Human Tuberculosis Research Articles

Redox biomarkers in asymptomatic latent human tuberculosis: a comparison with active disease.

The latent TB infection (LTBI) is an asymptomatic infection caused by Mycobacterium tuberculosis (M.bt). Previous studies have shown a host-protective role for Heme oxygenase-1 (HO-1) during Mtb infection and an important involvement of Glutathione peroxidase-4 (Gpx4) in the necrotic pathology of the disease. Furthermore, increasing evidence suggested a crucial role for Glutathione in the granulomatous response to M. tb infection, with altered GSH levels associated to decreased host resistance. The aim of this study was to provide additional tools for discriminating the pathologic TB state and the asymptomatic infection. We analyzed the gene expression of HO-1 and Gpx4 enzymes in blood of subjects with LTBI, active TB and healthy controls, and we also measured blood levels of the reduced (GSH) and oxidized (GSSG) forms of glutathione, together with the evaluation of GCL expression, the gene responsible for the GSH de novo synthesis. Our findings highlight a shift of glutathione homeostasis towards a more reducing conditions in LTBI, and a different modulation of GSH-dependent genes and HO-1 expression respect to active TB. This study can provide useful tools to understand the redox background that address the infection toward the asymptomatic or active disease.

Modeling the Transmission Dynamics of Tuberculosis in Humans

Tuberculosis (TB) is a major threat to human health particularly in most of developing countries. In this article, we formulate and analyze a deterministic model for the transmission dynamics of pulmonary and extra-pulmonary tuberculosis. The next generation method is employed to find the basic reproduction number R0 which helps to determine whether TB clears or persists in the human population. Global stability of model equilibria is done through Lyapunov functions whereas the normalized forward sensitivity index method is adopted to determine parameters that drive tuberculosis. Analysis shows that both TB free and endemic equilibria exist. The TB free equilibrium is globally asymptotically stable whenever the basic reproduction number R0 < 1 whereas the endemic equilibrium is globally asymptotically stable whenever R0 > 1. Sensitivity analysis shows that the TB infection rate, the fraction of individuals who progress to pulmonary tuberculosis and its induced death drive TB. Numerical results indicate that when there are no interventions, susceptible humans decline significantly with time until when they are attracted to the steady state whereas latently infected, pulmonary and extra-pulmonary TB individuals increase until when they settle at the equilibrium states supporting the analytical results for existence of the endemic equilibrium. In light of these findings, we recommend treating humans infected with pulmonary TB who are carriers of the disease.

An HLA-E-targeted TCR bispecific molecule redirects T cell immunity against Mycobacterium tuberculosis

Peptides presented by HLA-E, a molecule with very limited polymorphism, represent attractive targets for T cell receptor (TCR)-based immunotherapies to circumvent the limitations imposed by the high polymorphism of classical HLA genes in the human population. Here, we describe a TCR-based bispecific molecule that potently and selectively binds HLA-E in complex with a peptide encoded by the inhA gene of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis in humans. We reveal the biophysical and structural bases underpinning the potency and specificity of this molecule and demonstrate its ability to redirect polyclonal T cells to target HLA-E-expressing cells transduced with mycobacterial inhA as well as primary cells infected with virulent Mtb. Additionally, we demonstrate elimination of Mtb-infected cells and reduction of intracellular Mtb growth. Our study suggests an approach to enhance host T cell immunity against Mtb and provides proof of principle for an innovative TCR-based therapeutic strategy overcoming HLA polymorphism and therefore applicable to a broader patient population.

The rabbit model for spinal tuberculosis: An overview.

