 Ph.D.
University of California San Francisco |
Jian-Dong
Li Professor
of Microbiology & Immunology
Primary Appointment: GEBS
Cluster Affiliations: |
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| Contact Information: | ||
| University
of Rochester School of Medicine and Dentistry 601 Elmwood Ave, Box 672 Rochester, New York 14642 | Medical Center 3-9611 Phone: (585) 275-7195 Fax: (585) 473-9573 E-Mail: Jian-Dong_Li@urmc.rochester.edu |
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- Research Focus
- Molecular and Cellular Basis of Host-Bacterial Interactions
- Research Overview
- We primarily focus on understanding the molecular and cellular mechanisms by which the bacterial pathogens interact with host cells to cause diseases.
- Bacterial pathogens have evolved many sophisticated ways to subvert normal host cellular responses during infections. Two such subversive pathogens are the Gram-negative nontypeable Haemophilus influenzae (NTHi) and the Gram-positive Streptococcus pneumoniae (S. pneumoniae) that exemplify important, as yet underexplored, human respiratory pathogens in both children and adults. Despite the need for prophylactic measures, the molecular and cellular mechanisms underlying the pathogenesis of NTHi and S. pneumoniae infections remain largely unknown.
- Our long-term objectives are to fully investigate the molecular and cellular mechanisms including the signaling mechanism underlying NTHi and S. pneumoniae infections using multidisciplinary approaches including molecular genetics, cell biology, biochemistry, molecular biology, immunology, functional genomics and proteomics as well as knockout mice.
- Our
short-term goals are to elucidate the signaling
mechanisms involved in
NTHi and S. pneumoniae infections. Because NTHi and S.
pneumoniae infections, like most other respiratory bacterial
infections, are characterized by inflammation and mucus overproduction,
we particularly focus on investigating the signaling pathways including
the bacterial factors, host epithelial surface receptors, intracellular
signaling pathways and transcription factors involved in NTHi- and S.
pneumoniae-induced inflammatory and immune responses as well as mucin
up-regulation, a primary innate defensive response for mammalian
airways. Four major research areas we are
currently focusing on are as follows:
-
- Regulation of Inflammation in Bacterial Infections: Inflammation is a hallmark of respiratory bacterial infections. The molecular mechanisms underlying bacteria-induced inflammation remain largely undefined. Given that, in in vivo situations, multiple factors are existing simultaneously, we hypothesize that NF-κB, the key regulator of inflammation, is synergistically regulated by multiple pathogenic inducers via activation of multiple signaling pathways in the pathogenesis of respiratory bacterial infections. Indeed, we recently showed that NTHi and S. pneumoniae or NTHi and TNF-α synergistically activate NF-κB and cytokine production via multiple signaling pathways involving IκBα, p38 MAPK and MEKK1. We currently focus on identifying the bacterial factors and their host receptors as well as the molecular basis for the cross-talk between NF-κB and p38 MAP kinase pathways underlying the synergistic regulation of inflammation in respiratory bacterial infections. In addition, the signaling mechanisms underlying the synergistic activation of inflammation will also be investigated in vivo using knock-out mice.
- Regulation of Mucin in Bacterial Infections: Mucus overproduction, a hallmark of airway infections, is a primary innate defensive response for mammalian airways. The molecular mechanisms underlying mucin overproduction are largely unknown. Mucins protect and lubricate the epithelial surface and trap particles, including bacteria and viruses, for mucociliary clearance. In infections, excessive production of mucin occurs, overwhelming the normal mucociliary clearance mechanisms. As mucus levels increase, they contribute significantly to airway obstruction in airway infections and conductive hearing loss in middle ear infections. We currently focus on the molecular characterization of the novel bacterial virulence factors, the host receptor and its downstream positive and negative signaling pathways as well as the transcription factors involved in mucin transcription. Moreover we also explore the functional mimicry of host activities by NTHi because preliminary evidences have suggested that NTHi may manipulate the host signaling pathways possibly using some molecules similarly to host growth factors.
