During pulmonary Chlamydia pneumoniae (CP) infection in mice, innate immune sensing initiates a complex cascade of immune responses in order to eliminate the infection and minimize the damage done to the host. We have previously shown that plasmacytoid dendritic cells (pDCs) were required for proper innate immune responses to CP in mice and that without these cells, early cytokines were diminished and bacterial clearance was delayed. This lead to a profound chronic inflammation despite eventual bacterial clearance. While we know that pDCs are important for responses to CP infections in mice, Type I Interferon is not required for these processes, thus pDC's mechanism of action during a CP infection is still unknown. In preliminary data for this proposal, we performed a microarray analysis of pulmonary pDCs from CP infected mice and compared them with pDCs from nave animals. We found that pDCs from Cp infected lungs had extensive upregulation of NF?B driven products, including components of the inflammasome such as NLRP3, Caspase-1, and IL-1?. Further investigation revealed that pDCs in the lungs of CP infected mice contained active caspase-1, and we found that purified lung pDCs from infected mice secreted both IL-1? and IL-1?, suggesting that the inflammasome is active in these cells. pDCs are not known to be able to produce IL-1? via inflammasome activation, thus we may have identified a new paradigm for pDC involvement in innate immune responses. Additionally, IL-1? (and IL-1?) is a powerful cytokine and has been shown to be important for immune responses to CP infection in mice. Based on these preliminary data we hypothesize that during a C. pneumoniae infection in mice, the inflammasome gets activated in pDCs, which leads to IL-1? secretion and subsequent proper innate immune responses, resulting in CP clearance and inflammation resolution. We will test this hypothesis by proposing the following two Specific AIMs: 1) To elucidate the mechanism by which C. pneumoniae infection activates the inflammasome in plasmacytoid dendritic cells and 2) To determine if pDC inflammasome activity is responsible for pDC induced innate immune responses to C. pneumoniae infection in mice. The successful completion of this proposal will not only elucidate the mechanism by which pDCs direct innate immune responses during a Chlamydia pneumoniae infection in mice, but more importantly, we will have described for the first time the involvement of the inflammasome in pDC biology, thus describing a new paradigm for the potential involvement of pDCs in various pathologies. This will open the door for new treatments where pDC inflammasome activity may be involved. These studies will also offer insight for other researchers who might have found a proinflammatory pDC involvement that did not require Type I Interferon, such as described during a Legionella pneumophila infection in mice. Additionally, as pDCs are highly active during viral infections, pDC derived inflammasome activity may play a previously unappreciated role in those immune responses.
The inflammasome, an important component of innate immune responses, has not been described in plasmacytoid dendritic cells. This project will focus on Chlamydia pneumoniae, an important human pathogen, and what role the inflammasome plays in plasmacytoid dendritic cells during infection.
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