This proposal focuses on the earliest interactions of the F. tularensis the causative agent of tularemia with the host. Our hypothesis is that infection of particular cells in the lung results in a different pattern of host derived immunomodulatory molecules produced that shape the host innate and adaptive immune responses to benefit the pathogen. In this study we will identify the early cells infected in lung and skin infections. We will determine the molecules produced in the earliest cells following infection using a combination of fluorescence activated cell sorting and marked bacteria. By cell purification and in vitro infection we will learn how the impact the subsequent immune response. We will then determine the F. tularensis genes responsible, and their interactions with the host. Finally, we will determine mechanism for immune modulation.
The interaction between hosts and microbes is a complex one with signals going from the microbe to the host and vice versa. In this proposal we investigate how the bacterium that causes tularemia manages to end different signal to the host depending on where the initial infection occurs. We will identify the first cells nfected by the bacteria and how they respond depending on whether infection happens in the lungs or the skin. We will then determine how these cell influence the outcome of the immune response to the bacterium, and which bacteria genes are required. This will allow us to define targets for intervention by drugs.
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