Kevan L. Hartshorn, MD
Director, Fellowship Program
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Our research principally deals with innate immunity, which refers to immune responses that are hard-wired into the genome and provide a first line of protection against infection or transformed cells. Innate immune responses are sometimes also responsible for damaging inflammation. Defects or variants in innate immunity account for increased propensity for infections or harmful inflammation. As an example, people lacking one of the collectins found in blood are at greater risk for infection during neutropenia and have a greater risk for certain cancers. There is surprising complexity and specificity to innate immunity despite the fact that it provides protection even when a person has not been exposed to a specific infection. The main aspects of innate immunity we study include neutrophils and monocyte/macrophages, toll like receptors, and soluble immune defense proteins called collectins and defensins. We study how neutrophils and monocytes become activated in response to infectious organisms (viruses and bacteria), including studies of cell signaling, phagocytosis and oxidant production. We study how defensins and collectins kill bacteria or viruses and promote their uptake by neutrophils and monocytes. We have created or collaborate to create and test a variety of new recombinant versions of collectins and defensins, some of which have strongly increased antiviral or antibacterial activity. We also collaborate with members of the department of Biophysics in crystallographic studies of collectin structure in order to predict protein changes that might confer greater antimicrobial activity. We also collaborate in use of mouse models (e.g., mice in which collectin genes are deleted) to study the role of specific innate immune mediators in infection. A particular area of interest for us is the innate immune response to respiratory infection, especially influenza virus infection. Influenza virus and HIV (which we also study to some extent) are important examples of infections for which innate immunity is important since these viruses undergo continuous mutation thus evading adaptive immune responses (i.e., specific T and B cell responses). Below are listed some of our recent publications.
Mitch White, MPH
1. Tecle T, White MR, Crouch EC, and Hartshorn KL. 2007. Human neutrophil defensins increase neutrophil uptake of influenza A virus and bacteria and modify virus induced respiratory burst responses. Journal of Immunology. 178: 8046-8052.
2. White MR, Tecle T, Crouch EC, and Hartshorn KL. 2007. Impact of neutrophils on antiviral activity of human bronchoalveolar lavage fluid. American Journal of Physiology Lung Cell Molec Physiol. 293: L1293-9.
3. Tecle T, White MR, Sorensen GL, Gantz D, Kacak N, Holmskov U, Smith K, Crouch EC, Hartshorn KL. 2008. Critical role for crosslinking of trimeric lectin domains of surfactant protein D in antiviral activity against influenza A virus. Biochemical Journal. 412:323-9
4. Mitchell R. White, Eva J. Helmerhorst, Antoon Ligtenberg, Marshall Karpel, Tesfaldet Tecle, Walter L. Siqueira, Frank G. Oppenheim, Kevan L. Hartshorn. 2008. Multiple components contribute to the ability of saliva to inhibit influenza viruses. Oral Microbiology and Immunology. 24:18-24.
5. Hartshorn KL, Webby T, White MR, Tecle T, Pan C, Boucher S, Moreland RJ, Crouch EC, and Scheule RK. 2008. Role of viral hemagglutinin glycosylation in anti-influenza activities of recombinant surfactant protein D. Respiratory Research. Sept. 9:1
6. White MR, Kingma P, Tecle T, Kacak N, Linders B, Heuser J, Crouch EC, and Hartshorn KL. 2008. Multimerization of surfactant protein D, but not its collagen domain, is required for antiviral and opsonic acitivities related to influenza virus. Journal of Immunology. 181: 7936-7943.
7. Wang J, Oberley-Deegan, R, Wang S, Nikrad M, Funk J, Hartshorn KL and Mason RJ. Differentiated human alveolar type II cells secrete antiviral IL-29 (IFN-λ1) in response to influenza A infection. 2009. Journal of Immunology. Bol 182: 1296-1304.
8. Crouch EC, Hartshorn KL, Horlacher T, McDonald B, Smith K, Cafarella T, Seaton B, Seeberger PH, and J Head. Recognition of mannosylated ligands and influenza A virus by human surfactant protein D: contributions of an extended site and residue 343. 2009. 48: 3335-3345.
9. Doss M, White MR, Tecle T, Gantz D, Crouch EC, Jung G, Ruchala P, Waring AJ, Lehrer RI, Hartshorn KL: Interactions of alpha-, beta-, and theta-defensins with influenza A virus and surfactant protein D. J Immunol 2009;182: 7878-87.
10. Hartshorn, K. L., M. R. White, T. Tecle, G. L. Sorensen, U. Holmskov, and E. C. Crouch. Viral Aggregating and Opsonizing Activity in Collectin Trimers. Am J Physiol Lung Cell Mol Physiol. 2010. 298: L79-88.
