Xin-Xing Gu, M.D.

Acting Chief Vaccine Research Section

Research Statement

Our ultimate goal is to fully understand bacterial pathogenesis and host immune responses in order to develop highly effective vaccines against otitis media. Successful conquering bacteria associated otitis media - the most common disease in childhood requires systemic investigation on both pathogens and hosts including (1) revealing functional and structural features of bacterial components and (2) elucidating regulation of host immune responses. Our major focuses are on (1) identification of bacterial antigens and/or virulence factors that may be used as vaccine candidates, (2) characterization of these bacterial antigens and virulence factors in vitro, (3) evaluation of candidate vaccines in vivo and identification of their underlying protective mechanisms, and (4) initiation of clinical trials.

Nontypeable Haemophilus influenzae (NTHi) and Moraxella catarrhalis (M. cat.) are the major causes of otitis media in children. Several lines of evidence have shown that lipooligosaccharide (LOS), a dominant surface component on bacterial outer membrane, is not only a virulence factor but also a potential protective antigen which is expected to confer immunity to both pathogens. LOS consists of two major moieties: a lipid A and a core oligosaccharide (OS). The core OS can be dissected into a linker and three OS chains in M. cat. To study functional and structural features of the LOS molecule, a series of mutant strains have been created by molecular and genetic approaches. The results suggest that the complete OS chain moiety of the LOS is important for serum resistance and adherence to host cells, whereas the linker moiety is critical for maintenance of the outer membrane integrity and stability to preserve normal bacterial growth. Both the lipid A and linker moieties contribute to the LOS toxicity. In addition, a cellular cross-talk mechanism by which LOS induces excessive middle ear inflammation has been elucidated. All these findings have significantly moved forward our understanding on the pathogenesis of bacteria associated otitis media.

Because LOS has great potential to provide protection against both NTHi and M.cat, our group has been trying to develop detoxified LOS-based conjugate vaccines. Such vaccines have been demonstrated to elicit long-lasting antibodies with bactericidal activities against NTHi and M.cat., and confer protection against bacterial challenges in animal models. Furthermore, a phase I clinical trial to evaluate a NTHi conjugate vaccine in human volunteers has been successfully concluded and the result suggests that this vaccine is safe for human use. Our ongoing projects are to identify protective epitopes of LOS molecule and fully elucidate the underlying protective mechanisms of the LOS-based conjugate vaccines. Currently, new vaccine candidates such as different types of LOS based conjugate vaccines, outer membrane protein based conjugate vaccines, peptide/DNA vaccines, and genetically engineered vaccines are being developed and evaluated.

Lab Personnel

Hassan, Md Ferdaus, Ph.D., 301-402-2581(Send e-mail)
Ren, Dabin, Ph.D., 301-402-2581(Send e-mail)
Zhang, Wenhong, Ph.D., 301-402-2581 (Send e-mail)

