K. P. Connie Tam Laboratory

Research

My lab focuses on understanding the innate defense and immunoregulatory functions of corneal epithelial cells. Epithelial tissues form a protective lining of the body, including the outer surfaces that are exposed to the environment, as well as the inner body cavities, glands, and ducts. Through constitutive and inducible expression of danger- and pathogen-associated molecular pattern recognition receptors, innate defense molecules, cytokines and chemokines, epithelial cells serve as an essential component of the innate immune system to stop pathogens right at the points of entry before they can cause diseases, regulate regional immune and inflammatory responses, and maintain tissue homeostasis. Recently, we discovered that the C-terminal fragments of a cytokeratin protein, K6, in corneal epithelial cells are antimicrobial, and that endogenous K6 regulates signaling pathways to control production of inflammatory mediators. These are unexpected functions for keratin proteins since they have long been viewed as the building blocks of cytoskeleton that maintain structural integrity and resilience of epithelial cells. Given the wide distribution of K6 among different epithelial tissues, as well as the structural and functional similarities shared among different keratins, our studies aim to advance understanding of epithelial innate immune functions of the cornea and other sites of the body and to contribute to biocompatible anti-infective and immunoregulatory drug development in the post-antibiotic era.

Selected Publications

View publications for K. P. Connie Tam, PhD
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Bhushan A, Chan JK, Sun Y, Crabb JS, Jang G-F, Willard B, Crabb JW, Tam C. Epithelial cytokeratin 6a restricts secretory autophagy of proinflammatory cytokines by interacting with Sec16A. bioRxiv doi: 10.1101/2024.01.04.574264. Full text

Chan JK, Sun Y, Bhushan A, Willard B, Tam C. Keratin 6a attenuates Toll-like receptor-triggered proinflammatory response in corneal epithelial cells by suppressing ELKS/IKKe-dependent activation of NF-kB. bioRxiv doi: 10.1101/2023.10.24.563888. Full text

Sun Y, Chan J, Bose K, Tam C. Simultaneous control of infection and inflammation with keratin-derived antibacterial peptides targeting TLRs and co-receptors. Sci Transl Med. 2023 Mar 8;15(686):eade2909. doi: 10.1126/scitranslmed.ade2909. Epub 2023 Mar 8. PMID: 36888696. Full text

Rebibo L, Tam C, Sun Y, Shoshani E, Badihi A, Nassar T, Benita S. Topical tacrolimus nanocapsules eye drops for therapeutic effect enhancement in both anterior and posterior ocular inflammation models. J Control Release. 2021 May 10;333:283-297. Epub 2021 Mar 30. PubMed PMID: 33798665; PubMed Central PMCID: PMC8127065. Full text 

Lin K, Zhang L, Kong M, Yang M, Chen Y, Poptic E, Hoffner M, Xu J, Tam C, Lin F. Development of an anti-human complement C6 monoclonal antibody that inhibits the assembly of membrane attack complexes. Blood Adv. 2020 May 12;4(9):2049-2057. doi: 10.1182/bloodadvances.2020001690. PubMed PMID: 32396613; PubMed Central PMCID: PMC7218433.

Wu YT, Truong TN, Tam C, Mendoza MN, Zhu L, Evans DJ, Fleiszig SMJ. Impact of topical corticosteroid pretreatment on susceptibility of the injured murine cornea to Pseudomonas aeruginosa colonization and infection. Exp Eye Res. 2019 Feb;179:1-7. doi: 10.1016/j.exer.2018.10.010. Epub 2018 Oct 19. PubMed PMID: 30343040; PubMed Central PMCID: PMC6360113.

Metruccio MME, Wan SJ, Horneman H, Kroken AR, Sullivan AB, Truong TN, Mun JJ, Tam CKP, Frith R, Welsh L, George MD, Morris CA, Evans DJ, Fleiszig SMJ. A novel murine model for contact lens wear reveals clandestine IL-1R dependent corneal parainflammation and susceptibility to microbial keratitis upon inoculation with Pseudomonas aeruginosa. Ocul Surf. 2019 Jan;17(1):119-133. doi: 10.1016/j.jtos.2018.11.006. Epub 2018 Nov 12. PubMed PMID: 30439473; PubMed Central PMCID: PMC6365008.

