CURRICULUM VITAE
Lynette B. Corbeil (nee Keur), DVM, PhD
Education:
1956‑1957 Pre‑Veterinary Studies University of British Columbia
1957‑1962 Veterinary Medicine Ontario Veterinary College
University of Toronto
1962‑1963 Biblical Studies Graduate School of Missions
Columbia Bible College
1963‑1965 M.Sc. Program in Cytology Ontario Veterinary College
and Immunology University of Guelph
1971‑1974 PhD Program in Immunology New York State Veterinary College
and Pathogenic Bacteriology Cornell University
1974‑1975 NIH Postdoctoral Fellowship New York State Veterinary College
Immunology Cornell University
1975‑1978 NIH Postdoctoral Fellowship School of Medicine
Infectious Diseases University of California, San Diego
Experience:
1962‑1963 Part‑time Veterinary Magnolia Animal Hospital
Practice
1963‑1965 Graduate Research Assistant Ontario Veterinary College
1965‑1966 Assistant Professor of Ontario Veterinary College
Immunology
1966‑1967 Research Associate Mason Research Institute
(Immunology)
1967‑1971 Assistant Professor of Southeastern Massachusetts
Biology University
1971‑1974 Graduate Research Assistant New York State Veterinary College
1974‑1975 Postdoctoral Fellow New York State Veterinary College
1975‑1978 Postdoctoral Fellow School of Medicine
University of California, San Diego
1978‑1979 Associate Professor of College of Veterinary Medicine
Immunology Kansas State University
1979‑1982 Associate Professor of School of Medicine
Pathology and Director of University of California, San Diego
Laboratory Animal Diagnostic
Laboratory
1982‑1985 Associate Professor of Washington State University
Veterinary Microbiology
1985‑1987 Professor of Veterinary Washington State University
Microbiology
1985‑1986 Visiting Professor University of California, San Diego
1987‑1996 Adjunct Professor of University of California, San Diego
Pathology
1989-2002 Courtesy appointment University of California, Davis
Dept. Pop. Health & Reprod.
1996-Present Professor of Pathology University of California, San Diego
1999-2002 Interim Director UC San Diego and UC Davis
UC Veterinary Medical Center-
San Diego
2002- 2010 Co-Director, UC VMC-SD UCSD and UC Davis
Professor of Population Health UC Davis
& Reproduction
Assoc. Dean for S. California UC Davis, School of Veterinary Medicine
Comp. Med.
2010-Present Professor Emeritus
Population Health &
Reproduction UC Davis, School of Veterinary Medicine
RESEARCH FOCUS
Since my research training with Dr. A. J. Winter at Cornell, my goal has been to define host parasite relationships in infections of the reproductive tract. Initially, this involved studies of Campylobacter fetus for which we defined kinetics and functions of isotypic antibody responses in bovine cervicovaginal secretions, uterine secretions and serum. Also, bacterial antigenic variation in the face of a mucosal immune response was elucidated (in collaboration with Winter and Schurig) for the first time. More recently, my focus has shifted to Histophilus somni. Since the organism causes infertility by an ascending route, abortion by a hematogenous route and respiratory infection by a descending route, as well as septicemia, it allows investigation of several different virulence and defense mechanisms. My research team began by defining the natural infection and by reproducing the disease in the natural host (cattle). Then, we studied the specificity and isotypes of protective antibody responses. We defined the roles of IgG1 and IgG2 in protection as well as exploring the differences between the IgG2 allotypes (IgG2A1 and A2 or IgG2a and IgG2b). Sometime ago, we showed that IgG2 binds to H. somni nonspecifically via the Fc moiety. Strains which bound IgG2 were serum resistant, but some strains from asymptomatic carriers were serum sensitive and lacked IgG2 binding ability. To best define bacterial antigens and virulence factors, we constructed a genomic library, expressed H. somni antigens in E. coli and characterized the recombinants. Now, we have focused on genes which are expressed in serum resistant but not in 4 serum sensitive strains of H. somni. By Southern blotting, we showed the entire coding sequence of a very large virulence factor (Immunoglobulin binding Protein A – IbpA) is missing in the serum sensitive strains. Sequencing the 12.2 kb gene revealed several domains and motifs related to pathogenicity. Recombinant vaccines using 3 of these domains revealed protective subunits for mice and calves. Studies of the most protective domain (IbpA DR2), in collaboration with Jack Dixon’s lab, revealed a “Fic” motif which is cytotoxic. The most sensitive cell type was bovine alveolar epithelial type 2 cell, the target cell in bovine respiratory disease. The mechanism was shown to be adenylylation or Rho GTPases. In a parallel study we are investigating the immunopathogenesis of combined BRSV and H. somni in collaboration with Laurel Gershwin at UC Davis. We showed that the combined infection enhances IgE responses, clinical scores and duration of pneumonia. Surprisingly the primary specificity of the IgE response differed from that of IgG. Now we are investigating differences in epithelial cell gene expression after BRSV, H. somni or BRSV and H. somni infection. Thus, the research projects begin with the whole animal, progress to a cellular/molecular approach, and then determine the significance of the molecular studies in the natural host.