Selected Publications

• Hirano T, X Jiao, Z Chen, C Van Waes, XX Gu. Kinetics of mouse antibody and lymphocyte responses during intranasal vaccination with a lipooligosaccharide- based conjugate vaccine. Immunol Let, 107:131-139, 2006.
• Yu, S., XX. Gu. Biological and Immunological Characteristics of Lipooligosaccharide-Based Conjugate Vaccines for Serotype C Moraxella catarrhalis. Infect Immun. 75:2974-80, 2007.
• Peng D., WG Hu, B Choudhury, A Muszynski, RW Carlson, XX Gu. 2007. Role of different moieties from the lipooligosaccharide molecule in biological activities of the Moraxella catarrhalis outer membrane. FEBS J. 274:5350-59.
• Xie H and XX GU. 2008. Moraxella catarrhalis lipooligosaccharide selectively up-regulates ICAM-1 expression on human monocytes and stimulates adjacent naïve monocytes to produce TNF-alpha through cellular cross talk. Cell Microbiol. 2008. 10:1453-67.
• Yu, S, H Xie, A Datta, N Naidu, XX Gu. Galactose Residues on the Lipooligosaccharide (LOS) of Moraxella catarrhalis 26404 (Serotype C) Form the Epitope Recognized by the Bactericidal Antiserum from Conjugate Vaccination. Infect Immun. 2008 Jun 16.
• Peng D, Hong W, Choudhury BP, Carlson RW, Gu XX. Moraxella catarrhalis bacterium without endotoxin, a potential vaccine candidate. Infecton and Immunity 73(11):7569–77, 2005.
• Wu T, Chen J, Murphy TF, Green BA, Gu XX. Investigation of non-typeable Haemophilus influenzae outer membrane protein P6 as a new carrier for lipooligosaccharide conjugate vaccines. Vaccine 23(44):5177–85, 2005.
• Peng D, Choudhury BP, Petralia RS, Carlson RW, Gu XX. Roles of 3-deoxy-D-manno-2-octulosonic acid transferase from Moraxella catarrhalis in lipooligosaccharide biosynthesis and virulence. Infection and Immunity 73(7):4222–30, 2005.
• Yu S, Gu XX. Synthesis and characterization of lipooligosaccharide-based conjugate vaccines for serotype B Moraxella catarrhalis. Infection and Immunity 73(5):2790–6, 2005.
• Chen R, Lim JH, Jono H, Gu XX, Kim YS, Basbaum CB, Murphy TF, Li JD. Nontypeable Haemophilus influenzae lipoprotein P6 induces MUC5AC mucin transcription via TLR2-TAK1-dependent p38 MAPK-AP1 and IKKbeta-IkappaBalpha-NF-kappaB signaling pathways. Biochemical and Biophysical Research Communications 324(3):1087–94, 2004.
• Hu WG, Berry J, Chen J, Gu XX. Exploration of Moraxella catarrhalis outer membrane proteins, CD and UspA, as new carriers for lipooligosaccharide-based conjugates. FEMS Immunology and Medical Microbiology 41(2):109–15, 2004.
• Gu XX, Rudy SF, Chu C, McCullagh L, Kim HN, Chen J, Li J, Robbins JB, Van Waes C, Battey JF. Phase I study of a lipooligosaccharide-based conjugate vaccine against nontypeable Haemophilus influenzae. Vaccine 21(17–18):2107–2114, 2003.
• Hou Y, Gu XX . Development of peptide mimotopes of lipooligosaccharide from nontypeable Haemophilus influenzae as vaccine candidates. Journal of Immunology 170(8):4373–4379, 2003.
• Hirano T, Hou Y, Jiao X, Gu XX. Intranasal immunization with a lipooligosaccharide-based conjugate vaccine from nontypeable Haemophilus influenzae enhances bacterial clearance in mouse nasopharynx. FEMS Immunology and Medical Microbiology 35(1):1–10, 2003.
• Jiao X, Hirano T, Hou Y, Gu XX. Specific immune responses and enhancement of murine pulmonary clearance of Moraxella catarrhalis by intranasal immunization with a detoxified lipooligosaccharide conjugate vaccine. Infection and Immunity 70(11):5982–5989, 2002.
• Hou Y, Hu WG, Hirano T, Gu XX. A new intra-NALT route elicits mucosal and systemic immunity against Moraxella catarrhalis in a mouse challenge model. Vaccine 20(17–18):2375–2381, 2002.
• Hu WG, Chen J, McMichael JC, Gu XX. Functional characteristics of a protective monoclonal antibody against serotype A and C lipooligosaccharides from Moraxella catarrhalis. Infection and Immunity 69:1358–1363, 2001.
• Shuto T, Xu H, Wang B, Han J, Kai H, Gu XX, Murphy TF, Lim DJ, Li JD. Activation of NF-kB by nontypeable Hemophilus influenzae is mediated by toll-like receptor 2-TAK1-dependent NIK-IKKa/ß-IkBa and MKK3/6-p38 MAP kinase signaling pathways in epithelial cells. Proceedings of the National Academy of Sciences of the USA 98:8774–8779, 2001.
• Hu WG, Chen J, Battey JF, Gu XX. Enhancement of bacterial clearance from murine lungs by immunization of detoxified lipooligosaccharide from Moraxella catarrhalis conjugated to proteins. Infection and Immunity 68:4980–4985, 2000.
• Sun J, Chen J, Cheng Z, Robbins JB, Battey J, Gu XX. Biological activities of antibodies elicited by lipooligosaccharide based-conjugate vaccines of nontypeable Haemophilus influenzae in an otitis media model. Vaccine 18:1264–1272, 2000.
• Hu WG, Chen J, Collins FM, Gu XX. An aerosol challenge mouse model for Moraxella catarrhalis. Vaccine 18:799–804, 1999.
• Rahman MM, Gu XX, Tsai CM, Kolli VS, Carlson RW. The structural heterogeneity of the lipooligosaccharide (LOS) expressed by pathogenic non-typeable Haemophilus influenzae strain 9274. Glycobiology 9:1371–1380, 1999.
• Ueyama T, Gu XX, Tsai CM, Karpas AB, Lim DJ. Identification of common lipooligosaccharide types in isolates from patients with otitis media by monoclonal antibodies against nontypeable Haemophilus influenzae 9274. Clinical and Diagnostic Laboratory Immunology 6:96–100, 1999.
• Wu TH, Gu XX. Outer membrane proteins as a carrier for detoxified lipooligosaccharide conjugate vaccines to nontypeable Haemophilus influenzae. Infection and Immunity 67:5508–5513, 1999.
• Gu XX, Chen J, Barenkamp SJ, Robbins JB, Tsai CM, Lim DJ, Battey J. Synthesis and characterization of lipooligosaccharide-based conjugates as vaccine candidates for Moraxella (Branhamella) catarrhalis. Infection and Immunity 66:1891–1897, 1998.

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