11. White MR, Boland P, Tecle T, Gantz D, Sorensen G, Tornoe I, Holmskov U, McDonald B, Crouch EC, and Hartshorn KL. Enhancement of antiviral activity of collectin trimers through cross-linking and mutagenesis of the carbohydrate recognition domain. J Innate Immunity. 2009.
12. Hartshorn, K., M. White, M. Rynkiewicz, G. Sorensen, U. Holmskov, J. Head, and E. Crouch. 2010. Monoclonal antibody assisted structure function analysis of the carbohydrate recognition domain of surfactant protein D. American Journal Of Physiology Vol 299:
13. Hartshorn, K., M. White, K. Smith, G. Sorensen, Y. Kuroki, U. Holmskov, and E. Crouch. 2010. Increasing antiviral activity of surfactant protein D trimers by introducing residues from bovine serum collectins: dissociation of mannan-binding and antiviral activity. 2010 Scandanavian Journal of Immunology: Vol 72:22-30
14. Chang, W. C., M. R. White, P. Moyo, S. McClear, S. Thiel, K. L. Hartshorn, and K. Takahashi. 2010, Lack of the pattern recognition molecule mannose-binding lectin increases susceptibility to influenza A virus infection. BMC Immunol 11:64.
15. Kachnic LA, Tsai HK, Coen JJ, Blaszkowsky LS, Hartshorn K, Kwak EL, Willins JD, Ryan DP, Hong TS. Dose-painted Intensity-modulated Radiation Therapy for Anal Cancer: A Multi-institutional Report of Acute Toxicity and Response to Therapy. Int J Radiat Oncol Biol Phys. 2010 Nov 20. [Epub ahead of print] PubMed PMID: 21095071.
16. Hansen S, Selman L, Palaniyar N, Ziegler K, Brandt J, Kliem A, Jonasson M,Skjoedt MO, Nielsen O, Hartshorn K, Jørgensen TJ, Skjødt K, Holmskov U. Collectin 11 (CL-11, CL-K1) is a MASP-1/3-associated plasma collectin with microbial-binding activity. J Immunol. 2010 Nov 15;185(10):6096-104. Epub 2010 Oct 18. PubMed PMID: 20956340.
17. Chang, W. C., K. L. Hartshorn, M. R. White, P. Moyo, I. C. Michelow, H. Koziel, B. T. Kinane, E. V. Schmidt, T. Fujita, and K. Takahashi. 2010. Recombinant chimeric lectins consisting of mannose-binding lectin and L-ficolin are potent inhibitors of influenza A virus compared with mannose-binding lectin. Biochem Pharmacol 81:388-395
18. Wang, J., M. P. Nikrad, T. Phang, B. Gao, T. Alford, Y. Ito, K. Edeen, E. A. Travanty, B. Kosmider, K. Hartshorn, and R. J. Mason. 2011. Innate Immune Response to Influenza A Virus in Differentiated Human Alveolar Type II cells. Am J Respir Cell Mol Biol. 45: 582-91.
19. Qi, L., J. C. Kash, V. G. Dugan, B. W. Jagger, Y. F. Lau, Z. M. Sheng, E. C. Crouch, K. L. Hartshorn, and J. K. Taubenberger. 2011. The ability of pandemic influenza virus hemagglutinins to induce lower respiratory pathology is associated with decreased surfactant protein D binding. Virology 412:426-434.
20. van Eijk M, Bruinsma L, Hartshorn KL, White MR, Rynkiewicz MJ, Seaton BA, Hemrika W, Romijn RA, van Balkom BW, Haagsman HP.Introduction of N-Linked Glycans in the Lectin Domain of Surfactant Protein D: IMPACT ON INTERACTIONS WITH INFLUENZA A VIRUSES. J Biol Chem. 2011 Jun 10;286(23):20137-51. Epub 2011 Apr 13
21. Sever-Chroneos Z, Murthy A, Davis J, Florence JM, Kurdowska A, Krupa A, Tichelaar JW, White MR, Hartshorn KL, Kobzik L, Whitsett JA, Chroneos ZC. GM-CSF modulates pulmonary resistance to influenza A infection. Antiviral Res. 2011 Nov;92(2):319-28. Epub 2011 Sep 8. PMID: 21925209
22. Gong D, Farley K, White M, Hartshorn KL, Benarafa C, Remold-O’Donnell E Critical role of serpinB1 in regulating inflammatory responses in pulmonary influenza infection. J Infect Dis. 2011 Aug 15;204(4):592-600. PMID: 21791661
23. Numata M, Kandasamy P, Nagashima Y, Posey J, Hartshorn K, Woodland D, Voelker DR. Phosphatidylglycerol Suppresses Influenza A Virus Infection. Am J Respir Cell Mol Biol. 2011 Nov 3. [Epub ahead of print] PMID:22052877
24. Crouch E, Nikolaidis N, McCormack FX, McDonald B, Allen K, Rynkiewicz MJ, Cafarella TM, White M, Lewnard K, Leymarie N, Zaia J, Seaton BA, Hartshorn KL. Mutagenesis of Surfactant Protein D Informed by Evolution and X-ray Crystallography Enhances Defenses against Influenza A Virus in Vivo. J Biol Chem. 2011 Nov 25;286(47):40681-92. Epub 2011 Sep 30.
