The major objectives of this Sexually Transmitted Infections Co-operative Research Center (STI-CRC) entitled "Innate and Adaptive Immunity in Experimental and Human Gonococcal Infection in Women" are directed to providing a diverse and comprehensive understanding of the innate and adaptive immune mechanisms associated with gonococcal infection. We will emphasize basic host responses and innate immune mechanisms in infection with Neisseria gonorrhoeae with the immediate aim of improving understanding of gonococcal immunology and pathogenesis and a longer term goal to gain insights that will direct efforts to facilitate the prevention of gonococcal infections in humans, particularly women. We will use a promising animal model to examine these mechanisms and separately employ a generalized translational approach that will emphasize the links between immunobiology and clinical epidemiology to assess the potential of vaccine candidates in humans, which will then be investigated in the context of the humanized mouse model of infection. Five research projects and four service cores are proposed. In the first project (Douglas T Golenbock, MD, PL), we will address a basic and fundamental question in lipopolysaccharide (LPS, called lipooligosaccharide [LOS] in the case of N. gonorrhoeae) biology to understand the binding of LOS derived lipid A with its direct ligand that serves as an intermediary structure to activate and permit signaling of toll-like receptor (TLR)4. In Project 2 (Robin Ingalls, MD, PL), we will determine if naturally occurring mutations in gonococcal LOS or polymorphisms in the TLR4 adaptor Mai, account for differences in the host inflammatory response to infection. In Project 3 (Caroline A Genco, PhD, PL), we will examine the role that TLRs and cytosolic nucleotide oligomerization domain (NOD) protein receptors (NOD-like receptors [NLRs]) play as receptors for Neisseria ligands. In Project 4 (Sanjay Ram, MD, PL), we will examine novel roles for the alternative complement pathway (ACP) enhancing molecule. Properdin, in blocking TLR4 mediated signaling by LOS and separately, in amplifying potentially protective vaccine induced antibody function. In Project 5 (Peter A. Rice, MD), we will examine peptide mimics of gonococcal LOS as potential vaccine candidates in a humanized mouse model of gonococcal infection while also determining if natural antibodies against the candidates protect exposed women from gonococcal infection. The Center will have five Cores (Clinical, Laboratory, Animal Statistical, and administrative) providing support to 4 or 5 of the 5 Projects.
Gonorrhea is a common sexually transmitted infection worldwide. Women usually have few or no symptoms associated with infection, which often leads to delays in treatment and the development of complications such as pelvic inflammatory disease and infertility and increased likelihood of acquiring HIV infection. A better understanding of natural immunity to this pathogen will lead to treatments that can lessen the infectious complications and support the development of protective vaccine strategies.
|Mavrogiorgos, Nikolaos; Mekasha, Samrawit; Yang, Yibin et al. (2014) Activation of NOD receptors by Neisseria gonorrhoeae modulates the innate immune response. Innate Immun 20:377-89|
|Del Tordello, Elena; Vacca, Irene; Ram, Sanjay et al. (2014) Neisseria meningitidis NalP cleaves human complement C3, facilitating degradation of C3b and survival in human serum. Proc Natl Acad Sci U S A 111:427-32|
|Agarwal, Sarika; Vasudhev, Shreekant; DeOliveira, Rosane B et al. (2014) Inhibition of the classical pathway of complement by meningococcal capsular polysaccharides. J Immunol 193:1855-63|
|Lewis, Lisa A; Ram, Sanjay (2014) Meningococcal disease and the complement system. Virulence 5:98-126|
|Lewis, Lisa A; Vu, David M; Granoff, Dan M et al. (2014) Inhibition of the alternative pathway of nonhuman infant complement by porin B2 contributes to virulence of Neisseria meningitidis in the infant rat model. Infect Immun 82:2574-84|
|Rice, Peter A (2014) Editorial commentary: The shifting sands of gonococcal antimicrobial resistance. Clin Infect Dis 59:1092-4|
|Lewis, Lisa A; Vu, David M; Vasudhev, Shreekant et al. (2013) Factor H-dependent alternative pathway inhibition mediated by porin B contributes to virulence of Neisseria meningitidis. MBio 4:e00339-13|
|Daou, Nadine; Yu, Chunxiao; McClure, Ryan et al. (2013) Neisseria prophage repressor implicated in gonococcal pathogenesis. Infect Immun 81:3652-61|
|Granoff, Dan M; Ram, Sanjay; Beernink, Peter T (2013) Does binding of complement factor H to the meningococcal vaccine antigen, factor H binding protein, decrease protective serum antibody responses? Clin Vaccine Immunol 20:1099-107|
|Brookes, Charlotte; Kuisma, Eeva; Alexander, Frances et al. (2013) Development of a large scale human complement source for use in bacterial immunoassays. J Immunol Methods 391:39-49|
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