Upon respiratory infection, the immune response is initiated by a burst of pro-inflammatory cytokines, followed by a massive infiltration of cells to the lung. Evidence suggests that cells infiltrating the lung early during infection transport antigen to the lymph nodes which contributes to the initiation of adaptive immunity. Our preliminary data demonstrated that during a respiratory viral infection, in concordance with the lung pro-inflammatory burst, the levels of a number of cytokines rise in the blood followed by significant changes in cells in the bone marrow (BM). Intriguingly, the cells in the BM display an """"""""interferon signature"""""""" which involves the expression of a number of anti-viral genes. These adaptations of BM cells occur in the absence of virus infection in the BM or detectable virus in the blood. BM cells expressing this interferon signature are resistant to infection by a number of viruses. The BM, the primary site of hematopoiesis, is a likely supplier of pro-inflammatory cells to inflamed tissues. However, limited research has been done focusing on the crosstalk between the lung and the BM during a localized lung infection. Information regarding the contribution of monocytes, granulocytes, and other non-antigen specific cells recruited from the BM for lung immunity is also lacking. We hypothesize that signals produced in the lung during a viral infection are delivered to the BM to induce the concerted priming and release of cells to the blood for recruitment to the inflamed lung. These primed cells perform effectively when encountering pathogen cues in the lung.
Aim 1 of this grant will study the effect of lung derived interferons in BM cells during a well characterized model of mice infection with Sendai virus, and the consequences of this effect in the development of immunity. The exposure of cells to interferons in the BM could be greatly relevant for the effective development of immunity as pre-treatment of dendritic cells with type I IFN renders them hyperresponsive to virus infection in vitro. Are BM cells primed by interferon to resist virus infection while prepared to effectively respond to viral cues once recruited to the lung? How does the interferon signature of BM cells affect the outcome of lung immunity in vivo? Aim 2 will study the role of G-CSF and IL-6 in the activation and release of cells from the BM during lung infection. These proteins that are highly elevated in the blood of animals undergoing a lung infection have been associated with cell differentiation and release from the BM. Overall, in these studies we expect to define specific interactions between cytokines produced in the lung and the BM response during a lung viral infection. Given the relevance of the BM for hematopoiesis, and the demonstrated role of newly recruited cells for the development of lung immunity, the elucidation of the mechanism of crosstalk between these two compartments could create novel modes of intervention for the modulation of mucosal immunity during therapy and vaccination. The interaction between lung-derived signals and bone marrow cells during a respiratory virus infection has been overlooked. We have identified a number of changes in bone marrow cells during the onset of the immune response to a viral infection restricted to the lung. In this grant we aim to characterize the interaction of lung-derived cytokines and bone marrow cells and the effect of this interaction for the development of mucosal immunity. We expect to identify regulatory pathways during the crosstalk of lung and bone marrow that could serve as novel points of intervention for the manipulation of mucosal immunity.
The interaction between lung-derived signals and bone marrow cells during a respiratory virus infection has been overlooked. We have identified a number of changes in bone marrow cells during the onset of the immune response to a viral infection restricted to the lung. In this grant we aim to characterize the interaction of lung-derived cytokines and bone marrow cells and the effect of this interaction for the development of mucosal immunity. We expect to identify regulatory pathways during the crosstalk of lung and bone marrow that could serve as novel points of intervention for the manipulation of mucosal immunity.
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