Following infection with the gram positive bacterium Listeria monocytogenes (Lm), innate immune responses are rapidly triggered and are essential for host survival. Despite the importance of the innate immune system in fighting an Lm infection, little is known about the role of complement. There is now strong evidence that the complement anaphylatoxins, C3a and C5a, are potent modulators of T-cell effector functions in allergic diseases, including asthma. However, the biological relevance of C3a/C5a modulation of T-cell responses to bacterial pathogens remains largely unknown. In addition, there is very little understanding of how the anaphylatoxins impact CD8+ T-cell responses that are essential for host clearance of intracellular bacteria such as Lm. The long term goal of this research program is to delineate important biological pathways mediated by the complement anaphylatoxins in innate and adaptive immune responses so that appropriate therapeutic strategies can be developed that will abrogate the deleterious hyper-inflammatory effects of C3a and C5a without impairing the host immune response to infectious disease. These studies are driven by the central hypothesis that the anaphylatoxins on binding their specific receptors mediate numerous biological functions that are critical for the initiation, perpetuation, and regulation of pathways required for robust innate as well as adaptive immune responses. It is also hypothesized that the deleterious and potentially lethal effects that can result from the acute or chronic release of these extremely potent phlogistic molecules are regulated both systemically and locally by specific carboxypeptidases (CPN &TAFI) and by the putative "decoy" receptor C5L2R. The central hypothesis will be tested in the current application by two major specific aims that will employ novel combinations of C3aR, C5aR, C5L2R, and carboxypeptidase KO mice in a model of systemic Lm infection.
Aim 1 will delineate cellular and molecular mechanisms by which the C3a and C5a anaphylatoxins and their specific receptors (C3aR and C5aR, respectively) modulate innate and adaptive immunity in response to Lm infection.
Aim 2 will delineate how carboxypeptidase (CPN &TAFI) regulation and C5L2R binding impact anaphylatoxin modulation of innate and adaptive immunity in response to Lm infection. The proposed research provides a unique and powerful in vivo system to delineate comprehensively numerous innate and T-cell immunomodulatory pathways that are mediated by the complement anaphylatoxins. Moreover, the data from the proposed studies will provide novel and important data regarding complement's role in the host response to Lm, an important NIAID category B priority intracellular pathogen.

Public Health Relevance

Listeria monocytogenes is a Gram-positive intracellular bacterium that is acquired through tainted food and can lead to systemic and central nervous system infections, especially in the elderly, pregnant, or immune compromised individuals. It also has potential use as a food-borne pathogen by terrorists and is therefore categorized by NIAID as a Biodefense category B pathogen. The proposed research is relevant to public health because it fills an important gap in knowledge of how the innate (complement) immune system impacts the host's response to Listeria monocytogenes infection. It also provides critical knowledge for the development of therapeutics that can block inflammation without impairing the immune response to opportunistic pathogens.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01AI025011-18A1
Application #
8761525
Study Section
Innate Immunity and Inflammation (III)
Program Officer
Nasseri, M Faraz
Project Start
Project End
Budget Start
Budget End
Support Year
18
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
None
Type
Overall Medical
DUNS #
City
Houston
State
TX
Country
United States
Zip Code
77225
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
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
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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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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Hollmann, Travis J; Mueller-Ortiz, Stacey L; Braun, Michael C et al. (2008) Disruption of the C5a receptor gene increases resistance to acute Gram-negative bacteremia and endotoxic shock: opposing roles of C3a and C5a. Mol Immunol 45:1907-15
Wang, Dachun; Haviland, David L; Burns, Alan R et al. (2007) A pure population of lung alveolar epithelial type II cells derived from human embryonic stem cells. Proc Natl Acad Sci U S A 104:4449-54
Borders, C W; Courtney, A; Ronen, K et al. (2005) Requisite role for complement C5 and the C5a receptor in granulomatous response to mycobacterial glycolipid trehalose 6,6'-dimycolate. Scand J Immunol 62:123-30

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