Contrasting persistence strategies in Salmonella and Mycobacterium

Abstract

Long-term survival of persistent bacterial pathogens in mammalian hosts critically depends on their ability to avoid elimination by innate and adaptive immune responses. The persistent human pathogens that cause typhoid fever and tuberculosis exemplify alternative strategies for survival in the host: immune evasion and immune adaptation, respectively. Salmonella enterica serotype Typhi evades host innate immune responses and inflammation by expressing factors that interfere with its detection as a Gram-negative bacterium, enabling persistent colonization of an immunologically privileged niche, the gallbladder. In contrast, Mycobacterium tuberculosis has adapted to survive within phagocytic cells, which typically eliminate invading microbes, by deploying stress resistance mechanisms that counteract the harsh environment of the phagolysosome.

Figure 1. Pathogenesis of Salmonella Typhi infection

Typhoid fever is acquired by ingestion of food or water contaminated with S. Typhi (1). Bacteria that survive passage through the gastric acid barrier of the stomach invade intestinal epithelial cells and migrate through them to reach the lamina propria (2). In the intestinal mucosa, S. Typhi is phagocytosed by macrophages and survives within these phagocytic cells by T3SS-2 mediated secretion of effectors that interfere with host cell function. Following invasion, S. Typhi expresses factors that inhibit detection by the host innate immune system. This “masking” enables the bacteria to disseminate systemically to colonize macrophages in the liver (shown in red), spleen, and bone marrow (3). From the liver, S. Typhi can reach the gallbladder (shown in green) in bile. Infection of the gallbladder can lead to conversion to an asymptomatic carrier state (4). S. Typhi carriers continuously discharge the typhoid bacillus from the gallbladder to the small intestine in bile (5) and excrete viable bacteria in their stools (6) that can infect naïve hosts.

Figure 2. Pathogenesis of Mycobacterium tuberculosis infection

Infection with M. tuberculosis is initiated by inhalation of aerosols containing the bacterium (1). In the lung, M. tuberculosis is rapidly phagocytosed by resident alveolar macrophages. Actively replicating bacilli (shown in blue) induce inflammatory responses that recruit blood monocyte-derived macrophages. During growth of the primary lesion, some infected cells disseminate systemically to seed secondary lesions elsewhere in the lung (2, 3). In the majority of individuals, M. tuberculosis enters a latent state characterized by bacteria that are relatively quiescent (shown in grey) (4). When the immune system is compromised, for example by old age or HIV infection, M. tuberculosis resumes active growth (usually in secondary lesions) and elicits overt signs and symptoms of disease (5). Replication of M. tuberculosis leads to growth of the lesion and tissue destruction, which releases infectious bacteria into the lung airways (6). The characteristic cough of tuberculosis generates aerosols containing bacteria that can be inhaled by a naïve host to initiate a new round of infection.