- Regulation of Toll-like Receptor by Bacteria in Airway Infections: The recognition of invading microbes followed by the induction of effective innate immune response is crucial for host survival. Human surface epithelial cells are situated at host-environment boundaries, and thus act as the first line of host defense against invading microbes. They recognize the microbial ligands via Toll-like receptors (TLRs) expressed on the surface of epithelial cells. As the immune system needs to constantly strive a balance between activation and inhibition to avoid detrimental and inappropriate inflammatory responses, TLR signaling must be tightly regulated. We currently focus on investigating how TLR signaling is negatively regulated. We are particularly interested in understanding the inducible negative regulation during bacterial infections.
- Regulation of Host Survival in S. pneumoniae Infections: Streptococcus pneumoniae (S. pneumoniae) is a major cause of morbidity and mortality worldwide. It causes invasive diseases such as pneumonia. Pneumolysin, a pore-forming hemolysin, is a key virulence factor in S. pneumoniae infections. It plays an important role in inducing acute lung hemorrhage and lethality. Despite the importance of pneumolysin in pneumococcal diseases, little is known about the molecular mechanisms by which pneumolysin-induced hemorrhage and lethality is regulated. The Long-term Objective is to fully understand the molecular mechanisms by which S. pneumoniae pneumolysin-induced hemorrhage and lethality is regulated in S. pneumoniae infections so that potential therapeutic targets can be identified for treating these infections.
- Recent Publications
- Komatsu K, Jono H, Hyanglim J, Imasato A, Xu H, Kai H, Yan C, Li JD Glucocorticoids inhibit nontypeable Haemophilus influenzae-induced MUC5AC mucin expression via MAPK phosphatase-1-dependent inhibition of p38 MAPK. Biochem Biophys Res Commun. 2008 Oct 25;
- Ha UH, Lim JH, Kim HJ, Wu W, Jin S, Xu H, Li JD MKP1 regulates the induction of MUC5AC Mucin by S. pneumoniae Pneumolysin by inhibiting the PAK4-JNK signaling pathway. J Biol Chem. 2008 Sep 9;
- Taura M, Eguma A, Suico MA, Shuto T, Koga T, Komatsu K, Komune T, Sato T, Saya H, Li JD, Kai H p53 regulates TLR3 expression and function in human epithelial cell lines. Mol Cell Biol. 2008 Sep 8;
- Yang SR, Yao H, Rajendrasozhan S, Chung S, Edirisinghe I, Valvo S, Fromm G, McCabe Jr MJ, Sime PJ, Phipps RP, Li JD, Bulger M, Rahman I RelB is differentially regulated by I{kappa}B-Kinase{alpha} (IKK{alpha}) in B Cells and Mouse Lung by Cigarette Smoke. Am J Respir Cell Mol Biol. 2008 Aug 7;
- Lim JH, Ha UH, Woo CH, Xu H, Li JD CYLD is a crucial negative regulator of innate immune response in E. coli pneumonia. Cell Microbiol. 2008 Jul 15;
- Woo CH, Shishido T, McClain C, Lim JH, Li JD, Yang J, Yan C, Abe J Extracellular signal-regulated kinase 5 SUMOylation antagonizes shear stress-induced antiinflammatory response and endothelial nitric oxide synthase expression in endothelial cells. Circ Res. 2008 Mar 14;102(5):538-45
- Koga T, Lim JH, Jono H, Ha UH, Xu H, Ishinaga H, Morino S, Xu X, Yan C, Kai H, Li JD Tumor suppressor cylindromatosis (CYLD) acts as a negative regulator for Streptococcus pneumoniae-induced NFAT signaling. J Biol Chem. 2008 Mar 10