Chan JKL, Yuen D, Too PH, Sun Y, Willard B, Man D, Tam C. Keratin 6a reorganization for ubiquitin-proteasomal processing is a direct antimicrobial response. J Cell Biol. 2018 Feb 5;217(2):731-744. Epub 2017 Nov 30. PubMed PMID: 29191848; PubMed Central PMCID: PMC5800800. Full text

Metruccio MME, Tam C, Evans DJ, Xie AL, Stern ME, Fleiszig SMJ. Contributions of MyD88-dependent receptors and CD11c-positive cells to corneal epithelial barrier function against Pseudomonas aeruginosa. Sci Rep. 2017 Oct 23;7(1):13829. doi: 10.1038/s41598-017-14243-w. PubMed PMID: 29062042; PubMed Central PMCID: PMC5653778.

Marino GK, Santhiago MR, Santhanam A, Lassance L, Thangavadivel S, Medeiros CS, Bose K, Tam KP, Wilson SE. Epithelial basement membrane injury and regeneration modulates corneal fibrosis after pseudomonas corneal ulcers in rabbits. Exp Eye Res. 2017 Aug;161:101-105. Epub 2017 May 13. PubMed PMID: 28506643; PubMed Central PMCID: PMC5554721. Full text

Wu YT, Tam C, Zhu LS, Evans DJ, Fleiszig SM. Human tear fluid reduces culturability of contact lens-associated Pseudomonas aeruginosa biofilms but induces expression of the virulence-associated type III secretion system. Ocul Surf. 2017 Jan;15(1):88-96. doi: 10.1016/j.jtos.2016.09.001. Epub 2016 Sep 23. PubMed PMID: 27670247; PubMed Central PMCID: PMC5287294.

Lee JT, Wang G, Tam YT, Tam C. Membrane-active epithelial keratin 6a fragments (KAMPs) are unique human antimicrobial peptides with a non-αβ structure. Front Microbiol. 2016;7:1799. eCollection 2016. PubMed PMID: 27891122; PubMed Central PMCID: PMC5105358. Full text 

Wu YT, Zhu LS, Tam KP, Evans DJ, Fleiszig SM. Pseudomonas aeruginosa survival at posterior contact lens surfaces after daily wear. Optom Vis Sci. 2015 Jun;92(6):659-64. doi: 10.1097/OPX.0000000000000597. PubMed PMID: 25955639; PubMed Central PMCID: PMC4575223.

Sullivan AB, Tam KP, Metruccio MM, Evans DJ, Fleiszig SM. The importance of the Pseudomonas aeruginosa type III secretion system in epithelium traversal depends upon conditions of host susceptibility. Infect Immun. 2015 Apr;83(4):1629-40. doi: 10.1128/IAI.02329-14. Epub 2015 Feb 9. PubMed PMID: 25667266; PubMed Central PMCID: PMC4363407.

Mun J, Tam C, Chan G, Kim JH, Evans D, Fleiszig S. MicroRNA-762 is upregulated in human corneal epithelial cells in response to tear fluid and Pseudomonas aeruginosa antigens and negatively regulates the expression of host defense genes encoding RNase7 and ST2. PLoS One. 2013;8(2):e57850. doi: 10.1371/journal.pone.0057850. Epub 2013 Feb 28. PubMed PMID: 23469087; PubMed Central PMCID: PMC3585208.

Borkar DS, Fleiszig SM, Leong C, Lalitha P, Srinivasan M, Ghanekar AA, Tam C, Li WY, Zegans ME, McLeod SD, Lietman TM, Acharya NR. Association between cytotoxic and invasive Pseudomonas aeruginosa and clinical outcomes in bacterial keratitis. JAMA Ophthalmol. 2013 Feb;131(2):147-53. doi: 10.1001/jamaophthalmol.2013.778. PubMed PMID: 23411878; PubMed Central PMCID: PMC3796098.

Tam C, Mun JJ, Evans DJ, Fleiszig SM. Cytokeratins mediate epithelial innate defense through their antimicrobial properties. J Clin Invest. 2012 Oct;122(10):3665-77. Epub 2012 Sep 24. PubMed PMID: 23006328; PubMed Central PMCID: PMC3461926. Full text 

Ramirez JC, Fleiszig SM, Sullivan AB, Tam C, Borazjani R, Evans DJ. Traversal of multilayered corneal epithelia by cytotoxic Pseudomonas aeruginosa requires the phospholipase domain of exoU. Invest Ophthalmol Vis Sci. 2012 Jan 25;53(1):448-53. doi: 10.1167/iovs.11-8999. PubMed PMID: 22167094; PubMed Central PMCID: PMC3292376.

