Our Objective: To understand the host response to S. flexneri infection in developing potential host directed therapeutics. Hypothesis: Host genes and cellular processes are essential for efficient colonization and dissemination of S. flexneri in the human colon. These genes and cell processes can be discovered by comparing colonic biopsies during acute shigellosis to convalescence. Significance: Approximately 165 million cases of shigellosis are annually reported in low-income countries, with at least 1 million of these cases resulting in death, especially in children under five years of age (5). Very recently, Shigella ranked the highest among the overall pathogen burden, with a particularly high incidence in the second year of life (10). As is well known to CDC, multidrug resistant Shigella infections are a ?serious? threat (18). Currently, no effective vaccine with the ability to confer adequate protection against the many different serotypes of Shigella has been developed. Investigators: Dr. Zannatun Noor is an early career research scientist from Bangladesh and seeking a mentored research career development award. She will conduct the study under supervision of Bangladesh mentor Dr. Rashidul Haque at icddr, b and USA mentor Dr. William A. Petri at University of Virginia. Both mentors are working with collaboration for more than two decades and have successfully completed different studies. Innovation: Determine gene expression and cellular infiltration to identify the host immune response is ground-breaking in Shigellosis. We will conduct RNAseq and CyTOF of colon biopsies to determine host gene expression and cellular infiltration respectively. Approach: To test our hypothesis, our specific aims are- 1) Systematically determine and characterize colonic gene expression profiles in response to S. flexneri infection. 2) Determine the identity of infiltrating immune cells in the colon during S. flexneri infection vs convalescence. Environment: Key to success of the study are the experienced mentors and highly motivated candidate who is seeking for the necessary training, practical experience, and knowledge to become a leading independent investigator in implementing child health interventions to reduce burden of infectious diseases in Low and Middle-Income Countries. Mentors are complementary expertise, like US mentor at the University of Virginia in immunology and in advance technology and LMIC mentor at icddr, b in clinical investigation. Both the host institute at LMIC and US institute have strong commitment to the candidate and her proposed career development.
Annually, there are approximately 270 million reported or confirmed cases of cases worldwide, predominantly in low-income countries, with more than 200,000 of these resulting in death, especially in children under five years of age (5). Very recently, Shigella ranked the highest among the overall pathogen burden, with particularly high incidence in the second year of life (10). We propose for advancement of the understanding of host response to Shigella flexneri infection to lay the foundation for developing potential host-targeted treatment for this highly antibiotic-resistant bacterium.