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. IMPORTANCE In this report, we demonstrate that fluctuations in the expression of antimicrobial genes can define how single host cells control bacterial infections. We show that preexisting cell-to-cell variation in the expression of a single gene, that for inducible nitric oxide synthase, is sufficient to explain why some macrophages kill intracellular M. tuberculosis while others fail to control bacterial replication, possibly leading to disease progression. We introduce the concept that chance encounters between heterogeneous bacteria and host cells can determine the outcome of a host-pathogen interaction. This concept is particularly relevant for all the infectious diseases in which the number of interacting pathogens and host cells is small at some point during the infection.