Man and mouse TB: Contradictions and solutions

Abstract

We be of one blood, ye and I Rudyard Kipling, The Jungle BooksAs anyone who has attended tuberculosis research meeting in recent years can attest, disputes about validity of experimental animal models of tuberculosis (TB) erupt frequently, but mostly deteriorate into eloquence matches failing to produce satisfactory conclusions. Funding agencies also join the debate, since translating research into effective measures of TB control in humans is critically dependent on reliable testing of new interventions in animal models. Concerns about the validity of the most popular and accessible mouse model arouse as in some studies robust performance of a vaccine or a drug combination in mice failed to correlate with their efficacy in other species 1 . Here we address controversies that surround the mouse model of tuberculosis and offer a genetic perspective on how to make use of its full power for testing anti-tuberculosis interventions and dissecting pathogenesis of the disease.Much of the information on TB pathogenesis, genetic control and the immune response to infection was obtained in experiments using inbred laboratory mice, which demonstrated that humans and mice are similar in the main features of the innate and adaptive immune responses to mycobacteria, including the protective role of CD4 + T cells, IFN-γ, and TNF-α 2 . As in humans, in the mouse model the pathogen primarily targets the lungs causing a range of pathologies. Availability of unsurpassed genetic resources, which include hundreds of inbred, congenic, recombinant, mutant and genetically engineered strains, and abundance of immunological reagents and methodologies allow in-depth analysis of virtually any aspect of TB pathogenesis in mice, whereas their assortment is scarce for other animal species. Moreover, experiments in mice are less expensive as compared to other species, while genetic standardization further reduces the cost by decreasing individual variation and, hence, numbers of animals in experimental groups. In spite of these advantages, mouse experimental models of TB were repeatedly subjected to substantial criticism as mimicking the human disease with insufficient accuracy. Before we consider the soundness of the statement that TB course in the mouse lung poorly reflect the clinical disease in humans, a simple preamble on how principles of biological diversity are applied to humans and mice in TB studies is needed.Genetic heterogeneity is a fundamental property of all animal species, and it accounts for a considerable fraction of intraspecies variation in susceptibility to and severity of mycobacterial infections typical for all mammals (reviewed in 3, 4 ). Introductory sections of virtually all TB papers contain trivial sentences that: (i) only a small per cent of individuals infected with virulent M. tuberculosis develop clinical signs of infection; and (ii) infection can result in divergent outcomes in different individuals, ranging from spontaneous eradication, latent nonPublisher's Disclaimer: This is a PDF file of an unedited manusc...

Aerosol Infection Model of Tuberculosis in Wistar Rats

“…The histopathological changes observed in Wistar rats over a period of 18 weeks had no central necrosis similar to mice [7] and other rat strains like type 1 diabetic rats [13] and Lewis rats [14]. In contrast, American cotton rats [12] and F344/N-rnu nude rats [22] have been shown to exhibit central necrosis within granulomas suggesting variable immunological and pathological outcomes across different rat strains.…”

Genetic variants of MARCO are associated with susceptibility to pulmonary tuberculosis in a Gambian population

“…The lung pathology of tuberculosis is sufficiently different in mice, in that many of the hallmark features of disease (e.g. granulomas) do not occur, and genes found to be associated in human studies are not necessarily associated with murine susceptibility and vice versa (reviewed in [20]). In order to determine whether the class A scavenger receptors are crucial to protection against human disease, we have performed a case–control study of single nucleotide polymorphisms (SNPs) using samples from a well-described Gambian population [21,22].…”

Host Genetics in Granuloma Formation: Human-Like Lung Pathology in Mice with Reciprocal Genetic Susceptibility to M. tuberculosis and M. avium

“…It was repeatedly put forward that there is no central necrosis in lung granulomata of TB-infected mice [5], [6] and that granulomatous zones remain aerobic in the lungs of mice, in contrast to humans [7], [8]. As discussed recently [9], these observations may be explained in the first instance by the choice of experimental mouse models. Mostly, corresponding data were obtained in mice of a TB-resistant mouse strain B6 or its derivatives, whereas mice of several genetically TB-susceptible strains repeat features of human TB pathology substantially more accurately [10], [11].…”