Deciphering the pathogenesis of an enteric pathogen in neonatal and immunodeficient mice

Project summary
Infectious diarrhea remains a leading cause of morbidity and mortality in children and immunocompromised
patients worldwide. However, the lack of neonatal and immunodeficient animal models that closely mirror human
infection in these highly susceptible patient groups has limited our understanding of the disease. Therefore, we
propose here the use of novel neonatal and immunodeficient mouse models of disease to study the mechanisms
of pathogenesis and host immunity during enteric and systemic infection by the pathogens Citrobacter rodentium
and Salmonella enterica serovar Typhimurium.
Our first hypothesis is that C. rodentium employs different virulence factors to induce lethal systemic infection
in neonatal mice compared to those required for initial intestinal colonization. Specific Aim 1 was designed to
identify and characterize significant pathogen factors required for the establishment of bacteremia in neonates
using genome-wide screens and functional studies in vivo (1A-C). Specific Aim 2 will address our second
hypothesis regarding the protective role of IgG against enteric disease both in the neonatal and adult gut, and
the existence of compensatory or alternative mechanisms of pathogen eradication in the absence of IgG (2A-C).
Findings obtained with C. rodentium will be tested in the human pathogen S. Typhimurium to allow a broader
understanding of the general and specific aspects of microbial pathogenesis and host immunity during infection
in susceptible individuals (1D & 2D). These studies have high clinical significance as they may provide novel
insight into the pathogenesis of enteric and systemic disease both in children and patients with impaired adaptive
immunity, which aligns well with the goals of the National Institute of Allergy and Infectious Diseases (NIAID).
Additionally, we have also developed a robust and comprehensive career development and training plan that
will provide scientific training in alternative models of infection, mucosal and adaptive immunity, pathology and
disease progression, high-throughput data analysis, and state-of-the-art technologies to assess cell state and
inflammatory environment in the gut. This plan will also develop and strengthen key professional skills essential
to successfully lead an independent research program, including training in mentoring and teaching, scientific
communication, networking, grant preparation, and laboratory management. A group of highly qualified and
renowned scientists will guide and evaluate the applicant’s efforts to achieve his scientific and career goals.
Altogether, the research and career development activities outlined in this proposal, along with the outstanding
institutional environment at the University of Michigan, will fully prepare the PI to pursue an independent career
in health-oriented research, positioning him as a strong junior faculty in the fields of bacterial pathogenesis, host
immunity and host-pathogen interactions.

Grant Number: 5R00AI159620-04
NIH Institute/Center: NIH
Principal Investigator: Gustavo Caballero Flores