Date of Award

4-2015

Document Type

Thesis

Degree Name

Master of Science in Medical Sciences (MSMS)

Department

Medical Microbiology and Immunology

First Advisor

Prof. Basel al-Ramadi

Second Advisor

Dr. Maria J. Fernande:-Cabezudo

Third Advisor

Dr. Eyad Elkord

Abstract

Susceptibility to infection by the intracellular bacterial pathogen, Salmonella enterica serovar Typhimurium (S. typhimurium), is controlled by many genes of innate and adaptive immunity. One of the most critical genes is IFN-Y and mice deficient in IFN-Y synthesis are highly susceptible to salmonella. Previously, we demonstrated that mice deficient in MyD88, an adaptor that regulates TLR signaling, are susceptible to Salmonella infection. In the current study, we compared immune responses in mice deficient in IFN-Y or MyD88 with wild-type controls following infection with an attenuated strain of S. typhimurium (designated BRD509E) or a recombinant derivative engineered to express murine IFN-Y (GIDIFN). Infection studies with BRD509E or GIDIFN revealed that the latter strain was significantly less virulent in immunodeficient mice than BRD509E and correlated with decreased bacterial loads in systemic organs. Enhanced responsiveness was due to GIDIFN strain’s ability to activate effector macrophages, as shown by increased synthesis of inflammatory cytokines and anti-microbial effector molecules, including NO. Gene expression profiling by qPCR demonstrated stronger induction of key inflammatory modulators by GIDIFN in macrophages of immunodeficient animals. These findings suggest that immunotherapeutic approaches using attenuated bacterial strains expressing immunomodulatory genes is more efficacious and offers a superior safety profile even in severely immunodeficient hosts.

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