The mortality and morbidity associated with neonatal gram-negative bacillary meningitis have remained significant despite advances in antimicrobial chemotherapy and supportive care. E. coli is the most common gram-negative organism causing sepsis meningitis in the neonatal period. A search for other therapeutic approaches (e.g., immunotherapy) to these infections is limited by the inadequate understanding of host-microbial factors related with the development of neonatal meningitis due to gram-negative bacilli. For example, it is not clear why E. coli strains possessing the K1 capsular polysaccharide and certain somatic antigens (018, 07, 01 and 016) are closely associated with neonatal E. coli meningitis. We have established an infant rat model of E. coli bacteremia and meningitis which has important similarities to human E. coli infection (e.g., age dependency, hematogenous infection of the meninges without the need for adjuvants or direct inoculation of bacteria into cerebrospinal fluid). In addition, we have secured a collection of E. coli strains possessing different capsular and somatic antigens and a battery of specific monoclonal antibodies. Using this animal model and resources, we should be able to examine the following aims: 1. To investigate the pathogenetic mechanism(s) responsible for the development of E. coli meningitis. 2. To further understand the reasons for newborn infants' increased susceptibility to certain E. coli serotypes. 3. To evaluate mouse hybridoma antibody prepared with group B meningococcus for its ability to protect against K1 E. coli infections. 4. To assess the prophylactic efficacy of mouse hybridoma antibodies directed against the lipopolysaccharides of K1 E. coli. 5. To investigate the mechanisms by which these hybridoma antibodies directed against the capsule and lipopolysaccharides of E. coli are effective in vitro and in vivo against K1 E. coli strains. 6. To develop optimal therapeutic regimen for E. coli bacteremia and meningitis in the newborn rats using combinations of chemotherapy and immunotherapy. The information derived from this proposal should also enhance our understanding of the pathogenesis, prevention and treatment of neonatal meningitis due to other bacteria.
Showing the most recent 10 out of 103 publications
