Trends in Immunology
ReviewExploiting host immunity: the Salmonella paradigm
Introduction
The immune response has the important function of defending the host from pathogens and potentially harmful commensals (e.g., pathobionts). Nevertheless, pathogens cause disease, implying that they can at least temporarily overcome host immune defenses to establish an infection. Over the years, several studies have put forward the concept that the immune response can actually be of benefit to harmful microbes because various aspects can be exploited by pathogens to enhance their colonization and replication within the host.
A prime example of an infectious agent that exploits the host immune response is the pathogen Salmonella enterica (hereafter referred to as Salmonella), a facultatively intracellular bacterium that is responsible for an estimated 90 million cases of human gastroenteritis [1] and 20 million cases of human typhoid fever [2] per year. Although the disease elicited by Salmonella is dependent upon the serological variety (serovar) of the pathogen as well as the characteristics of the host, infections are generally either localized to the gastrointestinal tract or systemically disseminative 3, 4. For humans, localized gastrointestinal infections of Salmonella are caused by the many hundreds of ‘non-typhoidal’ serovars within the species, including the model serovar Typhimurium. The disease elicited by these serovars is usually self-limiting and is characterized by inflammatory diarrhea with massive recruitment of neutrophils to the site of infection [5]. Nevertheless, despite the robust innate immune response, non-typhoidal Salmonella serovars colonize the intestine to high numbers and are shed in the feces of infected individuals for up to 1 month. Consistent with these clinical observations, several studies have now shown that Salmonella exploits intestinal inflammation to compete with the resident microbiota and to thrive in the inflamed gut 6, 7, 8, 9, 10, 11, 12.
Although most Salmonella serovars elicit gastroenteritis in humans, and all are invasive with respect to the intestinal mucosa, relatively few ‘typhoidal’ serovars have evolved to exclusively cause disseminated, life-threatening infections 3, 4. Such is the case for serovar Typhi, the causative agent of typhoid fever in humans, a systemic disease characterized by fever and enlargement of the spleen and liver (hepatosplenomegaly) [13]. Survival at extraintestinal sites involves a complex interplay between Salmonella and immune cells, primarily macrophages, which are permissive for pathogen replication and constitute a niche that promotes Salmonella persistence within the host.
Recent advances have provided new insights into how Salmonella exploits and evades immunity to promote its colonization and replication within the host. We review emerging evidence on the mechanisms by which Salmonella circumvents innate immunity to disseminate and establish infection at systemic sites. We further examine recent findings describing approaches by which Salmonella co-opts the immune response in the inflamed gut to thrive and compete with the resident microbiota. Overall, our goal is to convey general concepts on how Salmonella exploits host immunity to its own advantage.
Section snippets
Strategies towards establishing systemic infection
Infection of the gastrointestinal tract and of systemic sites such as the spleen and liver involves multifaceted interactions between Salmonella and macrophages. Macrophages are efficient in the phagocytosis and killing of bacteria through mechanisms including acidification, the production of antimicrobial peptides and toxic free radicals, cell death by pyroptosis, and the recruitment of other mediators of immunity by releasing proinflammatory cytokines [14]. Even so, Salmonella successfully
Salmonella infection in the intestine
Non-typhoidal Salmonella triggers a massive inflammatory response, characterized by the secretion of proinflammatory cytokines including IL-18 (e.g., by epithelial cells and macrophages undergoing pyroptosis) and IL-23 (by dendritic cells and other mononuclear cells) (Figure 3) [42]. Both of these cytokines rapidly stimulate immune cells (specified below) to secrete proinflammatory cytokines during Salmonella infection, thereby amplifying the immune response to the pathogen 42, 43, 44, 45.
Concluding remarks
A generally accepted concept is that the immune response is beneficial to the host because it limits the replication and dissemination of pathogenic organisms. Nevertheless, to replicate in the host and to cause disease, pathogens must have evolved mechanisms to, at least temporarily, evade the immune system. Moreover, an increasing number of studies have demonstrated that pathogens not only evade the immune system, but actively exploit the host response to compete with the microbiota and to
Acknowledgments
Work in the laboratory of M.R. is supported by National Institutes of Health (NIH) Public Health Service Grants AI083663, AI101784, and AI105374, as well as by the Burroughs Wellcome Fund. A.P.L is supported by University of California Institute for Mexico and the United States (MEXUS) and CONACYT (El Consejo Nacional de Ciencia y Tecnología).
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2022, Redox BiologyCitation Excerpt :Taken together, these results suggest that NLRP6 is detrimental to the host control of S. Typhimurium infection and the maintenance of iron homeostasis. Macrophages are main contributors to host protection against S. Typhimurium infection and regulate iron recycling [11,12]. Therefore, we sought to assess the potential impact of NLRP6 on iron metabolism in S. Typhimurium-infected macrophages.