Alcohol is the most frequently abused drug that predisposes the host to bacterial infections. Alcoholic patients with severe bacterial infections, particularly septicemia, often present with granulocytopenia which is an indicator of increased mortality. In response to bacterial infection, the bone marrow of normal individuals increases granulocyte production at the expense of other lineage development in order to enhance host defense against invading pathogens. Our recent studies have revealed that the marrow pool of lineage(lin)-c- kit+Sca-1+ cells (LKS cells, an enriched hematopoietic stem cell population) is rapidly expanded during septicemia. This alteration of primitive hematopoietic precursors plays a key role in the granulopoietic response. Expression of Sca-1 by lin-c-kit+Sca-1- cells (primarily myeloid progenitors) is the major mechanism responsible for the rapid expansion of lin-c-kit+Sca-1+ cell pool following septicemia. Enhanced proliferation of lin-c-kit+Sca-1+ cells also contributes to the increase in the marrow lin-c-kit+Sca-1+ cell population. Alcohol intoxication impairs the expansion of the lin-c-kit+Sca-1+ cell population during bacterial infection. At the present time, no information is available about the mechanisms by which alcohol injures this initial stage of the granulopoietic response. In this project, we propose to systematically explore the underlying cell signaling mechanisms. Our overall hypothesis is that alcohol suppresses key cell signaling pathways involved in mediating the lin-c-kit+Sca-1+ cell response and impairs initial activation of granulocyte production in the bone marrow during septicemia. The three Specific Aims are: 1. To test the hypothesis that alcohol inhibits primitive hematopoietic precursor cell commitment to myeloid lineage development in response to septicemia via impairing the Sca-1/TLR4-PU.1 pathway;2. To test the hypothesis that alcohol inhibits expression of Sca-1 by lin-c-kit+Sca-1- cells in response to septicemia via impairing the TLR4-JNK-AP1 pathway;3. To test the hypothesis that alcohol inhibits activation of lin-c-kit+Sca-1+ cell proliferation in response to septicemia via impairing the TLR4-p44/42-cyclin D pathway. Results obtained from this investigation will fill a major gap in our knowledge regarding the impairment of host defense against serious infections at the level of hematopoietic stem/progenitor cells in alcohol abusers. It will also form a foundation for developing novel therapeutic interventions to treat serious infections in these immunocompromised hosts.

Public Health Relevance

Alcohol abuse predisposes the host to severe bacterial infection which is one of the leading causes of death in the United States. Many alcoholic patients with severe bacterial infection present with leukopenia, which is frequently fatal. This project investigates the mechanisms underlying this serious health problem and will help to identify therapeutic approaches for effective treatment of alcoholic patients with severe bacterial infection.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
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Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Wang, Joe
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Michigan State University
Schools of Medicine
East Lansing
United States
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Shi, Xin; Siggins, Robert W; Stanford, William L et al. (2013) Toll-like receptor 4/stem cell antigen 1 signaling promotes hematopoietic precursor cell commitment to granulocyte development during the granulopoietic response to Escherichia coli bacteremia. Infect Immun 81:2197-205
Melvan, John Nicholas; Siggins, Robert W; Stanford, William L et al. (2012) Alcohol impairs the myeloid proliferative response to bacteremia in mice by inhibiting the stem cell antigen-1/ERK pathway. J Immunol 188:1961-9
Shi, Xin; Zhang, Ping; Sempowski, Gregory D et al. (2011) Thymopoietic and bone marrow response to murine Pneumocystis pneumonia. Infect Immun 79:2031-42
Siggins, Robert W; Melvan, John N; Welsh, David A et al. (2011) Alcohol suppresses the granulopoietic response to pulmonary Streptococcus pneumoniae infection with enhancement of STAT3 signaling. J Immunol 186:4306-13
Melvan, John N; Siggins, Robert W; Bagby, Gregory J et al. (2011) Suppression of the stem cell antigen-1 response and granulocyte lineage expansion by alcohol during septicemia. Crit Care Med 39:2121-30