Abstract
Enteric fevers, caused by the Salmonella enterica serovars Typhi (ST), Paratyphi A (PA) and Paratyphi B (PB), are life-threatening illnesses exhibiting very similar clinical symptoms but with distinct epidemiologies, geographical distributions and susceptibilities to antimicrobial treatment. Nevertheless, the mechanisms by which the host recognizes pathogens with high levels of homology, such as these bacterial serovars, remain poorly understood. Using a three-dimensional organotypic model of the human intestinal mucosa and PA, PB, and ST, we observed significant differences in the secretion patterns of pro-inflammatory cytokines and chemokines elicited by these serovars. These cytokines/chemokines were likely to be co-regulated and influenced the function of epithelial cells, such as the production of IL-8. We also found differing levels of polymorphonuclear leukocyte (PMN) migration among various infection conditions that either included or excluded lymphocytes and macrophages (Mϕ), strongly suggesting feedback mechanisms among these cells. Blocking experiments showed that IL-1β, IL-6, IL-8, TNF-α and CCL3 cytokines were involved in the differential regulation of migration patterns. We conclude that the crosstalk among the lymphocytes, Mϕ, PMN and epithelial cells is cytokine/chemokine-dependent and bacterial-serotype specific, and plays a pivotal role in orchestrating the functional efficiency of the innate cells and migratory characteristics of the leukocytes.
Highlights
Typhoid and paratyphoid fevers are known as enteric fevers and are caused by the intracellular Gram-negative bacteria Salmonella enterica serovars Typhi (ST), Paratyphi A (PA) and Paratyphi B (PB)[1,2,3,4]
The incidence of enteric fevers is very low in industrialized countries, with most infections occurring in military personnel and individuals traveling to endemic areas
To investigate how the host recognizes distinct Salmonella serovars that share a high degree of homology, we took advantage of a multicellular three-dimensional (3-D) organotypic model of the human intestinal mucosa, which was developed and characterized by our group [34,35,36,37,38,39], and three genetically similar serovars, namely PA, PB, and ST
Summary
Typhoid and paratyphoid fevers are known as enteric fevers and are caused by the intracellular Gram-negative bacteria Salmonella enterica serovars Typhi (ST), Paratyphi A (PA) and Paratyphi B (PB)[1,2,3,4]. 11.9–20.6 million new cases of typhoid fever occur in low- and middle-income countries and are associated with approximately 129,000–223,000 deaths [11,12,13,14]. These deaths happen mostly in Asia in children under five years of age [15]. The emergence of multidrug-resistant strains of ST and PA has complicated the antimicrobial treatment of enteric fever and asymptomatic carriers [16,17,18,19] To address this public health problem, there is an increased emphasis on sanitation measures, such as water and sewage treatment, and vaccination to fight these infections [4]
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