- Yang SR, Valvo S, Yao H, Kode A, Rajendrasozhan S, Edrisinghe I, Caito S, Adenuga D, Henry R, Fromm G, Maggirwar S, Li JD, Bulger MD, Rahman I "IKK{alpha} Causes Chromatin Modification on Pro-inflammatory Genes by Cigarette Smoke in Mouse Lung." Am J Respir Cell Mol Biol. 2008 Jan 31;
- Woo CH, Shishido T, McClain C, Lim JH, Li JD, Yang J, Yan C, Abe JI " Extracellular Signal-Regulated Kinase 5 SUMOylation Antagonizes Shear Stress-Induced Antiinflammatory Response and Endothelial Nitric Oxide Synthase Expression in Endothelial Cells.<" Circ Res. 2008 Jan 24;
- Lim JH, Jono H, Koga T, Woo CH, Ishinaga H, Bourne P, Xu H, Ha UH, Xu H, Li JD "Tumor Suppressor CYLD Acts as a Negative Regulator for Non-Typeable Haemophilus influenza-Induced Inflammation in the Middle Ear and Lung of Mice." PLoS ONE. 2007;2(10):e1032
- Lim JH, Stirling B, Derry J, Koga T, Jono H, Woo CH, Xu H, Bourne P, Ha UH, Ishinaga H, Xu H, Andalibi A, Feng XH, Zhu H, Huang Y, Zhang W, Weng X, Yan C, Yin Z, Briles DE, Davis RJ, Flavell RA, Li JD "Tumor Suppressor CYLD Regulates Acute Lung Injury in Lethal Streptococcus pneumoniae Infections." Immunity. 2007 Aug;27(2):349-60
- Sakai A, Koga T, Lim JH, Jono H, Harada K, Szymanski E, Xu H, Kai H, Li JD "The bacterium, nontypeable Haemophilus influenzae, enhances host antiviral response by inducing Toll-like receptor 7 expression." FEBS J. 2007 Jul 3;
- Huang Y, Mikami F, Jono H, Zhang W, Weng X, Koga T, Xu H, Yan C, Kai H, Li JD "Opposing roles of PAK2 and PAK4 in synergistic induction of MUC5AC mucin by bacterium NTHi and EGF." Biochem Biophys Res Commun. 2007 Jun 5;
- Ishinaga, H., Jono, H., Lim, J.H., Kweon, S.M., Xu, H., Ha, U., Xu. H., Feng, X.H., Chen, L.F. & Li, J.D. TGF-β induces p65 acetylation to enhance bacteria-induced NF-κB activation. EMBO J. 2007 Feb 1;
- Ha, U.H., Lim, J.H., Jono, H., Srivastava, A., Malley, R., Pagès, G., Jacques Pouysségur, P. & Li, J.D. A Novel Role for IKKα and IKKβ in ERK-dependent Innate Mucosal Defense Response against Streptococcus pneumoniae. J Immunol. 2007 Feb 1;178(3):1736-47
- Kweon SM, Wang B, Rixter D, Lim JH, Koga T, Ishinaga H, Chen LF, Jono H, Xu H, Li JD. "Synergistic activation of NF-kappaB by nontypeable H. influenzae and S. pneumoniae is mediated by CK2, IKKbeta-IkappaBalpha, and p38 MAPK."Biochem Biophys Res Commun. 2006 Oct 17;
- Mikami F, Lim JH, Ishinaga H, Ha UH, Gu H, Koga T, Jono H, Kai H, Li JD. "TGF-beta -Smad3/4 signaling pathway acts as a positive regulator for TLR2 induction by bacteria via a dual-mechanism involving functional cooperation with NF-kbeta and MAPK phosphatase 1-dependent negative cross-talk with p38 MAPK." J Biol Chem. 2006 Jun 5;
- Yoshida, H, Jono, H, Kai, H, Li JD. "The tumor suppressor CYLD acts as a negative regulator for toll-like receptor 2 signaling via negative cross-talk with TRAF6 and TRAF7." J Biol Chem. 280:41111-41121, 2005.
- Mikami, F, Gu, H, Jono, H, Andalibi, A, Kai, H, Li JD. "Epidermal growth factor receptor acts as a negative regulator for bacterium nontypeable Haemophilus influenzae -induced Toll-like receptor 2 expression via an Src-dependent p38 mitogen-activated protein kinase signaling pathway." J Biol Chem . 280:36185-94, 2005.
- Watanabe, T., Jono, H., Han, J., Lim, D.J. and Li, J.D. Synergistic Activation of NF- k B by Nontypeable Haemophilus influenzae and Tumor Necrosis Factor- a . Proc. Natl. Acad. Sci. USA, 101:3563-8, 2004.