Mycobacterium tuberculosis infection has emerged as a global public health issue, predominantly manifesting as pulmonary tuberculosis. Bone and joint tuberculosis, with spinal tuberculosis accounting for approximately 50%, represents a significant form of extrapulmonary tuberculosis. Over the past years, there has been a rise in the incidence of spinal tuberculosis, and research concerning this area has gained significant attention. At present, animal models provide a means to investigate the pathogenesis, drug resistance, and novel treatment approaches for spinal tuberculosis. New Zealand rabbits, possessing a comparable anatomical structure to humans and capable of reproducing typical pathological features of human tuberculosis, are extensively employed in spinal tuberculosis research using animal models. This article comprehensively evaluates the strengths, considerations in strain selection, various modelling approaches, and practical applications of the rabbit model in studying spinal tuberculosis based on pertinent literature to guide fundamental research in this field by providing valuable insights into appropriate animal model selection.

Intra- and Extra-Medullary Tuberculoma: Case Report and Review of the Literature

Spinal cord tuberculoma is an extremely rare presentation of human tuberculosis in general, and of central nervous system involvement in particular. Only a dozen cases have been described in the literature. We report the case of a 62-year-old man who initially presented with neurological deficit in a context of febrile altered general condition. Diagnosis was made on MRI, which revealed necrotic lesions with medullary contrast.

The loss of the PDIM/PGL virulence lipids causes differential secretion of ESX-1 substrates in Mycobacterium marinum.

The mycobacterial cell envelope is a major virulence determinant in pathogenic mycobacteria. Specific outer lipids play roles in pathogenesis, modulating the immune system and promoting the secretion of virulence factors. ESX-1 (ESAT-6 system-1) is a conserved protein secretion system required for mycobacterial pathogenesis. Previous studies revealed that mycobacterial strains lacking the outer lipid PDIM have impaired ESX-1 function during laboratory growth and infection. The mechanisms underlying changes in ESX-1 function are unknown. We used a proteo-genetic approach to measure phthiocerol dimycocerosate (PDIM)- and phenolic glycolipid (PGL)-dependent protein secretion in M. marinum, a non-tubercular mycobacterial pathogen that causes tuberculosis-like disease in ectothermic animals. Importantly, M. marinum is a well-established model for mycobacterial pathogenesis. Our findings showed that M. marinum strains without PDIM and PGL showed specific, significant reductions in protein secretion compared to the WT and complemented strains. We recently established a hierarchy for the secretion of ESX-1 substrates in four (I-IV) groups. Loss of PDIM differentially impacted secretion of Group III and IV ESX-1 substrates, which are likely the effectors of pathogenesis. Our data suggest that the altered secretion of specific ESX-1 substrates is responsible for the observed ESX-1-related effects in PDIM-deficient strains.IMPORTANCEMycobacterium tuberculosis, the cause of human tuberculosis, killed an estimated 1.3 million people in 2022. Non-tubercular mycobacterial species cause acute and chronic human infections. Understanding how these bacteria cause disease is critical. Lipids in the cell envelope are essential for mycobacteria to interact with the host and promote disease. Strains lacking outer lipids are attenuated for infection, but the reasons are unclear. Our research aims to identify a mechanism for attenuation of mycobacterial strains without the PDIM and PGL outer lipids in M. marinum. These findings will enhance our understanding of the importance of lipids in pathogenesis and how these lipids contribute to other established virulence mechanisms.

Bacterial diversity dominates variable macrophage responses of tuberculosis patients in Tanzania

The Mycobacterium tuberculosis complex (MTBC) comprises nine human-adapted lineages that differ in their geographical distribution. Local adaptation of specific MTBC genotypes to the respective human host population has been invoked in this context. We aimed to assess if bacterial genetics governs MTBC pathogenesis or if local co-adaptation translates into differential susceptibility of human macrophages to infection by different MTBC genotypes. We generated macrophages from cryopreserved blood mononuclear cells of Tanzanian tuberculosis patients, from which the infecting MTBC strains had previously been phylogenetically characterized. We infected these macrophages ex vivo with a phylogenetically similar MTBC strain (“matched infection”) or with strains representative of other MTBC lineages (“mismatched infection”). We found that L1 infections resulted in a significantly lower bacterial burden and that the intra-cellular replication rate of L2 strains was significantly higher compared the other MTBC lineages, irrespective of the MTBC lineage originally infecting the patients. Moreover, L4-infected macrophages released significantly greater amounts of TNF-α, IL-6, IL-10, MIP-1β, and IL-1β compared to macrophages infected by all other strains. While our results revealed no measurable effect of local adaptation, they further highlight the strong impact of MTBC phylogenetic diversity on the variable outcome of the host–pathogen interaction in human tuberculosis.

