Date of Award

January 2015

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Sciences

First Advisor

David S. Bradley

Abstract

This study demonstrates the various aspects of host immune response to Yersinia pestis. Y. pestis, the causative agent plague is mainly a rodent pathogen but is usually transmitted to humans via infected flea bite. After transmission to mammalian hosts, Y. pestis evades the host innate immune response and develops a systemic infection. Mast cells are recognized as the powerful sentinel cells responsible for controlling the early responses to a disease. We sought to determine whether mast cells are involved in the early innate immune response to Y. pestis and thus blocking mast cell degranulation would alter the outcome of infection. Mast cells in resistant young B10.T(6R) mice were depleted by use of anti-c-kit (ACK2) antibodies during Y. pestis infection. Our results demonstrated that Y. pestis infected anti-C kit treated mice showed lower survival rate than Y. pestis infected control mice suggesting mast cells are involved in early innate immune responses to Y. pestis. The other study is focused to understand the difference in the outcome of infection induced by endemic KIM5 and pandemic CO92 strains of Y. pestis. Both of these Yersinia strains have functional Type Three Secretion Systems (T3SS), which secretes effector molecules like Yersinia outer proteins (Yops) into the host cytosol to modulate the host immune response. KIM5 and CO92 strains express different isoforms of one of the Yop effectors, YopJ, which has been shown to inhibit NF-κB and MAPK activation in

mammalian cells. The YopJ isoform in Y. pestis KIM5 has two amino acid substitutions, F177L and K206E, which are not present in YopJ proteins of Y. pestis CO92. We show that young B10.T (6R) mice that are resistant to the KIM5 strain (LD50 of 14,000 CFUs) were susceptible to the CO92 strain (LD50 of 17 CFUs). A set of KIM5 isogenic strains expressing various YopJ isoforms allowed a demonstration that amino acid differences in YopJ were largely responsible for the increased virulence of the pandemic strain, CO92 in the B10.T (6R) mice.

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