Abstract
The Gram-negative bacterium Shigella flexneri is the causative agent of shigellosis, a diarrhoeal disease also known as bacillary dysentery. S. flexneri infects the colonic and rectal epithelia of its primate host and induces a cascade of inflammatory responses that culminates in the destruction of the host intestinal lining. Molecular characterization of host-pathogen interactions in this infection has been challenging due to the host specificity of S. flexneri strains, as it strictly infects humans and non-human primates. Recent studies have shown that S. flexneri infects the soil dwelling nematode Caenorhabditis elegans, however, the interactions between S. flexneri and C. elegans at the cellular level and the cause of nematode death are unknown. Here we attempt to gain insight into the complex host-pathogen interactions between S. flexneri and C. elegans. Using transmission electron microscopy, we show that live S. flexneri cells accumulate in the nematode intestinal lumen, produce outer membrane vesicles and invade nematode intestinal cells. Using two-dimensional differential in-gel electrophoresis we identified host proteins that are differentially expressed in response to S. flexneri infection. Four of the identified genes, aco-1, cct-2, daf-19 and hsp-60, were knocked down using RNAi and ACO-1, CCT-2 and DAF-19, which were identified as up-regulated in response to S. flexneri infection, were found to be involved in the infection process. aco-1 RNAi worms were more resistant to S. flexneri infection, suggesting S. flexneri-mediated disruption of host iron homeostasis. cct-2 and daf-19 RNAi worms were more susceptible to infection, suggesting that these genes are induced as a protective mechanism by C. elegans. These observations further our understanding of the processes involved in S. flexneri infection of C. elegans, which is immensely beneficial to the routine use of this new in vivo model to study S. flexneri pathogenesis.
Highlights
Shigellosis, more commonly known as bacillary dysentery, is caused by enteric bacteria belonging to the genus Shigella
This study aims to further our understanding of the interactions between S. flexneri and C. elegans in order to establish this in vivo model as a viable alternative to study S. flexneri pathogenesis
Wild type S. flexneri serotype 3b kills C. elegans and killing requires the expression of bacterial virulence plasmidencoded genes Previously, Burton et al [18] and Kesika et al [19] have shown that wild type strains of S. flexneri serotypes 2a and 2b kill C. elegans
Summary
Shigellosis, more commonly known as bacillary dysentery, is caused by enteric bacteria belonging to the genus Shigella. Shigella flexneri strains most frequently associated with the disease invade the colonic and rectal epithelia of their host and induce a strong inflammatory response that culminates in severe tissue damage; this manifests in a spectrum of clinical symptoms ranging from watery diarrhoea to severe dysentery characterized by fever, abdominal cramping and bloody, mucoid stool [1]. The lack of a relevant in vivo model of shigellosis has been one of the major impediments to the development of preventive and therapeutic measures. The most commonly used in vivo models are the murine pulmonary model of shigellosis [3,4,5] and the guinea pig keratoconjunctivitis model [6], both these in vivo models lack clinical relevance as the site of S. flexneri infection and symptoms produced do not mirror infection in humans
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