Abstract
The initiation, progression and transmission of most bacterial infections is dependent upon the ability of the invading pathogen to acquire iron from each of the varied environments encountered during the course of a natural infection. In total, 95% of iron within the human body is complexed within heme, making heme a potentially rich source of host-associated nutrient iron for invading bacteria. As heme is encountered only within the host, pathogenic bacteria often regulate synthesis of heme utilization factors such that production is maximal under host-associated environmental conditions. This study examines the regulated production of ShuA, an outer-membrane receptor required for the utilization of heme as a source of nutrient iron by Shigella dysenteriae, a pathogenic bacterium that causes severe diarrheal diseases in humans. Specifically, the impact of the distinct environmental temperatures encountered during infection within a host (37°C) and transmission between hosts (25°C) on shuA expression is investigated. We show that shuA expression is subject to temperature-dependent post-transcriptional regulation resulting in increased ShuA production at 37°C. The observed thermoregulation is mediated by nucleic acid sequences within the 5′ untranslated region. In addition, we have identified similar nucleotide sequences within the 5′ untranslated region of the orthologous chuA transcript of enteropathogenic E. coli and have demonstrated that it also functions to confer temperature-dependent post-transcriptional regulation. In both function and predicted structure, the regulatory element within the shuA and chuA 5′ untranslated regions closely resembles a FourU RNA thermometer, a zipper-like RNA structure that occludes the Shine-Dalgarno sequence at low temperatures. Increased production of ShuA and ChuA in response to the host body temperature allows for maximal production of these heme acquisition factors within the environment where S. dysenteriae and pathogenic E. coli strains would encounter heme, a host-specific iron source.
Highlights
Shigella species are gram-negative, facultative intracellular bacteria and the causative agents of shigellosis, a severe diarrheal disease in humans
A strain of S. dysenteriae lacking shuA (DshuA) was used as a negative control in this assay and as expected, shows no specific reactivity with the anti-ShuA antibody (Figure 1). These data indicate that ShuA levels are modulated in response to environmental temperature with increased ShuA levels achieved at the host-associated temperature of 37uC as compared to the non-host associated temperatures of 25uC and 30uC
This study demonstrates that the expression of S. dysenteriae shuA and E. coli chuA, genes essential for the utilization of heme as a source of nutrient iron, is modulated in response to environmental temperature by a post-transcriptional regulatory mechanism
Summary
Shigella species are gram-negative, facultative intracellular bacteria and the causative agents of shigellosis, a severe diarrheal disease in humans. Shigella transit the gastrointestinal system of the human host to the colon, where a shigellosis infection is initiated by invasion of the bacterium into cells within the colonic epithelium [2]. During infection within and transit between hosts, Shigella species, like most pathogenic bacteria, must acquire iron to survive. Bacteria have evolved to produce specialized high affinity uptake systems to mediate the acquisition of nutrient iron from heme and other host-associated iron sources [7,8]. Shigella species contain several conserved iron uptake systems [9,10,11,12,13,14,15,16,17,18,19,20]; unique to S. dysenteriae is the Shu (Shigella Heme Uptake) system, a system dedicated to the utilization of heme and heme containing proteins as sources of nutrient iron [13,14,21,22]
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