The Mouse Model of Chronic Tuberculosis
Animals infected with M. tuberculosis – mice, guinea pigs, or rabbits – typically develop a chronic, progressive form of the disease that varies in severity depending on the species, the guinea pig being the most susceptible, the rabbit the most resistant, and the mouse somewhere in between.
The mouse has become the animal of choice in the study of TB. In fact, Robert Koch himself employed mice in his pio-neering experiments over 100 years ago. A chronic infection in mice can be established by inoculation of bacilli by intravenous injection or by aerosol exposure. The bacilli multiply logarithmically during the first two to four weeks postinfection and then stop increasing in numbers in the lung and start to slowly decline in numbers in the liver and spleen. Depending on the titer of the initial inoculum, the chronic infection can last from months to over a year. The model is useful in that it allows host–M. tuberculosis interactions to be studied in the context of a prolonged persistent infection. The maintenance of a relatively high bac-terial load, accompanied by accumulating pathology, might pertain to human active TB, while the apparent lack of bacterial replication might be relevant to both active TB and LTBI. Among the limitations of the mouse model are differences in the com-position and organization of the granulo-matous structures compared with those formed in human lungs, and in the location of the bacilli in the infected lungs – almost exclusively intracellular in mice, consider-ably more extracellular in humans.
Spontaneous M. tuberculosis latency in animals only occurs in nonhuman pri-mates. A drug-induced model of latency known as the Cornell model, in which M. tuberculosis–infected mice are sterilized by drug treatment, and then allowed to reac-tivate spontaneously or by immunesup-pression, was developed in the 1950s by McCune and Tompsett. This model allows host–pathogen interactions to be stud-ied in the context of an infection where very low numbers of bacteria are present and has been used to study host factors involved in establishing and maintaining this type of “latency.” However, the rel-evance of the model to true latency awaits validation.