Preexisting Heterogeneity of Inducible Nitric Oxide Synthase Expression Drives Differential Growth of Mycobacterium tuberculosis in Macrophages

Mycobacterium tuberculosis infection is initiated by the inhalation and implantation of bacteria in the lung alveoli, where they are phagocytosed by macrophages. Even a single bacterium may be sufficient to initiate infection. Thereafter, the clinical outcome is highly variable between individuals, ranging from sterilization to active disease, for reasons that are not well understood. Here, we show that the rate of intracellular bacterial growth varies markedly between individual macrophages, and this heterogeneity is driven by cell-to-cell variation of inducible nitric oxide synthase (iNOS) activity. At the single-cell level, iNOS expression fluctuates over time, independent of infection or activation with gamma interferon. We conclude that chance encounters between individual bacteria and host cells randomly expressing different levels of an antibacterial gene can determine the outcome of single-cell infections, which may explain why some exposed individuals clear the bacteria while others develop progressive disease.