No animal model replicates the multiple phases of M. tuberculosis infection in the human host as outlined above. Nevertheless, small animal models are necessary to understand M. tuberculosis pathogenesis because they allow analysis of bacterial burden, tissue pathology, and host survival of various host and pathogen mutants. The animal models that are used most extensively are discussed below.
The mouse is the most widely used animal model for M. tuberculosis
infection because of the broad availability of immunological reagents, genetically engineered strains, and ease of housing. M. tuberculosis
infection of the mouse by aerosol inhalation or intravenous injection follows a reproducible pattern characterized by bacterial growth over the first 2-3 weeks, followed by a plateau of the bacterial burden. The beginning of this plateau phase is coincident with onset of host adaptive immunity and can continue for over a year, until the death of the animal. This “persistence phase” of the murine infection clearly represents a balance between host immunity and the pathogen's ability to resist elimination. Host defects in cell mediated immunity such as lack of IFNγ, CD4 T cells, or TNFα cause progressive infection without a persistence phase [4
However, several aspects of murine infection with M. tuberculosis
do not replicate human infection, at least as assessed in standard laboratory mouse strains such at C57Bl/6. M. tuberculosis
infected C57Bl/6 mice do not develop the architecturally complex cavitary granulomas that are characteristic of human Tuberculosis. Recently, alternative mouse strains have been generated by breeding which do develop cavitary lesions and the murine genetic determinant has been identified [5
]. However, in all models, the persistence phase of the murine infection is characterized by stably high bacterial loads, indicating that the murine immune system is incapable of reducing M. tuberculosis
to latency. In addition, recent evidence indicates that M. tuberculosis
continues to replicate during the persistence phase [6
], further reducing similarities to human latency.
In an attempt to better reconstitute the granulomatous environment of the murine model, the mouse hollow fiber model was developed [8
]. The hollow fiber model uses encapsulation of bacilli in semidiffusible hollow fibers that are implanted subcutaneously into mice. Hypoxic granulomatous lesions develop around the hollow fibers, wherein the bacteria exhibit decreased metabolic activity and an antimicrobial susceptibility pattern similar to persistent bacilli [8
Another variation of mouse infection is the Cornell model of persistent infection and reactivation, in which M. tuberculosis
infected mice are treated with antimycobacterial agents until the bacterial titer becomes undetectable by microscopic inspection or culture. Following suppression of the host immune system by steroids, mice develop reactivated infection. However, the observed phenomenon of reactivation in infected mice is highly variable [9
An alternative animal model to the mouse is the guinea pig. Following low dose aerosol infection, lung lesions in guinea pigs infected with M. tuberculosis have striking similarities to natural infections in humans, such as necrosis, mineralization, and hypoxia. However, this infection invariably results in progressive Tuberculosis characterized by marked weight loss, cachexia, and death occurring usually within 15-20 weeks after infection, and therefore natural latent infection does not occur.
The quest for an animal model that more closely replicates human infection has led some investigators to study infection in non-human primates. Infection of these animals does reproduce many aspects of human Tuberculosis, including latency, reactivation, and granuloma structure [11
]. Although the proportion of infected animals that develop progressive primary infection (approximately 50%) is higher than adult human infection, latency is observed, making this model the closest to human TB [11
]. The major limitation of this model is the cost and logistics of maintaining primate colonies, an obstacle that will likely limit its general use in the research community.