Prevalence, Epidemiological, and Clinical Profile of Patients Coinfected with Human Immunodeficiency Virus and Tuberculosis in the Coronavirus Disease 2019 Context in Health Facilities in the East Region, Cameroon.

Suspected cases of tuberculosis (TB) are identified for confirmation by bacteriological tests through clinical screening for TB in people living with human immunodeficiency virus (HIV) during routine visits or when antiretrovirals (ARVs) are dispensed. Our aim is to determine the prevalence and describe the epidemiological and clinical characteristics of HIV-TB coinfected patients in the coronavirus disease 2019 (COVID-19) setting in health facilities in the East Region of Cameroon. This study addresses knowledge gaps on HIV-TB coinfection during COVID-19, aiming to provide insights into the interaction and impact of HIV, TB, and COVID-19 on individuals' health. This was an observational study. It involved two retrospective cohorts of HIV-TB coinfected patients before and after the COVID-19 pandemic. We conducted manual reviews of the medical records and antiretroviral therapy (ART) and TB registers of 262 patients. These patients were coinfected with HIV and TB during the period from April 2019 to April 2021 in 11 health facilities in the East Cameroon health region. The sociodemographic and clinical characteristics of the cases were extracted from the consultation registers and entered into the KoBo Collect application, then analyzed using the Statistical Package for the Social Sciences (SPSS) software, version 25. In this study of 262 HIV-TB coinfection cases, 60.3% occurred before COVID-19, and 39.7% during the pandemic. HIV-TB coinfection prevalence among HIV patients was 1%. Patients averaged 39.3 years in age, with a significant shift in sex ratios from 0.65 to 1.33 between pre-COVID-19 and COVID-19 cohorts. Education varied, with 45.8% having secondary education, 44.8% with primary, 2.4% having higher education, and 7.1% having none. Most (78.9%) had professional occupations, and 53.7% lived in rural areas. The majority were newly diagnosed (96.3% before COVID-19; 93.3% during COVID-19), with 3.7% relapses and 4.2% discontinuing treatment. Most had pulmonary TB (84.9%) and were aware of treatment duration (94.6%). About 65.4% experienced treatment-related adverse events. Regarding family support, 69.3% received help with medication. However, the concern was 80.6% did not adhere to anti-COVID-19 measures. Gender was significantly associated with compliance. Most patients were on treatment, but a small percentage had discontinued it. Patients need to be made aware of the importance of complying with anti-COVID-19 barrier measures to prevent a potential worsening of the health situation. Moreover, clinical and biological monitoring needs to be stepped up throughout the course of anti-TB treatment.

Infectious Diseases and Basal Ganglia Calcifications: A Cross-Sectional Study in Patients with Fahr's Disease and Systematic Review.

