Thomas Moore, Ph.D.
Background: Klebsiella pneumoniae is a leading cause of gram-negative bacterial pneumonia. A significant clinical complication of K. pneumoniae infection is peripheral blood dissemination, resulting in bacteremia concurrent with the initial pulmonary infection. The liver innate immune responses are primarily responsible for clearance of blood-borne infections before the detrimental effects of overwhelming bacteremia and/or septic shock can occur. The liver lymphoid system, in contrast to the systemic system, is dominated by "innate immune" cells, including gamma-delta-T cells and NK-T cells, which utilize antigen recognition receptors of limited diversity.
Project 1: Gamma delta-T cells play a critical role in the host acute inflammatory response during gram-negative bacteremia via recognition of heat shock protein 60 expression in the liver following infection.
Studies indicate increased mortality and uncontrolled bacterial growth in gamma delta-T cell deficient mice following intravenous bacterial inoculation, suggesting impaired liver anti-bacterial host defenses. Rapid expression of heat shock protein 60 (hsp60), a known ligand for gamma delta-T cells, was observed following intravenous infection. Furthermore, in vitro co-culture experiments clearly indicate the ability of hsp60 protein to stimulate production of IFN-gamma and TNF-alpha from naïve liver lymphocytes. I postulate that hepatic filtration of blood-borne K. pneumoniae results in Kupffer cell interaction with bacteria and subsequent hsp60 upregulation, setting the stage for gamma delta-T cell activation at the initial site of infection.
Project 2: Natural Killer-T (NK-T) cells play a critical role in the host acute inflammatory response during gram-negative bacteremia via CD1-mediated bacterial glycolipid presentation.
NK-T cells represent a minor but unique subset of T cells expressing cell surface markers commonly associated with Natural Killer (NK) cells. The majority of NK-T cells are positively selected by the MHC class I-like molecule CD1 and are activated by CD1 ligation. CD1 molecules can present exogenous (bacterial) glycolipids to CD1-restricted NK-T cells. NK-T cell deficient mice displayed increased mortality following infection that correlated with uncontrolled bacterial growth. NK-T cell subsets display differential activational states at early versus late timepoints following infection, suggesting unique roles for these NK-T cell subsets during the early and late phases of infection.
Bhan U, Lukacs NW, Osterholzer JJ, Newstead MW, Zeng X , Moore TA, McMillan TR, Krieg AM, Akira S, Standiford TJ. TLR9 is required for protective innate immunity in Gram-negative bacterial pneumonia: role of dendritic cells. J Immunol . 2007 Sep 15;179(6):3937-46.
Lindell DM, Moore TA , McDonald RA, Toews GB, Huffnagle GB. Distinct compartmentalization of CD4+ T-cell effector function versus proliferative capacity during pulmonary cryptococcosis. Am J Pathol . 2006 Mar;168(3):847-55.
Horowitz JC, Cui Z, Moore TA, Meier TR, Reddy RC, Toews GB, Standiford TJ, Thannickal VJ. Constitutive activation of prosurvival signaling in alveolar mesenchymal cells isolated from patients with nonresolving acute respiratory distress syndrome. Am J Physiol Lung Cell Mol Physiol . 2006 ar;290(3):L415-25
Moore BB , Kolodsick JE , Thannickal VJ , Cooke K , Moore TA , Hogaboam C , Wilke CA , Toews GB . Interferon-inducible protein 10, but not monokine induced by gamma interferon, promotes protective type 1 immunity in murine Klebsiella pneumoniae pneumonia. Infect Immun . 2005 Dec;73(12):8226-36.
Moore TA, Lau HY, Cogen AL, Standiford TJ. Defective innate antibacterial host responses during murine Klebsiella pneumoniae bacteremia: tumor necrosis factor (TNF) receptor 1 deficiency versus therapy with anti-TNF-alpha. Clin Infect Dis . 2005 Aug 1;41 Suppl 3:S213-7.
Lindell DM, Moore TA , McDonald RA, Toews GB, Huffnagle GB. Generation of antifungal effector CD8+ T cells in the absence of CD4+ T cells during Cryptococcus neoformans infection. J Immunol. 2005 Jun 15;174(12):7920-8.
Moore BB, Kolodsick JE, Thannickal VJ, Cooke K, Moore TA , Hogaboam C, Wilke CA, Toews GB. CCR2-mediated recruitment of fibrocytes to the alveolar space after fibrotic injury. Am J Pathol . 2005 Mar;166(3):675-84.
Zeng X, Moore TA , Newstead MW, Deng JC, Kunkel SL, Luster AD, Standiford TJ. IP-10 mediates selective mononuclear cell accumulation and activation in response to intrapulmonary transgenic expression and during adenovirus-induced pulmonary inflammation. J Interferon Cytokine Res . 2005 Feb;25(2):103-12.
Deng JC, Moore TA , Newstead MW, Zeng X, Krieg AM, Standiford TJ. CpG oligodeoxynucleotides stimulate protective innate immunity against pulmonary Klebsiella infection. J Immunol . 2004 Oct 15;173(8):5148-55.
Deng JC, Zeng X, Newstead M, Moore TA , Tsai WC, Thannickal VJ, Standiford TJ. STAT4 is a critical mediator of early innate immune responses against pulmonary Klebsiella infection. J Immunol . 2004 Sep 15;173(6):4075-83.
Moore TA, Lau HY, Cogen AL, Monteleon CL, Standiford TJ. Anti-tumor necrosis factor-alpha therapy during murine Klebsiella pneumoniae bacteremia: increased mortality in the absence of liver injury. Shock . 2003 Oct;20(4):309-15.