The proposed International Collaborations in Infectious Disease Research renewal program comprises a multidisciplinary and coordinated set of epidemiological, clinical and laboratory research activities in enteric disease, and will specifically focus on Giardia lamblia, Cryptosporidium, and E. coli infection in children. A major integrating theme will be to determine relationships between manifestations of infection in the host, and characteristics of the host and of the enteric pathogen. We will explore how infectively of each agent, and clinical expression of infection relate to the environmental, nutritional, and immunological status of the child, and to genetic and/or antigenic variability of Giardia lamblia, Cryptosporidium, and E. coli. The proposed ICIDR will be organized as five research projects and six core components and will be a collaborative thematically cohesive program among investigators from US institutions (Columbia University, Cornell University, University of Maryland, Centers for Disease Control, Univacs, ImmuCell, Merck) and institutions in Israel (Ben-Gurion University, Hebrew University, Army Health Branch Research Unit). Project 1 will prospectively follow 240 Bedouin infants from birth to age 2 years, to examine the environmental, host, and organism characteristics and the interactions between them, leading to the range of clinical manifestations associated with the three organisms. Using novel methods of pathogen identification and characterization (ELISA assays, DNA probes), genomic karyotyping, hygienic intervention protocols, and in depth analysis of nutritional/immune/environmental status, we will establish the time course and causality of these relationships, and also how asymptomatic Giardia lamblia carriage diminishes infections with other pathogens. Since Project 1 will not provide a sufficient number of cases to explore these relationships in children with severe clinical manifestations, Project 2 will identify environmental/host/organism factors associated with diarrhea in sick hospitalized children. Project 2 will also specifically assess two therapeutic interventions (azithromycin and hyperimmune anti-Cryptosporidum colostrum immunoglobulin) on the course of cryptosporidial diarrhea in a hospitalized population. Project 3 will probe the distribution of strain diversity of Giardia lamblia and Cryptosporidium using karyotype analysis and other strain markers; utilize PCR approaches for identifying and characterizing Giardia lamblia, and study in vitro cytopathogenic effects of Giardia lamblia on human intestinal epithelial cell cultures and lymphocytes. Project 4 will focus on the cellular immune response in infants in infants and young children, in relation to symptomatic and asymptomatic infections with the three groups of organisms with particular emphasis on development of different lymphocyte subpopulations e.g. 'memory cells'. Project 5 will provide an in depth understanding of the basic molecular genetic pathways underlying the high frequency of mutation and chromosome rearrangements in Giardia lamblia, and its variable gene expression. The Core components include: (a) ICIDR administration, (b) a Visiting Investigator Program, (c) Microbiology, (d) Giardia lamblia Serology, (e) Cryptosporidium/E. coli Serology, and (f) a Biostatistics center. The proposed ICIDR Program provides a unique opportunity to examine, in a Middle Eastern population with diarrheal disease patterns of developing nations, the role of Giardia lamblia, Cryptosporidium and different categories of E.coli in diarrheal diseases, and contribute knowledge essential for development of new intervention strategies.
