Mycobacterial infection in guinea pigs.

We described published reports of the chaos which exists in research concerning laboratory animal models for assay of tuberculosis (TB) vaccines and proposed a "rational animal model" as a solution to the problem. This animal model, an aerosol challenge model in guinea pigs, was recently applied to the problem of differences in growth characteristics of sputum isolates of low and high virulence. The same model was used to investigate the protective effect of high dose BCG given aerogenically. Based on studies in the guinea pig model of experimental airborne TB, and a review of the literature on pathogenesis of human TB, we described an "integrated model" for the pathogenesis of TB, a model which includes a role for both the endogenous reactivation and the exogenous reinfection pathways. Our hypothesis is that tubercle bacilli must be able to gain access to the "vulnerable region" in the lung apex in order to survive the effects of the CMI response. In endogenous reactivation TB (virulent tubercle bacilli), this access occurs via the bloodstream. Whereas in exogenous reinfection TB, access to the vulnerable region occurs via multiple exposures via the respiratory tract. Central to our perspective is the acceptance of the evidence that during first infection with virulent organisms, tubercle bacilli enter the bloodstream via the efferent lymphatics. We believe the hypotheses we have proposed have the potential to lead to a further increase in our knowledge of these mechanisms and are a prerequisite to studies aimed at the development of new vaccines.