The mechanism of Shigella flexneri adherence during the early infection process

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DESCRIPTION (provided by applicant): This K22 Research Scholar Development Award focuses on the long-term research goals of the candidate, Christina S. Faherty, Ph.D., to become an independent investigator and to generate additional data for a future R01 application. Dr. Faherty has extensive research experience in Shigella flexneri pathogenesis, and has a strong collaborative relationship with experts in the field. The proposal is significant because it will begin to elucidate the early colonization process of S. flexneri to determine if adherence is an important first step in infection, which is a major gap in knowledge regarding Shigella pathogenesis. S. flexneri is a facultative-intracellular pathogen that causes a significan global burden by infecting 160 million people annually, predominately in children under the age of five years in developing countries, resulting in 1 million deaths. Infection is due to the abiliy of the bacteria to invade the colonic epithelium. While the invasion process and immune evasion of S. flexneri have been extensively studied, the early infection process has not been adequately investigated. Principally, it remains unknown how the bacteria recognize the colonic environment and if S. flexneri utilizes adherence factors to adhere to epithelial cells prior to invasion. The central hypothesis of this work is that S. flexneri utilizes adhesins to make contact with the colonic epithelium prior to invasion. Therefore, the long-term goals and objectives of this proposal are to determine how S. flexneri recognizes the colon and adheres to the colonic epithelium during pre-invasion virulence. The specific aims of this proposal are to: 1) identify th adhesins utilized by S. flexneri to adhere to the apical surface of the colonic epithelium; and 2) identify proteins on the apical surface of epithelial cells that facilitate S. flexneri adherence. he data obtained from these aims could lead to future studies to determine if antibodies directed against the adhesins inhibit adherence, which could reduce invasion of epithelial cells. Therefore, the proposed research could lead to innovative treatments or an improved vaccine candidate by targeting adherence factors. Finally, the data could not only translate to other enteric pathogens with homologous adhesins, but could also enhance the current S. flexneri infection paradigm by establishing the colonization events that occur prior to invasion. RELEVANCE: The proposed research is relevant to public health because it addresses key gaps in the infection process of Shigella flexneri, a bacterial pathogen that causes 160 million cases of dysentery each year around the globe. The research meets the goals of the mission for the National Institutes of Allergy and Infectious Diseases, and may lead to improved vaccine candidates to prevent the devastating infection rates.