Unmet clinical need in treatment of diarrheagenic E. coli
Diarrheal diseases are estimated to affect more than one billion people annually and to kill around two million children every year. In the United States, diarrheal diseases annually cause 128,000 hospital admissions and more than 3,000 deaths. Enteropathogenic E. coli (EPEC) and enterohemorrhagic E. coli (EHEC) cause severe diarrhea and other complications that lead to life-threatening conditions. Standard antibiotics are not efficacious against these pathogens, and in fact exacerbate the disease by promoting release of bacterial toxins into the bloodstream, causing a systemic infection that can affect kidneys, cause neurological damage, and are lethal in 5 – 15% of severe cases. Treatments vary from hydration, maintenance of electrolyte balance, dialysis and blood transfusions depending on disease severity. Many patients experience prolonged hospital stays, often in the intensive care unit, expensive and invasive procedures, and follow-up visits, all of which amounts to a significant financial burden. Thus, therapies to treat EPEC and EHEC infections are urgently needed.
Therapeutic strategy targeting pathogenic E. coli virulence factors
Researchers at the University of Michigan have elucidated a connection between the host immune system, the commensal gut microbiota, and pathogen eradication that can be utilized as a novel treatment strategy for EPEC and EHEC infections. EPEC and EHEC pathogens express virulence factors, and their expression is very tightly regulated in response to environmental signals. Researchers discovered that early in infection, these virulence factors serve to compete out the commensal microbiota and thus establish favorable conditions for pathogen colonization and survival. In later stages of infection (2 weeks), microbiota is able to compete out the pathogen and eradicate it from the host organism. In the absence of microbiota, infection is not cleared, indicating a key role for indigenous microorganisms in removing the pathogen. However, microbiota in hosts with a compromised immune system is unable to eradicate the pathogen, and the host succumbs to infection. Researchers determined that the host immune system is able to down-regulate expression of virulence factors and their down-regulation is the reason that microbiota is able to successfully out-compete the pathogen. The interplay between microbiota, virulence factors, and the immune system opens a new mode of action for EPEC and EHEC infection treatment. All of the experiments were carried out in vivo in a well-established mouse model of E. coli infection.
Applications and Advantages
- Antibacterial therapeutic for EPEC and EHEC infections
- New mode of action
- Model system for microbiota – immune system interaction
- No specific treatment for EPEC and EHEC infections is available
- Treatment of EPEC and EHEC infections in early stages can prevent costly hospital stays, procedures, and follow-up care