Evidence, Challenges, and Knowledge Gaps Regarding Latent Tuberculosis in Animals (original) (raw)
Related papers
The Lancet Microbe, 2020
Background Zoonotic tuberculosis is defined as human infection with Mycobacterium bovis. Although globally, India has the largest number of human tuberculosis cases and the largest cattle population, in which bovine tuberculosis is endemic, the burden of zoonotic tuberculosis is unknown. The aim of this study was to obtain estimates of the human prevalence of animal-associated members of the Mycobacterium tuberculosis complex (MTBC) at a large referral hospital in India. Methods We did a molecular epidemiological surveillance study of 940 positive mycobacteria growth indicator tube (MGIT) cultures, collected from patients visiting the outpatient department at Christian Medical College (Vellore, India) with suspected tuberculosis between Oct 1, 2018, and March 31, 2019. A PCR-based approach was applied to subspeciate cultures. Isolates identified as MTBC other than M tuberculosis or as inconclusive on PCR were subject to whole-genome sequencing (WGS), and phylogenetically compared with publicly available MTBC sequences from south Asia. Sequences from WGS were deposited in the National Center for Biotechnology Information Sequence Read Archive, accession number SRP226525 (BioProject database number PRJNA575883). Findings The 940 MGIT cultures were from 548 pulmonary and 392 extrapulmonary samples. A conclusive identification was obtained for all 940 isolates; wild-type M bovis was not identified. The isolates consisted of M tuberculosis (913 [97•1%] isolates), Mycobacterium orygis (seven [0•7%]), M bovis BCG (five [0•5%]), and nontuberculous mycobacteria (15 [1•6%]). Subspecies were assigned for 25 isolates by WGS, which were analysed against 715 MTBC sequences from south Asia. Among the 715 genomes, no M bovis was identified. Four isolates of cattle origin were dispersed among human sequences within M tuberculosis lineage 1, and the seven M orygis isolates from human MGIT cultures were dispersed among sequences from cattle. Interpretation M bovis prevalence in humans is an inadequate proxy of zoonotic tuberculosis. The recovery of M orygis from humans highlights the need to use a broadened definition, including MTBC subspecies such as M orygis, to investigate zoonotic tuberculosis. The identification of M tuberculosis in cattle also reinforces the need for One Health investigations in countries with endemic bovine tuberculosis. Funding Bill & Melinda Gates Foundation, Canadian Institutes for Health Research.
Infection and Immunity, 2003
The rabbit model of tuberculosis has been used historically to differentiate between Mycobacterium tuberculosis and Mycobacterium bovis based on their relative virulence in this animal host. M. tuberculosis infection in market rabbits is cleared over time, whereas infection with M. bovis results in chronic, progressive, cavitary disease leading to death. Because of the innate resistance of commercial rabbits to M. tuberculosis, 320 to 1,890 log-phase, actively growing inhaled bacilli were required to form one grossly visible pulmonary tubercle at 5 weeks. The range of inhaled doses required to make one tubercle allows us to determine the relative pathogenicities of different strains. Fewer inhaled organisms of the M. tuberculosis Erdman strain were required than of M. tuberculosis H37Rv to produce a visible lesion at 5 weeks. Furthermore, with the Erdman strain, only 7 of 15 rabbits had healed lesions at 16 to 18 weeks; among the other animals, two had chronic, progressive cavitary disease, a phenotype usually seen only with M. bovis infection. Genotypic investigation of the Erdman strain with an H37Rv-based microarray identified gene differences in the RD6 region. Southern blot and PCR structural genetic analysis showed significant differences between M. tuberculosis strains in this region. Correlation of the relative pathogenicity, including disease severity, in the rabbit model with the strain genotype may help identify stage-specific M. tuberculosis genes important in human disease.
