Program III. Bacteria & Protozoa that Invade or Cause Disease via the Mucosa

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.

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.

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.

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).

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.

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.

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.

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.