Complications arising from pathogen infection incur a tremendous societal cost both in morbidity and mortality (as high as 50-60%), as well as in care and treatment estimated in billions of dollars. In susceptible patients, infection induces mis-regulation of the innate immune system that can culminate in systemic inflammation, severe illness and death. The development of probiotics with the capacity to dampen or modulate this response would have enormous value and numerous medical applications. Scarab Genomics has developed Clean Genome(r) E. coli strains that are devoid of all deleterious gene sequences and are tolerated better than existing strains in mammalian systems. Such reduced E. coli strains can provide immediate protection against a lethal dose of infecting bacteria as well as toxins in mice, presumably by suppressing the extreme inflammatory response, or by raising the level of preparedness of the innate immune system, or both. This protective effect has great potential for use in clinical populations, both as an intervention for serious infections including sepsis and septic shock, and as a prophylactic to reduce the chance of infection in at-risk patients. Ideally the treatment would provide universal protection against any pathogenic challenge. In Phase I of the proposal, feasibility parameters including dosing regimen, route of delivery and the ability of non-viable preparations to protect against sepsis will be examined. In Phase 2, Clean Genome(r) strains that contain alterations in membrane lipopolysaccharide (the bacterial component strongly associated with innate immune activation) will be evaluated for protection against sepsis. Further, we will determine whether protection by reduced genome strains extends to other Gram-negative bacterial strains. To establish clinical relevance, a mouse model will be used to demonstrate protection by Clean Genome(r) strains of lethal doses of pathogenic E. coli strains including O157:H7, a colonizing, Shiga toxin-producing strain. An additional protective strain that will be tested in this context is the E. coli strain Nissle 1917, which has been in use as a probiotic for many decades and which has the capacity of colonize the intestine. Nissle 1917 is currently undergoing genome- reducing deletions at Scarab that have been targeted to enhance its safety and stability. The development of Nissle 1917 as a probiotic against infection and sepsis will result in protective colonizing bacteria for oral delivery. Our core competence in the targeted reduction and modification of E. coli will enable us to develop probiotics for the treatment of infection and sepsis.
The impact of these Clean Genome(r) products on human health could be highly significant, reducing complications associated with surgery or antibiotic treatments. Protection is likely to extend to many other bacteria and viruses, providing innate protection against septic toxicity and/or ameliorating their pathology, resulting in substantial savings in health care costs. Further, development costs would be much lower than for conventional drugs, and pharmaceutical production of clean bacteria would be economical and highly efficient.