The Journal of Infectious Diseases, 2007
Background. Mouse and guinea pig models have been used to identify Mycobacterium tuberculosis mutants attenuated for survival. However, unlike mice, M. tuberculosis-infected guinea pigs form caseating granulomas, which may simulate human disease more closely. Methods. We used designer arrays for defined mutant analysis, a high-throughput subtractive competition assay, for genotypically defined M. tuberculosis mutants and compared the survival of the same mutant pools in guinea pig and mouse aerosol models. Selected mutants found to be attenuated in either aerosol model were also analyzed in the mouse hollow-fiber model. Results. M. tuberculosis mutants representing 74 genes were tested. Eighteen M. tuberculosis mutants were attenuated for survival in either aerosol model, with 70% of selected mutants also attenuated in the mouse hollowfiber model. The majority of attenuated mutants in the mouse aerosol model were detected only after 90 days of infection. There was a high degree of concordance between the genes identified by the 2 aerosol models, with detection being significantly earlier in the guinea pig (). P ! .0003 Conclusions. We identified M. tuberculosis genes required for survival in mammalian lungs. The majority of mouse late-stage survival mutants were detected significantly earlier in the guinea pig, which suggests that differences in tuberculosis-induced lung pathologic changes may account for this accelerated detection. Tuberculosis is one of the leading infectious causes of morbidity and mortality worldwide, with an estimated 8.8 million new patients acquiring tuberculosis each year [1]. Humans become infected with Mycobacterium tuberculosis via the respiratory route. After successful implantation, M. tuberculosis replicates in the lungs. This initial infection may lead to disease; however, it is frequently controlled by the host immune system, leading to latent infection. Identification of the M. tuber
The biology of mycobacterium tuberculosis infection
Mediterranean journal of hematology and infectious diseases, 2013
Tuberculosis (TB) still poses a major threat to mankind and during the last thirty years we have seen a recrudescence of the disease even in countries where TB was thought to be conquered. It is common opinion that more effective control tools such as new diagnostics, a new vaccine and new drugs are urgently needed to control the global pandemic, though the so far insufficient understanding of the Mycobacterium tuberculosis (Mtb) mechanism of pathogenesis is a major obstacle for the development of these control tools. In this review, we will summarize the recent advancement in the understanding of Mtb biology and on the pathogenesis of Mtb infection with emphasis on latent infection, with the change in paradigm of the last few years where the dichotomy between latent and active disease has been reconsidered in favor of a dynamic equilibrium between the host and the bacilli, encompassing a continuous spectrum of conditions that has been named TB spectrum. Implications for the diagnos...
PLoS ONE, 2010
Experiments in the late 19th century sought to define the host specificity of the causative agents of tuberculosis in mammals. Mycobacterium tuberculosis, the human tubercle bacillus, was independently shown by Smith, Koch, and von Behring to be avirulent in cattle. This finding was erroneously used by Koch to argue the converse, namely that Mycobacterium bovis, the agent of bovine tuberculosis, was avirulent for man, a view that was subsequently discredited. However, reports in the literature of M. tuberculosis isolation from cattle with tuberculoid lesions suggests that the virulence of M. tuberculosis for cattle needs to be readdressed. We used an experimental bovine infection model to test the virulence of well-characterized strains of M. tuberculosis and M. bovis in cattle, choosing the genome-sequenced strains M. tuberculosis H37Rv and M. bovis 2122/97. Cattle were infected with approximately 10 6 CFU of M. tuberculosis H37Rv or M. bovis 2122/97, and sacrificed 17 weeks post-infection. IFN-c and tuberculin skin tests indicated that both M. bovis 2122 and M. tuberculosis H37Rv were equally infective and triggered strong cell-mediated immune responses, albeit with some indication of differential antigen-specific responses. Postmortem examination revealed that while M. bovis 2122/97-infected animals all showed clear pathology indicative of bovine tuberculosis, the M. tuberculosis-infected animals showed no pathology.
Scientific reports, 2018
The Mycobacterium tuberculosis complex (MTBC) is the collective term given to the group of bacteria that cause tuberculosis (TB) in mammals. It has been reported that M. tuberculosis H37Rv, a standard reference MTBC strain, is attenuated in cattle compared to Mycobacterium bovis. However, as M. tuberculosis H37Rv was isolated in the early 1930s, and genetic variants are known to exist, we sought to revisit this question of attenuation of M. tuberculosis for cattle by performing a bovine experimental infection with a recent M. tuberculosis isolate. Here we report infection of cattle using M. bovis AF2122/97, M. tuberculosis H37Rv, and M. tuberculosis BTB1558, the latter isolated in 2008 during a TB surveillance project in Ethiopian cattle. We show that both M. tuberculosis strains caused reduced gross pathology and histopathology in cattle compared to M. bovis. Using M. tuberculosis H37Rv and M. bovis AF2122/97 as the extremes in terms of infection outcome, we used RNA-Seq analysis t...
