC) disease is a typical non-tuberculous mycobacterial infection. The incidence of pulmonary MAC is increasing worldwide. This study aimed to clarify the pharmacokinetic parameters of anti-pulmonary MAC disease drugs in silkworms. The pharmacokinetic parameters investigated included maximum concentration, area under the concentration–time curve, total clearance, and volume of distribution at steady-state. In addition, protein-binding rates, fat body transferability, and drug-drug interactions were examined. Antibiotic concentrations were measured using a validated high-performance liquid chromatography-mass spectrometry method. Among the antibiotics investigated, amikacin was not eliminated from silkworms during the 48-h observation period. In contrast, dose-proportional pharmacokinetics were observed in silkworms for all antibiotics tested, except for amikacin. Protein-binding rates in hemolymph for clarithromycin, azithromycin, rifampicin, ethambutol, and amikacin were 39.6 ± 3.0%, 39.5 ± 4.3%, 76.3 ± 3.2%, 20.9 ± 4.2%, and 73.1 ± 4.7%, respectively (mean ± standard deviation). The distribution of antibiotics in the fat bodies of silkworms was related to drug lipophilicity. No drug-drug interactions were observed in the silkworms. The pharmacokinetics of these drugs in silkworms differed significantly from those in humans. Therefore, while it is challenging to predict the pharmacokinetics of these drugs in humans based on silkworm data, the silkworm infection model has facilitated a comprehensive assessment of the relationship between antibiotic exposure and efficacy.

Necrosis drives susceptibility to Mycobacterium tuberculosis in POLG mtDNA mutator mice.

The genetic and molecular determinants that underlie the heterogeneity of Mycobacterium tuberculosis (Mtb) infection outcomes in humans are poorly understood. Multiple lines of evidence demonstrate that mitochondrial dysfunction can exacerbate mycobacterial disease severity and mutations in some mitochondrial genes confer susceptibility to mycobacterial infection in humans. Here, we report that mutations in mitochondria DNA (mtDNA) polymerase gamma (POLG) potentiate susceptibility to Mtb infection in mice. POLG mutator mtDNA mice fail to mount a protective innate immune response at an early infection timepoint, evidenced by high bacterial burdens, reduced M1 macrophages, and excessive neutrophil infiltration in the lungs. Immunohistochemistry reveals signs of enhanced necrosis in the lungs of Mtb-infected POLG mice and POLG mutator macrophages are hyper-susceptible to extrinsic triggers of necroptosis ex vivo. By assigning a role for mtDNA mutations in driving necrosis during Mtb infection, this work further highlights the requirement for mitochondrial homeostasis in mounting balanced immune responses to Mtb.