Background: It is unclear whether patients with basal ganglia calcifications (BGC) should undergo infectious disease testing as part of their diagnostic work-up. We investigated the occurrence of possibly associated infections in patients with BGC diagnosed with Fahr's disease or syndrome and consecutively performed a systematic review of published infectious diseases associated with BGC. Methods: In a cross-sectional study, we evaluated infections in non-immunocompromised patients aged ≥ 18 years with BGC in the Netherlands, who were diagnosed with Fahr's disease or syndrome after an extensive multidisciplinary diagnostic work-up. Pathogens that were assessed included the following: Brucella sp., cytomegalovirus, human herpesvirus type 6/8, human immunodeficiency virus (HIV), Mycobacterium tuberculosis, rubella virus, and Toxoplasma gondii. Next, a systematic review was performed using MEDLINE and Embase (2002-2023). Results: The cross-sectional study included 54 patients (median age 65 years). We did not observe any possible related infections to the BGC in this population. Prior infection with Toxoplasma gondii occurred in 28%, and in 94%, IgG rubella antibodies were present. The positive tests were considered to be incidental findings by the multidisciplinary team since these infections are only associated with BGC when congenitally contracted and all patients presented with adult-onset symptoms. The systematic search yielded 47 articles, including 24 narrative reviews/textbooks and 23 original studies (11 case series, 6 cross-sectional and 4 cohort studies, and 2 systematic reviews). Most studies reported congenital infections associated with BGC (cytomegalovirus, HIV, rubella virus, Zika virus). Only two studies reported acquired pathogens (chronic active Epstein-Barr virus and Mycobacterium tuberculosis). The quality of evidence was low. Conclusions: In our cross-sectional study and systematic review, we found no convincing evidence that acquired infections are causing BGC in adults. Therefore, we argue against routine testing for infections in non-immunocompromised adults with BGC in Western countries.

Recognition of Mycobacterium tuberculosis by macrophage Toll-like receptor and its role in autophagy.

The pathogen responsible for tuberculosis is called Mycobacterium tuberculosis. Its interaction with macrophages has a significant impact on the onset and progression of the disease. The respiratory pathway allows Mycobacterium tuberculosis to enter the body's lungs where it battles immune cells before being infected latently or actively. In the progress of tuberculosis, Mycobacterium tuberculosis activates the body's immune system and creates inflammatory factors, which cause tissue inflammation to infiltrate and the creation of granulomas, which seriously harms the body. Toll-like receptors of macrophage can mediate host recognition of Mycobacterium tuberculosis, initiate immune responses, and participate in macrophage autophagy. New host-directed therapeutic approaches targeting autophagy for drug-resistant Mycobacterium tuberculosis have emerged, providing new ideas for the effective treatment of tuberculosis. In-depth understanding of the mechanisms by which macrophage autophagy interacts with intracellular Mycobacterium tuberculosis, as well as the study of potent and specific autophagy-regulating molecules, will lead to much-needed advances in drug discovery and vaccine design, which will improve the prevention and treatment of human tuberculosis.

ПЕРИКАРДИТ, АССОЦИИРОВАННЫЙ С ВИЧ-ИНФЕКЦИЕЙ И ТУБЕРКУЛЕЗОМ

Introduction. HIV infection, despite the measures taken, continues to spread throughout the world. Unfavorable course of diseases is often determined by some concomitant pathologies. Among HIV-infected patients, tuberculosis is the most common disease forming the comorbid condition named “TB/HIV” that reaches more than a half of all the cases of newly diagnosed tuberculosis in some regions of Russia. In recent years, due to the increase in the HIV- infected patients’ life expectancy based on antiretroviral therapy, cardiovascular diseases, such as primarily infectious pericarditis, are gradually beginning to hold a significant place. Aim: To select and analyze publications dealing with HIV- and tuberculosis-associated infectious pericarditis. Materials and Methods. A systematic search was conducted for publications that examined possible associations between pericardial damage, HIV infection and tuberculosis. A search of publications was carried out in the electronic databases PubMed, www.pubmed.gov; MEDLINE, www.ncbi. nlm.nih.gov; and Russian scientific database eLibrary, https://www.elibrary.ru. Preference was given to meta-analyses or systematic reviews, and studies with duplicate materials were excluded from the analysis. Results and Discussion. Publications on the epidemiology of infectious pericarditis associated with HIV infection and tuberculosis in the world and Russia are presented by authors from different countries; both the human immunodeficiency virus and mycobacterium tuberculosis are important for the development of pericarditis. Tuberculous pericarditis, being a rare manifestation of tuberculosis, usually reflects the severity of the disease and an unfavorable prognosis. In cases of unexplained pericardial effusion, it is advisable to include testing for HIV infection in the differential diagnosis plan. Conclusions. Diagnosis of pericarditis requires a multidisciplinary approach; late diagnosis has an unfavorable prognosis.