- Jono, H, Lim, JH, Chen, L.F. Xu, H, Trompouki, E., Pan, ZK, Mosialos, G, Li, J.D. NF- k B Is Essential for Induction of CYLD, the Negative Regulator of NF- k B. J. Biol. Chem . (Accelerated Publication) 279, 36171-36174, 2004.
- Sakai, A., Han, J., Cato, A.C., Akira, S., Li, J.D. Inhibition of MAPK p38 and JNK by glucocorticoids via induction of MAP kinase phosphatase-1 enhances IL-β-induced expression of Toll-like receptor 2. BMC Mol. Bol. 5(1):2, 2004.
- Chen, R., Lim, J.H., Jono, H., Gu, X.X., Kim, Y., Basbaum, C.B., Murphy, T.F. and Li, J.D. Nontypeable Haemopilus influenzae Lipoprotein P6 Induces MUC5AC Mucin Transcription via TLR2-TAK1-dependent p38 MAPK-AP1 and IKKβ-IκBα-NF-κB signaling pathways. Biochem. Biophys. Res. Commun. 324, 1087-1094, 2004.
- Jono, H., Xu, H., Kai, H., Lim, D.J., Kim, Y.S., Feng, X.H. and Li, J.D. TGF-β-Smad Signaling Pathway Negatively Regulates Nontypeable Haemophilus influenzae-induced MUC5AC Mucin Transcription via MAPK Phosphatase-1-dependent Inhibition of p38 MAPK. J. Biol. Chem. 278, 27811-27819, 2003.
- Wang, B., Cleary, P.P, Xu, H and Li, J.D. Up-Regulation of Interleukin-8 by Novel Small Cytoplasmic Molecules of Nontypeable Haemophilus influenzae via p38 and Extracellular Signal-Regulated Kinase Pathways. Infect. Immun. 71, 5523-30, 2003.
- Li, J.D. Exploitation of host epithelial signaling networks by respiratory bacterial pathogens. J. Pharmacol. Sci. 91:1-7, 2003
- Imasato, A., Desbois-Mouthon, C., Han, J., Kai, H., Cato, A.C., Akira, S., Li, J.D. Inhibition of p38 MAPK by glucocorticoids via induction of MAP kinase phosphatase-1 enhance nontypeable Haemophilus influenzae-induced expression of toll-like receptor 2. J. Biol. Chem. 277:47444-47450, 2002.
- Jono, H., Shuto, T., Xu, H., Kai, H., Lim, D.J., Gum, J.R., Kim, Y.S., Yamaoka, S, Feng, X.H. and Li, J.D. Transforming Growth Factor-β-Smad Signaling Pathway Cooperates with NF-κB to Mediate Nontypeable Haemophilus influenzae-induced MUC2 Mucin Transcription. J. Biol. Chem. 277:45547-45557, 2002.
- Shuto, T., Imasato, I., Jono, H., Xu, H., Watanabe, T., Kai, H., Andalibi, A., Linthicum, F., Guan, Y.L., Han, J., Cato, A.C., Akira, S., Lim, D.J. and Li, J.D. Glucocorticoids synergistically enhance Nontypeable Haemophilus influenzae-induced Toll-like receptor 2 expression via a negative cross-talk with p38 MAP kinase. J. Biol. Chem. 277:17263-17270, 2002.
- Wang, B., Lim, D.J., Han, J., Kim, Y.S., Basbaum, C.B. and Li, J.D. Novel Cytoplasmic Proteins of Nontypeable Haemophilus influenzae Up-regulate Human MUC5AC Mucin Transcription via a Positive p38 MAP Kinase Pathway and a Negative PI 3-Kinase-Akt Pathway. J. Biol. Chem. 277:949-957, 2002.
- Shuto, T., Xu H., Wang, B, Han, J., Kai, H., Gu, X.X., Murphy, T., Lim, D.J. and Li, J.D. Activation of NF-κB by Nontypeable Haemophilus influenzae is mediated by Toll-like Receptor-2-TAK1-dependent NIK-IKKα/β-IκBα and MKK3/6-p38 MAP kinase signaling pathways. Proc. Natl. Acad. Sci. USA, 98:8774-8779, 2001.
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