25. Oiknine-Djian E, Houri-Haddad Y, Weiss EI, Ofek I, Greenbaum E, Hartshorn K, Zakay-Rones Z. High Molecular Weight Constituents of Cranberry Interfere with Influenza Virus Neuraminidase Activity. Planta Med. 2012 May 15. [Epub ahead of print] PMID: 22588835
26. Larvie M, Shoup T, Chang WC, Chigweshe L, Hartshorn K, White MR, Stahl GL, Elmaleh DR, Takahashi K. Mannose-Binding Lectin Binds to Amyloid β Protein and Modulates Inflammation. J Biomed Biotechnol. 2012;2012:929803. Epub 2012 Mar 27. PMID: 22536027
27. Wang J, Nikrad MP, Travanty EA, Zhou B, Phang T, Gao B, Alford T, Ito Y, Nahreini P, Hartshorn K, Wentworth D, Dinarello CA, Mason RJ. Innate immune response of human alveolar macrophages during influenza A infection. PLoS One. 2012;7(3):e29879. Epub 2012 Mar 2. PMID: 22396727
28. Doss M, Ruchala P, Tecle T, Gantz D, Verma A, Hartshorn A, Crouch EC, Luong H, Micewicz ED, Lehrer RI, Hartshorn KL. Hapivirins and diprovirins: novel θ-defensin analogs with potent activity against influenza A virus. J Immunol. 2012 Mar 15;188(6):2759-68. Epub 2012 Feb 15. PMID: 22345650
29. Kosmider B, Messier EM, Janssen WJ, Nahreini P, Wang J, Hartshorn KL, and RJ Mason. Nrf2 protects human alveolar epithelial cells against injury induced by influenza A virus. 2012. Respiratory Research. 2012 Jun 6;13:43.
30. Verma A, White MR, Vathipadiekal V, Tripathi S, Mbianda J, Ieong M, Qi L, Taubenberger JK, Takahashi K, Jensenius JC, Thiel S, and Hartshorn KL. Human H-ficolin inhibits replication of seasonal and pandemic influenza A viruses. J Immunol 2012. 189(5):2478-87.
31. Gally F, Weaver MR, Pate KM, Hartshorn KL, Oberley-Deegan RE. FABP5 enhances susceptibility to H1N1 influenza A virus-induced lung inflammation. Submitted.
32. Tripathi S, Tecle T, White M, Crouch E, Hartshorn KL. The human cathelicidin, LL-37, inhibits influenza A viruses through a mechanism distinct from that of surfactant protein D or defensins. J Gen Virol. 2013. 94: 40-49
33. Volandes AE, Paasche-Orlow MK, Mitchell SL, El-Jawahri A, Davis AD, Barry MJ, Hartshorn KL, Jackson VA, Gillick MR, Walker-Corkery ES, Chang Y, López L, Kemeny M, Bulone L, Mann E, Misra S, Peachey M, Abbo ED, Eichler AF, Epstein AS, Noy A, Levin TT, Temel JS. Randomized controlled trial of a video decision report tool for cardio-pulmonary resuscitation decision making in advanced cancer. J Clin Oncol. 2013 Jan 20;31(3):380-6. doi: 10.1200/JCO.2012.43.9570. Epub 2012 Dec 10.
34. Gally F, Kosmider B, Weaver MR, Pate KM, Hartshorn KL, Oberley-Deegan RE FABP5 deficiency enhances susceptibility to H1N1 influenza A virus-induced lung inflammation. Am J Physiol Lung Cell Mol Physiol. 2013 Apr 26. [Epub ahead of print]
35. Shao C, Shi X, White M, Huang Y, Hartshorn K, Zaia J. Comparative glycomics of leukocyte glycosaminoglycans. FEBS J. 2013 May;280(10):2447-61. doi: 10.1111/febs.12231. Epub 2013 Apr 2.