Date Published: January 1, 2010
Publisher: Public Library of Science
Author(s): Adam O. Whelan, Michael Coad, Paul J. Cockle, Glyn Hewinson, Martin Vordermeier, Stephen V. Gordon, Niyaz Ahmed. http://doi.org/10.1371/journal.pone.0008527
Abstract: 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 106 CFU of M. tuberculosis H37Rv or M. bovis 2122/97, and sacrificed 17 weeks post-infection. IFN-γ 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. Culturing of infected tissues revealed that M. tuberculosis was able to persist in the majority of animals, albeit at relatively low bacillary loads. In revisiting the early work on host preference across the M. tuberculosis complex, we have shown M. tuberculosis H37Rv is avirulent for cattle, and propose that the immune status of the animal, or genotype of the infecting bacillus, may have significant bearing on the virulence of a strain for cattle. This work will serve as a baseline for future studies into the genetic basis of host preference, and in particular the molecular basis of virulence in M. bovis.
Partial Text: Genome sequencing across the Mycobacterium tuberculosis complex has underlined the remarkable genetic identity shown between the constituent members, with for example Mycobacterium bovis and Mycobacterium tuberculosis sharing greater than 99.95% identity at the nucleotide level , . However this genetic identity contrasts with the distinct host preference of the tubercle bacilli, which can be seen as series of ecotypes marked by fixed molecular differences . This is evident from epidemiological data, with M. tuberculosis a highly successful pathogen of humans, yet not able to sustain in animal populations; the converse is true for M. bovis, a pathogen of wild and domesticated mammals that rarely transmits between immunocompetent humans. As the genome sequences of M. bovis and M. tuberculosis are available, we should now be able to define the genetic differences that lead to host tropism, and therefore to define virulence factors that drive host preference across the tubercle bacilli.
It is well acknowledged that M. tuberculosis is a human-adapted pathogen with an exquisite ability to infect and persist in human populations. Infection of animals by M. tuberculosis has been reported, but again it is generally accepted that this represents spill-over of infection from humans to animals, and that animal populations cannot sustain M. tuberculosis. This apparent attenuation of M. tuberculosis in animal hosts is all the more intriguing given that genome studies have shown us that the M. bovis genome is merely a reduced version of the M. tuberculosis genome; hence, M. bovis does not have any “virulence” loci for animals per se that have been lost in M. tuberculosis. Instead it appears likely that differential expression of a range of genes between M. tuberculosis and M. bovis explains their specific host predilections.