A secondary focus involves bovine trichomoniasis. The project was chosen for several reasons. Firstly, unlike H. somnus infection, the organism remains in the reproductive tract, providing a straightforward local host-parasite relationship for study. Secondly, it is caused by a protozoan with a single stage life cycle, which grows well in broth or soft agar. Thirdly, the disease is of great economic significance in areas where natural breeding is practiced. For example, approximately 15% of herds in California were infected in a randomized study. Fourthly, it is the only naturally occurring animal model for human trichomoniasis. Our team (including Bob BonDurant at UC Davis) started by determining antibody specificities and isotypes which may be protective. This was done with bovine immune and convalescent sera as well as with a panel of monoclonal antibodies (Mabs) prepared in our laboratory. When Mabs were found which immobilized and agglutinated the organism, mediated complement killing and prevented adherence to vaginal epithelial cells, we immunoaffinity purified the surface antigen (TF1.17). Collaborations with BN Singh at SUNY Syacuse revealed that the antigen was a Lipophosphoglycan/protein conjugate. Immunization/challenge studies with this antigen in virgin heifers showed significantly faster clearance of T. foetus in vaccinates than in adjuvant controls (p <0.002). The systemically vaccinated heifers not only demonstrated increases in serum and vaginal IgG antibodies to T. foetus but also demonstrated an anamnestic vaginal IgA response on challenge with T. foetus. We vaccinated animals with protocols to enrich for IgG or IgA antibodies in genital secretions. One group had greatly enriched IgA antibodies to TF 1.17 antigen and a second group, greatly enriched specific IgG antibody levels in vaginal secretions. Both groups cleared the infection faster than the controls, but were not different from one another. Thus, genital IgG and IgA antibodies to the same trichomonad antigen were equally protective. We showed that systemic priming with this antigen followed by either vaginal or intranasal boosting stimulated genital IgA responses and resulted in early clearance of the organism. Most recently, we found that IgE antibodies to TF1.17 antigen were associated with mast cell degranulation, IgG1 antibody influx into genital secretions and clearance of the parasite. We investigated T. foetus extracellular cysteine proteinase (CP8) as a virulence factor demonstrating it to cleave bovine IgG1, IgG2, C3 and lactoferrin. The gene was shown to be expressed by T. foetus isolated but not further cultured from the bovine uterus during infection. We have also developed mouse models for T. foetus and T. vaginalis infection and for T. foetus induced reproductive failure. Most recently we demonstrated that CP inhibitors reduce cytotoxicity of T. foetus for bovine trophoblasts and decrease murine vaginal infection. Therefore, the focus of T. foetus research is also host parasite relationships in the whole animal and at the molecular level.