Genomic insights into anthropozoonotic tuberculosis in captive sun bears (Helarctos malayanus) and an Asiatic black bear (Ursus thibetanus) in Cambodia

Contact between humans and wildlife presents a risk for both zoonotic and anthropozoonotic disease transmission. In this study we report the detection of human strains of Mycobacterium tuberculosis in sun bears and an Asiatic black bear in a wildlife rescue centre in Cambodia, confirming for the first time the susceptibility of these bear species to tuberculosis when in close contact with humans. After genotyping revealed two different strains of M. tuberculosis from cases occurring between 2009 and 2019, 100 isolates from 30 sun bear cases, a single Asiatic black bear case, and a human case were subjected to whole genome sequencing. We combined single nucleotide polymorphism analysis and exploration of mixed base calls with epidemiological data to indicate the evolution of each outbreak. Our results confirmed two concurrent yet separate tuberculosis outbreaks and established a likely transmission route in one outbreak where the human case acted as an intermediatory between bear cases. In both outbreaks, we observed high rates of transmission and progression to active disease, suggesting that sun bears are highly susceptible to tuberculosis if exposed under these conditions. Overall, our findings highlight the risk of bi-directional transmission of tuberculosis between humans and captive bears in high human tuberculosis burden regions, with implied considerations for veterinary and public health. We also demonstrate the use of standard genomic approaches to better understand disease outbreaks in captive wildlife settings and to inform control and prevention measures.

Oral and Maxillofacial Manifestations of Tuberculosis Presented to Primary Health Care Centres in Port Sudan, Sudan

Tuberculosis is a chronic granulomatous disease caused by various strains of mycobacteria, usually Mycobacterium Tuberculosis in humans. Robert Koch, a German physician, discovered the Tuberculosis bacillus in 1882 [1]. It has been a worldwide major health problem for centuries. Although the disease’s prevalence reduced decades ago, it still has extremely high prevalence in Asian and African countries. It may take any form clinically, but with decline in number, these tuberculosis lesions of oral cavity have become so rare that they are frequently overlooked in the differential diagnosis of oral lesions. Although, oral manifestations of tuberculosis has a rare occurrence, but it has been considered to account for 0.1-5% of all TB infections.

Plasma Ribonuclease Activity in Antiretroviral Treatment-Naive People With Human Immunodeficiency Virus and Tuberculosis Disease.

The role of ribonucleases in tuberculosis among people with human immunodeficiency virus (HIV; PWH) is unknown. We explored ribonuclease activity in plasma from PWH with and without tuberculosis. Participants were identified from a cohort of treatment-naive PWH in Ethiopia who had been classified for tuberculosis disease (HIV positive [HIV+]/tuberculosis positive [tuberculosis+] or HIV+/tuberculosis negative [tuberculosis-]). Ribonuclease activity in plasma was investigated by quantification of synthetic spike-in RNAs using sequencing and quantitative polymerase chain reaction and by a specific ribonuclease activity assay. Quantification of ribonuclease 1, 2, 3, 6, 7, and T2 proteins was performed by enzyme-linked immunosorbent assay. Ribonuclease activity and protein concentrations were correlated with markers of tuberculosis and HIV disease severity and with concentrations of inflammatory mediators. Ribonuclease activity was significantly higher in plasma of HIV+/tuberculosis+ (n = 51) compared with HIV+/tuberculosis- (n = 78), causing reduced stability of synthetic spike-in RNAs. Concentrations of ribonucleases 2, 3, and T2 were also significantly increased in HIV+/tuberculosis+ compared with HIV+/tuberculosis-. Ribonuclease activity was correlated with HIV viral load, and inversely correlated with CD4 cell count, mid-upper arm circumference, and body mass index. Moreover, ribonuclease activity was correlated with concentrations of interleukin 27, procalcitonin and the kynurenine-tryptophan ratio. PWH with tuberculosis disease have elevated plasma ribonuclease activity, which is also associated with HIV disease severity and systemic inflammation.

