In Vivo Phenotypic Dominance in Mouse Mixed Infections with Mycobacterium tuberculosis Clinical Isolates

Clinical isolates of Mycobacterium tuberculosis demonstrate significant heterogeneity in virulence potential in animal models of infection. Isolate CDC1551, for example, has previously been described in mouse survival studies as being hypovirulent, and isolate HN878 has been described as being hypervirulent. Observed dif-ferences in this mouse infection experiment have been proposed to reflect differential engagement of the host immune response. To assess whether this is a local or a systemic effect, C57BL/6 mice were infected simul-taneously with mixtures of CDC1551 and HN878 in varying ratios and were monitored for mycobacteri-al growth kinetics, strain proportions during infection, and mouse survival. Strain mixtures that contained primarily HN878 grew more quickly during the first 5 weeks of infection and were more lethal for mice, and HN878 was enriched during in vivo growth. The absolute number of implanted HN878 bacilli at infection correlated inversely with mouse survival and was independent of concomitant infection with CDC1551. In infections of nonactivated mouse macrophages, HN878 grew more quickly. However, phagocyte preactivation reduced and equalized the growth rate of both strains. These results suggest that HN878 exerts a dominant immunosuppressive effect limited to the granuloma in which it is contained. Infection with Mycobacterium tuberculosis continues to be a leading cause of death globally. It is estimated tha