RESEARCH PROGRAM III - Bacteria and Protozoa that Invade or Cause Disease via the Mucosa
Program Shepherds: Richard L. Guerrant (UVA) and Alan Cross (UMB)
The central themes of this Research Program are: 1) how various pathogens interact with the gastrointestinal and respiratory mucosa; and 2) ways to stimulate different arms of the mucosal and systemic immune system. The objectives are to seek common features and virulence mechanisms among the different pathogens that may be amenable to the design of broad spectrum therapeutic interventions to interrupt pathogenesis and synergistic immune responses to confer broad spectrum protection.
Immune defenses at the mucosal surface constitute a generic early barrier that is common for all pathogens that cause enteric or respiratory infection, including ones that invade systemically or whose products have systemic effects. Enteric pathogens elaborate an array of virulence factors by which they cause enteric infections including acute diarrheal disease, dysentery, persistent diarrhea and enteric fever, and systemic complications. The emerging bacterial pathogens to be studied in Program III include Shigella, enteric fever Salmonella (Typhi, Paratyphi A & B), non-typhoidal Salmonella, enteroaggregative Escherichia coli (EAEC), enterotoxigenic E. coli (ETEC), enterohemorrhagic E. coli and Shiga toxin-producing E. coli (EHEC & STEC), Yersinia pestis, Francisella tularensis, Bacillus anthracis, Burkholderia pseudomallei, and the protozoan Cryptosporidium. These interactive projects are expected to generate significant new information about pathogenesis and immune response and also to yield new broad spectrum prophylactic and therapeutic interventions.
Broad-spectrum vaccines to enteric fevers in humans: cross-protective immunity
A recent meta-analysis of 2 randomized, controlled field trials conducted in Santiago, Chile, with the licensed live oral typhoid vaccine Ty21a showed that vaccination not only conferred protection against S. Typhi disease, but also against paratyphoid B fever. The overall goal of this application is to study the immunological mechanisms that could mediate this cross-protection.
Vaccine strategy for broad spectrum protection against non-typhoidal Salmonella
While non-typhoidal Salmonella (NTS) have long been known to cause gastroenteritis, multiple antibiotic-resistant highly virulent strains are emerging as important causes of invasive bacteremia and focal infections in the USA and globally, resulting in hospitalizations and deaths.
Phase I Trial of Two Candidate Live Oral Salmonella Enterica Serovar Paratyphi A Vaccines
We propose to conduct a Phase 1 trial of two live oral S. Paratyphi A vaccine candidates that are attenuated by a deletion in guaBA and in either clpX or clpP.
Broad spectrum Enteropathogen Vaccine Development
The overall goal of this proposal is to construct a vaccine that is broadly protective against multiple enteropathogens of public health importance to the U.S. population. These enteropathogens include Shigella (including S. dysenteriae 1, a bioterror threat agent), enterotoxigenic E. coli (ETEC) (the major cause of traveler’s diarrhea) and the emerging pathogens shiga toxin producing E. coli (STEC) (main cause of hemolytic uremic syndrome, HUS) and enteroaggregative E. coli (EAEC) (recently recognized as an important agent of pediatric diarrheal disease in the U.S.A).
Novel therapeutics, models, and immune interactions for cryptosporidiosis
In keeping with MARCE-2 goals of developing broadly applicable novel therapeutics, models, and approaches to improving innate and acquired host defenses for important health threats, this project builds upon substantial progress and several publications on developing new models and quantifying both clinical outcomes and intensity and duration of infection with the highly chlorine resistant water borne Cryptosporidium spp.
Leptin regulation of intestinal inflammation and infection
Hypothesis: Leptin is an important regulator of the intestinal inflammatory response to infection, and does so through its effects on either hematopoietic or non-hematopoietic cells of the gut.
Pulmonary infection by aerosol: Pathogenesis and intervention
Aerosolization is the most dangerous route of infection by select agents. Because of difficulty in diagnosis, it would be valuable to have therapies active against a broad range of aerosolized pathogens. Remarkably, little is known about the pathophysiology, microbiology, and immunology associated with aerosol delivery. This is due mostly to infrastructure requirements for aerosolization experiments, the specialized equipment that is necessary, and the limited number of individuals trained in the field of aerobiology.
Innate and adaptive immune responses to Francisella tularensis
Francisella tularensis (Ft), a Gram negative intracellular bacterium, the etiologic agent of tularemia, and is classified as a Category A agent because it can contracted with low inocula by the respiratory route and causes rapid morbidity and mortality if untreated. While attenuated for humans, mice infected i.n. or i.p. with Ft Live Vaccine Strain (LVS), a type B strain, contract a tularemia-like disease.