Biomedical Sciences ETDs

Publication Date

5-1-2012

Abstract

Respiratory infections with the virulent type A strains of Francisella tularensis (Ft) cause pneumonic tularemia, an illness which results in high case fatalities in the absence of timely antibiotic treatment. Although immunization is an effective countermeasure, vaccines against pulmonary tularemia are currently unavailable. A better understanding of protective immune components is therefore needed to develop licensable vaccines against pulmonary tularemia. While the indispensability of cell-mediated immunity in protection against this gram-negative intracellular bacterium is well-documented, the protective role of antibodies (Abs) is unclear. Hence we examined the role of humoral immunity by developing a passive immunization model of respiratory tularemia in Fischer 344 (F344) rats. Naive F344 rats treated prophylactically with immune rat serum (IRS) or purified immune IgG obtained from rats vaccinated subcutaneously with the attenuated live vaccine strain (LVS) were protected against a lethal intratracheal infection with Ft type A strain SCHU S4. The resistance conferred by IRS was dependent on both anti-serum volume and SCHU S4 challenge dose, and was abrogated when IRS treatment was delayed beyond 48 h after the infection. Ab-mediated protection correlated with decreased dissemination to liver and spleen where the histopathology was less severe and depended on CD8 T cells. In vitro and in vivo bacterial burden analyses implicated other protective mechanisms of IRS in addition to enhancing phagocytosis and delaying bacterial growth. Further experimental analyses showed decreased levels of inflammatory cytokines and tissue damage markers in the sera and tissues of IRS-treated rats, which also showed markedly decreased apoptosis in their lungs. At the peak of infection, unlike the lung-associated lymph nodes (LALN) of normal serum treated rats, LALN of IRS-treated rats had lower SCHU S4 burden and higher number of viable dendritic cells, T cells, B cells and IFNγ —secreting cells. These results therefore demonstrate the ability of Abs to limit inflammation and cell death during pulmonary SCHU S4 infection to generate protective immunity and have important implications for understanding SCHU S4 virulence and development of Ab-based vaccines and therapeutics.

Keywords

Passive Immunity, Antibodies, Pulmonary tularemia, Vaccines, Inflammation, Cell death

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Advisor

Lyons, C. Rick

First Committee Member (Chair)

Rubin, Robert

Second Committee Member

Chackerian, Bryce

Third Committee Member

Byrd III, Thomas

Fourth Committee Member

Wu, Terry

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