Advances in Antiretroviral Therapy for Patients with Human Immunodeficiency Virus-Associated Tuberculosis.

Tuberculosis is one of the most common opportunistic infections and a prominent cause of death in patients with human immunodeficiency virus (HIV) infection, in spite of near-universal access to antiretroviral therapy (ART) and tuberculosis preventive therapy. For patients with active tuberculosis but not yet receiving ART, starting ART after anti-tuberculosis treatment can complicate clinical management due to drug toxicities, drug-drug interactions and immune reconstitution inflammatory syndrome (IRIS) events. The timing of ART initiation has a crucial impact on treatment outcomes, especially for patients with tuberculous meningitis. The principles of ART in patients with HIV-associated tuberculosis are specific and relatively complex in comparison to patients with other opportunistic infections or cancers. In this review, we summarize the current progress in the timing of ART initiation, ART regimens, drug-drug interactions between anti-tuberculosis and antiretroviral agents, and IRIS.

Molecular basis for substrate transport of Mycobacterium tuberculosis ABC importer DppABCD.

The type I adenosine 5'-triphosphate (ATP)-binding cassette (ABC) transporter DppABCD is believed to be responsible for the import of exogenous heme as an iron source into the cytoplasm of the human pathogen Mycobacterium tuberculosis (Mtb). Additionally, this system is also known to be involved in the acquisition of tri- or tetra-peptides. Here, we report the cryo-electron microscopy structures of the dual-function Mtb DppABCD transporter in three forms, namely, the apo, substrate-bound, and ATP-bound states. The apo structure reveals an unexpected and previously uncharacterized assembly mode for ABC importers, where the lipoprotein DppA, a cluster C substrate-binding protein (SBP), stands upright on the translocator DppBCD primarily through its hinge region and N-lobe. These structural data, along with biochemical studies, reveal the assembly of DppABCD complex and the detailed mechanism of DppABCD-mediated transport. Together, these findings provide a molecular roadmap for understanding the transport mechanism of a cluster C SBP and its translocator.

Do medical spending and income reduce the prevalence of human immunodeficiency virus and tuberculosis? A study on Sub-Saharan Africa

Several countries in sub-Saharan Africa (SSA) suffer from economic hardship and high unemployment rates; furthermore, this region has higher rates of human immunodeficiency virus (HIV) and tuberculosis (TB). This study examined the relationships between HIV and TB, income, and total medical spending and its components, private and public healthcare expenditure, for 41 SSA countries. Random and fixed-effects models were utilized in this study to explore relationships by studying time series and cross-sectional panel data obtained from the World Bank. Results demonstrated that there is a positive relationship between HIV and unemployment and a negative relationship with income and medical spending. We also observed that, when private and public medical expenditures are compared, private medical expenditures alleviate the HIV epidemic. Considering the association with TB, income, total, and its components, private and public medical expenditures are negatively related. Since prevention of such life-threatening diseases as HIV and TB becomes vital to find remedies for, there is a need for more government initiatives, including job creation, increased productivity, and increased income levels, which can be seen as preconditions in fighting and controlling HIV and TB.

Absence of Tuberculosis-Causing Mycobacteria from Slaughtered Livestock Tissues and Environmental Samples, Gauteng Province, South Africa.

