The replication of a bacterial virus is not necessary to cause lethal disease in a mouse model of a food-borne pathogen called Enterohemorrhagic Escherichia coli (EHEC), according to a study published January 10 in the open-access journal PLOS Pathogens by Sowmya Balasubramanian of Tufts University School of Medicine, and colleagues. The surprising findings could lead to the development of novel strategies for the treatment of EHEC and life-threatening kidney-related complications in children.
Enterohemorrhagic Escherichia coli (EHEC), a food-borne pathogen that produces Shiga toxin, is associated with serious disease outbreaks worldwide, including over 390 food poisoning outbreaks in the U.S. in the last two decades. Humans acquire EHEC by ingesting contaminated food or water, or through contact with animals or their environment.
EHEC colonize intestinal epithelium
EHEC colonize intestinal epithelium by generating characteristic attaching and effacing (AE) lesions. They are lysogenized by prophage that encode Shiga toxin 2 (Stx2), which is responsible for severe clinical manifestations. As a lysogen, prophage genes leading to lytic growth and stx2 expression are repressed, whereas induction of the bacterial SOS response in response to DNA damage leads to lytic phage growth and Stx2 production both in vitro and in germ-free or streptomycin-treated mice.
Some commensal bacteria diminish prophage induction and concomitant Stx2 production in vitro, whereas it has been proposed that phage-susceptible commensals may amplify Stx2 production by facilitating successive cycles of infection in vivo. Infection and toxin production may result in localized hemorrhagic colitis, but may progress to life-threatening systemic hemolytic uremic syndrome (HUS), the leading cause of kidney failure in children.
Treatment for EHEC or HUS remains elusive, as antibiotics have been shown to exacerbate disease. Shiga toxin genes reside on a dormant bacterial virus present in the EHEC genome, but are expressed when the virus is induced to leave its dormant state and begin to replicate. Extensive virus replication has been thought necessary to produce sufficient toxin to cause disease.
Sufficient Shiga toxin was produced to cause lethal mouse disease, even without viral replication
Using viral and bacterial mutants in our EHEC disease mouse model, researchers showed that whereas an inducing signal needed to begin viral replication was essential for lethal disease, virus production was not: sufficient Shiga toxin was produced to cause lethal mouse disease, even without viral replication. Future analyses of EHEC-infected human samples will determine whether this same phenomenon applies, potentially directing intervention strategies.
According to John Leong, one of the authors, “An important next step will be to learn what parts of the viral life cycle occur in human patients, and whether there are ways to prevent those aspects that lead to disease”.