The fifth component of complement (C5) is a glycoprotein that, after proteolytic activation into C5a and C5b polypeptides, mediates important inflammatory and cytolytic processes. The small C5 activation fragment, C5a, is a very potent phlogistic molecule which, upon binding to the C5a-Receptor (C5a-R), mediates contraction of smooth muscle, vasodilation, and chemotaxis and secretion of granular enzymes from many inflammatory cells; moreover, C5a plays a role in augmenting humoral and cell mediated immune responses. The large C5 activation fragment, C5b, initiates the assembly of the C5b-9 membranolytic attack complex that is directly responsible for complement-mediated target cell cytolysis of bacterial and viral pathogens. Sera from homozygous C5-deficient (C5D) individuals lack bactericidal activity and have a severely impaired ability to induce chemotaxis; as a result, C5D individuals have a propensity for severe recurrent bacterial infections particularly to Neisserial species, including meningitis and extragenital gonorrhea. In certain pathological conditions, damage of healthy tissue occurs after C5 activation as a result of C5b-9 mediated lysis of non-target (bystander) cells and proteolytic destruction by enzymes released from neutrophils recruited and activated by C5a. For example, tissue damage mediated by C5 activation polypeptides is strongly implicated in the pathogenesis of pulmonary, and myocardial diseases, atherosclerotic lesions, and certain central nervous system disorders, including Alzheimer disease. Furthermore, C5 activation polypeptides play a critical role in the hyperactive rejection of discordant xenografts. The broad long-term goal of this study is to understand and thereby selectively modulate the inflammatory and cytolytic effects resulting from C5 activation. Molecular knowledge of the structural-functional aspects of complement C5 activation and the receptor-cellular interactions that are mediated by the C5a cleavage polypeptide are of paramount importance in achieving this goal. This is especially true as the discovery of C5a-R expression by non-myeloid tissue cells have indicated that the biological functions mediated by C5a are even more pleiotropic than originally assumed. Our immediate objectives are to: 1) determine the molecular genetic and structural basis of human C5 deficiency by DNA, RNA, and protein studies of seven different C5- deficient kindred, 2) determine functionally important binding domains in C5 by extensive mapping studies with monoclonal antibodies and synthetic peptides, 3) determine tissue cells expressing the C5a- receptor by in situ hybridization and immunohistochemistry studies, and 4) determine the effects that selected cytokines have on C5a-R expression using appropriate tissue derived cells, and 5) initiate investigations into the biological functions mediated by the C5a-R on tissue cells by examining expression of acute phase proteins, adhesion molecules involved in neutrophil emigration, and HLA class I and class II molecules involved in antigen presentation.

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National Institute of Allergy and Infectious Diseases (NIAID)
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Allergy and Immunology Study Section (ALY)
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Jones, Melinda
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University of Texas Health Science Center Houston
Schools of Medicine
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Mueller-Ortiz, Stacey L; Calame, Daniel G; Shenoi, Nancy et al. (2017) The Complement Anaphylatoxins C5a and C3a Suppress IFN-? Production in Response to Listeria monocytogenes by Inhibition of the Cyclic Dinucleotide-Activated Cytosolic Surveillance Pathway. J Immunol 198:3237-3244
Calame, Daniel G; Mueller-Ortiz, Stacey L; Wetsel, Rick A (2016) Innate and adaptive immunologic functions of complement in the host response to Listeria monocytogenes infection. Immunobiology 221:1407-1417
Hu, Xianzhen; Wetsel, Rick A; Ramos, Theresa N et al. (2014) Carboxypeptidase N-deficient mice present with polymorphic disease phenotypes on induction of experimental autoimmune encephalomyelitis. Immunobiology 219:104-8
Calame, Daniel G; Mueller-Ortiz, Stacey L; Morales, John E et al. (2014) The C5a anaphylatoxin receptor (C5aR1) protects against Listeria monocytogenes infection by inhibiting type 1 IFN expression. J Immunol 193:5099-107
Mueller-Ortiz, Stacey L; Morales, John E; Wetsel, Rick A (2014) The receptor for the complement C3a anaphylatoxin (C3aR) provides host protection against Listeria monocytogenes-induced apoptosis. J Immunol 193:1278-89
Dutow, Pavel; Fehlhaber, Beate; Bode, Jenny et al. (2014) The complement C3a receptor is critical in defense against Chlamydia psittaci in mouse lung infection and required for antibody and optimal T cell response. J Infect Dis 209:1269-78
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Lim, Hoyong; Kim, Young Uk; Drouin, Scott M et al. (2012) Negative regulation of pulmonary Th17 responses by C3a anaphylatoxin during allergic inflammation in mice. PLoS One 7:e52666
Wang, Dachun; Morales, John E; Calame, Daniel G et al. (2010) Transplantation of human embryonic stem cell-derived alveolar epithelial type II cells abrogates acute lung injury in mice. Mol Ther 18:625-34
Mueller-Ortiz, Stacey L; Wang, Dachun; Morales, John E et al. (2009) Targeted disruption of the gene encoding the murine small subunit of carboxypeptidase N (CPN1) causes susceptibility to C5a anaphylatoxin-mediated shock. J Immunol 182:6533-9

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