Mycobacterium tuberculosis complex (MTBC) is a group of bacteria responsible for causing tuberculosis in animals and humans. In South Africa (S.A), slaughterhouses are registered by the government and closely inspected and audited for hygienic slaughter practices. Meat inspection to detect lesions has been used for passive surveillance, monitoring, and diagnosis of the disease status. Information on the current status of bovine tuberculosis (bTB) in livestock in the country is limited. Hence, we investigated the occurrence of Mycobacterium spp. in the tissues of slaughtered livestock and environmental samples in abattoirs in Gauteng province of South Africa (S.A). The cross-sectional study employing random sampling from cattle, pigs, and sheep (with the collection of liver, lung, spleen, and different lymph nodes) irrespective of lesions was carried out in 19 red meat abattoirs. Five hundred animals were sampled, comprising cattle (n = 369), pigs (n = 90), and sheep (n = 41). Additionally, 19 environmental samples were collected from feedlots, or where animals drink water while awaiting slaughter, to identify mycobacterial species using culture, acid-fast bacteria staining, and polymerase chain reaction (PCR). The Chi-square and Fisher's Exact tests were used to detect statistically significant differences in the frequency of detection of Mycobacterium spp. according to the variables investigated (types of tissues, livestock, abattoirs, etc.). The PCR assays detected no MTBC complex species DNA in the bacterial isolates from cattle (n = 32). Sequence analysis (16S rDNA) of the isolates from eight cattle confirmed only two species, namely Mycobacterium colombiense (99.81% identity) and Mycobacterium simiae (99.42% identity). The remaining isolates were identified as members of the Actinomadura species. From the environmental samples, bacterial isolation was made from three samples, and two could only be identified up to the genus level (Mycobacterium species) while the remaining isolate was identified as Mycobacterium senuense (99.22% identity). The study revealed the absence of bovine tuberculosis-causing pathogens in red meat abattoirs of the Gauteng province. Although non-tuberculous Mycobacteria have been implicated as potentially causing tuberculosis-like diseases in livestock, their occurrence in the current study was found to be low, but the potential to cause disease cannot be ignored.

Dependency on host vitamin B12 has shaped Mycobacterium tuberculosis Complex evolution

Human and animal tuberculosis is caused by the Mycobacterium tuberculosis Complex (MTBC), which has evolved a genomic decay of cobalamin (vitamin B12) biosynthetic genes. Accordingly, and in sharp contrast to environmental, opportunistic and ancestor mycobacteria; we demonstrate that M. tuberculosis (Mtb), M. africanum, and animal-adapted lineages, lack endogenous production of cobalamin, yet they retain the capacity for exogenous uptake. A B12 anemic model in immunocompromised and immunocompetent mice, demonstrates improved survival, and lower bacteria in organs, in B12 anemic animals infected with Mtb relative to non-anemic controls. Conversely, no differences were observed between mice groups infected with M. canettii, an ancestor mycobacterium which retains cobalamin biosynthesis. Interrogation of the B12 transcriptome in three MTBC strains defined L-methionine synthesis by metE and metH genes as a key phenotype. Expression of metE is repressed by a cobalamin riboswitch, while MetH requires the cobalamin cofactor. Thus, deletion of metE predominantly attenuates Mtb in anemic mice; although inactivation of metH exclusively causes attenuation in non-anemic controls. Here, we show how sub-physiological levels of B12 in the host antagonizes Mtb virulence, and describe a yet unknown mechanism of host-pathogen cross-talk with implications for B12 anemic populations.

Characterization of Mycobacterium orygis, Mycobacterium bovis, and Mycobacterium caprae Infections in Humans in Western Canada.

Epidemiologic research on zoonotic tuberculosis historically used Mycobacterium bovis as a surrogate measure; however, increased reports of human tuberculosis caused by other animal-associated Mycobacterium tuberculosis complex members like Mycobacterium orygis necessitates their inclusion. We performed a retrospective cohort study including persons infected with any animal-lineage M tuberculosis complex species in Alberta, Canada, from January 1995 to July 2021, identifying 42 patients (20 M bovis, 21 M orygis, 1 M caprae). Demographic, epidemiologic, and clinical characteristics were compared against persons with culture-confirmed M tuberculosis infection. The proportion of culture-positive infections caused by M orygis increased continuously from 2016 to 2020. Significantly more females at a higher median age were impacted by M orygis, with all patients originating from South Asia. Mycobacterium bovis caused significantly more extrapulmonary disease and disproportionately impacted young females, particularly those pregnant or postpartum. All infections were acquired abroad. These findings can aid in developing targeted public health interventions.