Hritonenko V, Mun JJ, Tam C, Simon NC, Barbieri JT, Evans DJ, Fleiszig SM. Adenylate cyclase activity of Pseudomonas aeruginosa ExoY can mediate bleb-niche formation in epithelial cells and contributes to virulence. Microb Pathog. 2011 Nov;51(5):305-12. PubMed PMID: 21843628; PubMed Central PMCID: PMC3213052. Full text

Tam C, LeDue J, Mun JJ, Herzmark P, Robey EA, Evans DJ, Fleiszig SM. 3D quantitative imaging of unprocessed live tissue reveals epithelial defense against bacterial adhesion and subsequent traversal requires MyD88. PLoS One. 2011;6(8):e24008. PubMed PMID: 21901151; PubMed Central PMCID: PMC3162028. Full text 

Mun JJ, Tam C, Evans DJ, Fleiszig SM. Modulation of epithelial immunity by mucosal fluid. Sci Rep. 2011;1:8. PubMed PMID: 22355527; PubMed Central PMCID: PMC3216496. Full text

Alarcon I, Tam C, Mun JJ, LeDue J, Evans DJ, Fleiszig SM. Factors impacting corneal epithelial barrier function against Pseudomonas aeruginosa traversal. Invest Ophthalmol Vis Sci. 2011 Mar 14;52(3):1368-77. PubMed PMID: 21051692; PubMed Central PMCID: PMC3101686. Full text

Augustin DK, Heimer SR, Tam C, Li WY, Le Due JM, Evans DJ, Fleiszig SM. Role of defensins in corneal epithelial barrier function against Pseudomonas aeruginosa traversal. Infect Immun. 2011 Feb;79(2):595-605. PubMed PMID: 21115716; PubMed Central PMCID: PMC3028852. Full text

Tam C, Mun JJ, Evans DJ, Fleiszig SM. The impact of inoculation parameters on the pathogenesis of contact lens-related infectious keratitis. Invest Ophthalmol Vis Sci. 2010 Jun;51(6):3100-6. PubMed PMID: 20130275; PubMed Central PMCID: PMC2891469. Full text

Mun JJ, Tam C, Kowbel D, Hawgood S, Barnett MJ, Evans DJ, Fleiszig SM. Clearance of Pseudomonas aeruginosa from a healthy ocular surface involves surfactant protein D and is compromised by bacterial elastase in a murine null-infection model. Infect Immun. 2009 Jun;77(6):2392-8. PubMed PMID: 19349424; PubMed Central PMCID: PMC2687330. Full text

Ni M, Tam C, Verma A, Ramphal R, Hawgood S, Evans DJ, Fleiszig SM. Expression of surfactant protein D in human corneal epithelial cells is upregulated by Pseudomonas aeruginosa. FEMS Immunol Med Microbiol. 2008 Nov;54(2):177-84. PubMed PMID: 18657106. Full text

Tam C, Lewis SE, Li WY, Lee E, Evans DJ, Fleiszig SM. Mutation of the phospholipase catalytic domain of the Pseudomonas aeruginosa cytotoxin ExoU abolishes colonization promoting activity and reduces corneal disease severity. Exp Eye Res. 2007 Dec;85(6):799-805. PubMed PMID: 17905228; PubMed Central PMCID: PMC3213055. Full text

Tam CK, Morris C, Hackett J. The Salmonella enterica serovar Typhi type IVB self-association pili are detached from the bacterial cell by the PilV minor pilus proteins. Infect Immun. 2006 Sep;74(9):5414-8. PubMed PMID: 16926438; PubMed Central PMCID: PMC1594823. Full text

Tam CK, Hackett J, Morris C. Rate of inversion of the Salmonella enterica shufflon regulates expression of invertible DNA. Infect Immun. 2005 Sep;73(9):5568-77. PubMed PMID: 16113273; PubMed Central PMCID: PMC1231127. Full text

Tam CK, Hackett J, Morris C. Salmonella enterica serovar Paratyphi C carries an inactive shufflon. Infect Immun. 2004 Jan;72(1):22-8. PubMed PMID: 14688076; PubMed Central PMCID: PMC343949. Full text

Morris C, Tam CK, Wallis TS, Jones PW, Hackett J. Salmonella enterica serovar Dublin strains which are Vi antigen-positive use type IVB pili for bacterial self-association and human intestinal cell entry. Microb Pathog. 2003 Dec;35(6):279-84. PubMed PMID: 14580391. Full text