A third area of research addresses the role of bovine IgG2 in defense against pyogenic infections. With H. somnus infection, we have reported several lines of evidence that suggest IgG2 is key in defense. Since IgG2 is a better opsonin than IgG1, it should also be important in defense against trichomonads, which are known to be killed by PMNs. Others have shown that IgG2 is important in other pyogenic infections also (especially pneumonia and mastitis). For example, Red Danish Milk cattle deficient in IgG2 have significantly more pyogenic infections than normal controls. We showed that young calves develop IgG2b antibodies much later than IgG2a. Then we investigated the functions of the two IgG2 allotypes in: a) resistance to digestion by trichomonad or staphylococcal proteinases, b) binding to surface immunoglobulin binding proteins of H. somni, Staphylococcus aureus, and Streptococcus spp., c) initiation of the complement cascade. These studies showed that IgG2b is approximately twice as effective in complement activation as IgG2a. A second series of experiments showed that IgG2b bound to H. somnus IgBPs but IgG2a did not. Lastly, IgG2a was digested more rapidly by T. foetus extracellular cysteine proteinase than IgGb. The hope is that further studies will enable correlation of susceptibility of animals to pyogenic infection with their IgG2 allotype (IgG2a/a, IgG2a/b or IgG2b/b). This would provide a genetic marker for disease susceptibility along with understanding of the underlying mechanisms of susceptibility/resistance.
PUBLICATION LIST
1. Campbell JJR, Phelps RH, Keur LB: Dependence of oxidation‑reduction potential of milk on its vitamin C content. J Milk Food Technol 22:346‑ 347, 1959.
2. Campbell JJR, Keur LB: Role of xanthine oxidase in the reduction of resazurin by raw milk. J Dairy Sci 44:425‑429, 1961.
3. Corbeil LB: Differentiation of rhabdomyosarcoma and neonatal muscle cells in vitro. Cancer 20:572‑578, 1967.
4. Corbeil LB: Antigenicity of rhabdomyosarcomas induced by nickel sulfide (Ni3S2). Cancer 21:184‑189, 1968.
5. Corbeil LB: Observations on multinucleation of rhabdomyosarcoma and neonatal muscle cells in vitro. Life Sciences 8:651‑656, 1969.
6. Ingram DG, Corbeil LB, Malcomson ME: Antibodies to Escherichia coli in young calves: K antigens. Am J Vet Res 31:71‑79, 1970.
7. Schurig GD, Hall CE, Burda K, Corbeil LB, Duncan JR, Winter AJ: Persistent genital tract infection with Vibrio fetus intestinalis associated with serotypic alteration of the infecting strain. Am J Vet Res 34:1399‑1403, 1973.
8. Schurig GD, Hall CE, Burda K, Corbeil LB, Duncan JR, Winter AJ: Infection patterns in heifers following cervico‑vaginal or intrauterine instillation of Campylobacter (Vibrio) fetus veneralis. Cornell Vet 64:533‑548, 1974.
9. Davies DH, Corbeil LB, Ward D, Duncan JR: A humoral suppressor of in vitro lymphocyte transformation in cattle with Johne's disease. Proc Soc Exp Biol Med 145:1372‑1377, 1974.
10. Corbeil LB, Schurig GD, Duncan JR, Corbeil RR, Winter AJ: Immunoglobulin classes and biological functions of Campylobacter (Vibrio) fetus antibodies in serum and cervicovaginal mucus. Infect Immunity 10:422‑429, 1974.
11. Corbeil LB, Duncan JR, Schurig GGD, Hall CE, Winter AJ: Bovine venereal vibriosis: Variations in immunoglobulin class of antibodies in genital secretions and serum. Infect Immunity 10:1084‑1090, 1974.
12. Corbeil LB, Schurig GGD, Bier PJ, Winter AJ: Bovine venereal vibriosis: Antigenic variation of the bacterium during infection. Infect Immunity 11:240‑244, 1975.
13. Schurig GGD, Hall CE, Corbeil LB, Duncan JR, Winter AJ: Bovine venereal vibriosis: Cure of genital infection in females by systemic immunization. Infect Immunity 11:245‑251, 1975.
14. Corbeil LB, Corbeil RR, Winter AJ: Bovine venereal vibriosis: Activities of inflammatory cells in protective immunity. Am J Vet Res 36:403‑406, 1975.
15. Duncan JR, Corbeil LB, Davies DH, Schultz RD, Whitlock RH: Persistent
papillomatosis associated with immunodeficiency. Cornell Vet 65:205‑211, 1975.
