Elucidation of effector mechanisms that induce protective immunity against Francisella tularensis




Sanapala, Shilpa

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Francisella tularensis is a Gram-negative coccobacillus and the etiological agent of the zoonotic disease tularemia. It is characterized by a facultative intracellular lifestyle and its ability to survive and proliferate within macrophages, hence evading extracellular immune surveillance mechanisms. The Francisella Pathogenicity Island (FPI) is a prominent virulence locus essential for phagosomal escape and cytosolic replication. Several genes have been identified to be important for phagosomal escape and intracellular growth. An FPI mutant DeltaiglB is deficient in phagosomal escape and is predicted to be processed within the phagosome through Class II pathway. On the other hand, Delta fopC, a mutant lacking the outer membrane lipoprotein FopC which is required for evasion of IFN-gamma mediated signaling, is speculated to escape into the cytosol and be processed through Class I pathway. This study examined the comparative protective efficacy of DeltaiglB and DeltafopC against pulmonary LVS challenge. Although the initial priming mechanism is different for the two mutants, vaccination with either strain offered protection in wild type mice and mice lacking Class I or Class II pathway mediators to a similar extent. However, Delta fopC vaccinated perforin knockout mice were markedly susceptible to the challenge. Greater bacterial burdens were also exhibited by Delta fopC vaccinated CD 8 knockout mice post LVS challenge. NK and T cells significantly killed LVS infected cells through cytotoxicity dependent pathway. Collectively, these results suggest that perforin in concert with granzyme is required for DeltafopC mediated immunity and both NK as well as T cells are involved in the cytolytic action.


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Integrative Biology