Alcohol, hedgehog signal, and HSC dysfunction in host defense against septicemia

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DESCRIPTION (provided by applicant): Alcohol abusers are susceptible to bacterial infection. Alcoholic patients with serious infection, particularly septicemia, frequently present with granulocytopenia which is an indicator for increased mortality. Our recent studies have revealed that in response to bacterial infection, bone marrow pool of lineage(lin)-stem cell factor receptor(ckit)+stem cell antigen-1(Sca1)+ cells (LKS cells, a cell population enriched with hematopoietic stem cells) is rapidly increased in mice. The emergency expansion of LKS cell population is associated with reprogramming of these primitive precursors to enhance their commitment to granulocyte lineage development. Alcohol impairs this critical step of the granulopoietic response. At the present time, the underlying cell signaling mechanisms remain unclear. The hedgehog signal transduction pathway has been reported to participate in the regulation of certain stem/progenitor cell functions in normal state during embryogenesis and in adulthood. In preliminary experiments, we observed that Sonic hedgehog (SHH) expression was significantly up-regulated in the bone marrow of mice with septicemia. The Toll-like receptor (TLR)4-extracellular signal-regulated kinases (ERK)1/2-specificity protein 1(Sp1) signal cascade provided the essential signal for up-regulation of SHH expression by marrow cells. LKS cells were the most active cells responding to SHH. Activation of SHH-glioma zinc finger transcription factor 1 (Gli1)-cyclin D1 signaling promoted LKS cell proliferation, whereas activation of SHH-Gli1-PU.1 (an ETS-domain transcription factor encoded by the SPI1 gene) signaling mediated LKS cell reprogramming for enhanced commitment to granulocyte lineage development. Alcohol exposure disrupted this signaling system. Therefore, we propose to systematically investigate the effects of alcohol on SHH signaling in the regulation of primitive hematopoietic precursor cell activation during the granulopoietic response to septicemia. Our central hypothesis is that alcohol impairs primitive hematopoietic precursor cell function during the granulopoietic response to systemic infection by disrupting SHH signaling. Three specific aims are: 1) to test the prediction that alcohol inhibits activation of the SHH signal pathway in LKS cells in response to septicemia; 2) to test the prediction that alcohol inhibits LKS cell proliferation in response t septicemia via impairing the GLI1-cyclin D1 pathway; and 3) to test the prediction that alcohol inhibits LKS cell reprogramming for enhancing granulocyte lineage commitment during septicemia via impairing the Gli1-PU.1 signal cascade. Results obtained from this investigation will greatly advance our knowledge about the impairment of host defense against serious infections in alcohol abusers. It will also identify key targets for developing novel therapeutic interventions to treat fatal infections in these immunocompromised hosts.