Modulation of innate defences in the neonatal gastrointestinal tract by colonizing neuropathogenic Escherichia coli

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Neonatal bacterial meningitis (NBM) contributes substantially to mortality and neurological disability worldwide. In developed countries, NBM affects approximately one in 3,000 newborn infants. Antibiotic therapy may not always be effective as the infection progresses very rapidly and antibiotic resistant bacteria are now more commonly found. The risks are far worse in developing countries and disease incidence is increasing due to higher survival rates of premature infants coupled with limited access to medicines. The incidence may be as high as six per 1,000 live births in regions in Africa and the disease carries significant mortality. Survivors often suffer severe consequences such as cerebral palsy, mental retardation, seizures, epilepsy and hearing impairment. Rates of neonatal sepsis, which is linked to NBM, are even higher. A strategy of prevention rather than treatment once the infection has occurred would have clear benefit but vaccination, often effective in controlling bacterial infections, cannot be employed to protect the newborn from NBM.One of the major causes of NBM is Escherichia coli. This bacterium produces a protective capsule, termed K1, and it can harmlessly colonize the mother's intestinal tract. Sometimes the infant acquires the bacterium from the mother during or shortly after birth. The K1 bacterium colonizes the gastrointestinal (GI) tract of the newborn infant and for reasons that are poorly understood may relocate to the blood and disseminate to other organs, including the brain. These potentially lethal infections tend to occur within the first four weeks of life. Key features of the human infection, particularly the strong age dependency, can be replicated in the experimental rat. Two-day-old (P2) rats are highly susceptible to infection after colonization whereas nine-day-old animals are completely resistant. I wish to understand the basis of this age dependency as this may provide a platform for novel preventative measures to protect the newborn infant. Recent work by my collaborator has established that the small intestine is protected by a thin layer of mucus and a high concentration of peptides that protect this region of the gut. In the colon, protection is primarily afforded by a very thick, structured layer of mucus. My group has very recently shown that in the younger (P2) neonates neither of the barriers to infection is well-formed. In addition, the incoming K1 colonizers appear to suppress maturation of the mucus layers and do not provoke secretion of the antibacterial peptides. These physical and chemical barriers keep bacteria at a safe distance from the gut wall; allowing them to get close to cell surfaces may support their relocation to the blood. We now wish to determine if these factors are responsible for the age dependency of the infection and to define key steps in the infection process. We will establish the site in the GI tract from which K1 bacteria escape into the circulation; this will be important in formulating strategies for preventing this relocation. The "defensin" peptides are produced by Paneth cells in the small intestines; these are present in only small numbers in the P2 rats. We will examine the role of these cells by assessing the impact of K1 colonization on peptide secretion and by chemically interfering with peptide secretion. We will track the development of the intestinal mucus layer over the first two weeks of life and determine how K1 colonization affects this maturation. If we can establish that circumvention of these barriers by K1 bacteria is the basis of susceptibility to infection, we will dose K1-colonized P2 rats with a protein, termed Tff2, which drives the assembly of the protective mucus barrier. If Tff2 can reduce or prevent infection in susceptible rat pups by promoting mucus layer maturation, it could be used as a new approach to the prevention of this disease.