Guinea pig model of Mycobacterium tuberculosis latent/dormant infection
Microbes and Infection, 2008
Most experimental studies of latent or dormant tuberculosis infection have been conducted in murine models. Although guinea pigs are considered one of the animals that best reproduce human tuberculosis, surprisingly little data exist describing latent or dormant infection in these animals. The present work addresses this issue and shows that guinea pigs infected with a streptomycin auxotrophic mutant of Mycobacterium tuberculosis (strain 18b) replicate most of the known clinical, immunological, and pathological manifestations of this phase of the infectious process in humans. To establish infection, animals were inoculated with the mutant followed by administration of streptomycin for three weeks. Withdrawal of streptomycin caused microbial dormancy and few microorganisms remained viable and could be recovered from the animals' lungs and spleen several months later. Guinea pigs with dormant infection steadily gained weight and presented no clinical signs (scuff fur and lethargy) of active disease. The histopathology of the tuberculous lesions mimicked human lesions well. In addition, PBMC from infected animals strongly responded to stimulation with PPD or soluble culture filtrate proteins of M. tuberculosis throughout the duration of the experiment (six months). Finally, the tuberculin skin test (a clinical hallmark of latent infection) performed in guinea pigs infected with the auxotrophic mutant remarkably reproduced the response of humans to this test. Together, these findings confirm that infection of guinea pigs with M. tuberculosis strain 18b results in an infectious process that can be used as an interesting alternative model of latent or dormant tuberculosis infection in this animal specie.
Zoonotic tuberculosis in human beings caused by Mycobacterium bovis—a call for action
The Lancet Infectious Diseases, 2017
25 26 Mycobacterium tuberculosis is recognized as the primary causal agent of human tuberculosis (TB) throughout the 27 world. However, there is substantial evidence that the burden of Mycobacterium bovis (M. bovis), the causal agent 28 of bovine TB, may be underestimated in humans as the causal agent of zoonotic TB. In 2013, a systematic review 29 and meta-analysis of global zoonotic TB concluded that the same challenges and concerns expressed 15 years ago 30 remain valid. The challenges faced by people with zoonotic TB may not be proportional to the scientific attention 31 and resources allocated in recent years to other diseases. There is a critical need to reassess the burden of 32 zoonotic TB in humans, especially in areas where bovine TB is endemic and people live in conditions that favor 33 direct contact with infected animals or animal products. As countries move towards detecting the 3 million TB 34 cases estimated to be missed annually, and in light of the World Health Organization (WHO) 'END TB' strategy 35 endorsed by the health authorities of WHO Member States in 2014 to achieve a world free of TB by 2035, we call 36 on all TB stakeholders to act to accurately diagnose and treat TB caused by M. bovis in humans.
Location of Persisting Mycobacteria in a Guinea Pig Model of Tuberculosis Revealed by R207910
Antimicrobial Agents and Chemotherapy, 2007
The lengthy chemotherapy of tuberculosis reflects the ability of a small subpopulation of Mycobacterium tuberculosis bacteria to persist in infected individuals. To date, the exact location of these persisting bacteria is not known. Lung lesions in guinea pigs infected with M. tuberculosis have striking similarities, such as necrosis, mineralization, and hypoxia, to natural infections in humans. Guinea pigs develop necrotic primary lesions after aerosol infection that differ in their morphology compared to secondary lesions resulting from hematogenous dissemination. In infected guinea pigs conventional therapy for tuberculosis during 6 weeks reduced the bacterial load by 1.7 logs in the lungs and, although this completely reversed lung inflammation associated with secondary lesions, the primary granulomas remained largely unaffected. Treatment of animals with the experimental drug R207910 (TMC207) for 6 weeks was highly effective with almost complete eradication of the bacteria throughout both the primary and the secondary lesions. Most importantly, the few remnants of acid-fast bacilli remaining after R207910 treatment were to be found extracellular, in a microenvironment of residual primary lesion necrosis with incomplete dystrophic calcification. This zone of the primary granuloma is hypoxic and is morphologically similar to what has been described for human lung lesions. These results show that this acellular rim may, therefore, be a primary location of persisting bacilli withstanding drug treatment.