16. McCoy EC, Doyle D, Burda K, Corbeil LB, Winter AJ: Superficial antigens of Campylobacter (Vibrio) fetus: Characterization of an antiphagocytic component. Infect Immunity 11:517‑525, 1975.
17. Corbeil LB, Shively JN, Duncan JR, Schurig GGD, Winter AJ: Bovine venereal vibriosis: Ultrastructure of endometrial lesions. Lab Invest 33:187‑192, 1975.
18. Corbeil LB, Duncan JR, Winter AJ: Bovine venereal vibriosis: Animal model for gonorrhea. Bull Comp Pathol 7:2, 1975.
19. George JW, Corbeil LB, Duncan JR, Fabricant J: A rheumatoid‑like arthritis in calves. Cornell Vet 66:110‑117, 1976.
20. Corbeil LB, George JW, Shively JN, Duncan JR, Schultz R: Canine visceral leishmaniasis with amyloidosis: An immunopathological case study. Clin Immunol Immunopathol 6:165‑173, 1976.
21. Corbeil LB, Hall CE, Lein D, Corbeil RR, Duncan JR, Winter AJ: Immunoglobulin classes in genital secretions of mycoplasma infected and normal heifers. Infect Immunity 12:1595‑1600, 1976.
22. Corbeil LB, Hall CE, Bier P, Duncan JR, Winter AJ: Immune response to genital mycoplasmosis in bulls. Theriogenol 6:39‑44, 1976.
23. Corbeil LB, Wunderlich AC, Braude AI: Technique for transcervical intrauterine inoculation of the mouse. Lab Ani Sci 28:314‑316, 1978.
24. Corbeil LB, Wunderlich AC, McCutchan JA, Braude AI: A murine model of gonococcal bacteremia, in Brooks GF et. al. (eds): Immunobiology of Neisseria gonorrhoeae. Washington, DC, Amer Soc Microbiol, 1978, p 317‑318.
25. Corbeil LB, Winter AJ: Animal model for the study of genital immune mechanisms: Venereal vibriosis of cattle, in Brooks GF et al (eds): Immunobiology of Neisseria gonorrhoeae. Washington, DC, Amer Soc Microbiol, 1978, p 293‑299.
26. Braude AI, Corbeil LB, Levine S, Ito J, McCutchan JA: The possible influence of cyclic menstrual changes on resistance to the gonococcus, in Brooks GF et al (eds): Immunobiology of Neisseria gonorrhoeae. Washington, DC, Amer Soc Microbiol, 1978, p 328‑337.
27. Corbeil LB: The role of complement in immunity and immunopathology. Vet Clin N Am 8:585‑611, 1978.
28. Corbeil LB, Wunderlich AC, Ito JI, McCutchan JA: Plaque assay for measuring serum bactericidal activity against gonococci. J Clin Micro 8:618‑620, 1978.
29. Ito JI, Corbeil LB, Wunderlich AC, McCutchan JA, Braude AI: Common heat stable protective antigen in gonococci. Trans Assoc Am Physicians 92:160‑168, 1979.
30. Corbeil LB, Wunderlich AC, Corbeil RR, McCutchan JA, Ito JI, Braude AI. Disseminated gonococcal infection in mice. Infect Immun 26:984‑990, 1979.
31. Corbeil LB: Criteria for the development of animal models of human diseases of the reproductive system. Am J Pathol 101:S241‑254, 1980.
32. Streeter PR, Corbeil LB: Gonococcal infection in endotoxin resistant and endotoxin susceptible mice. Infect Immunity 32:105‑110, 1981.
33. Corbeil LB, Schurig GG, Duncan JR, Wilkie BN, Winter AJ: Immunity in the female bovine reproductive tract based on the response to Campylobacter fetus, in JE Butler (ed): The Ruminant Immune System. Plenum Press. Adv Exp Med Biol 137:729‑743, 1981.
34. Marks MI, Ziegler EJ, Douglas H, Corbeil LB, Braude AI: Induction of immunity against lethal Haemophilus influenzae Type B infection by Escherichia coli core lipopolysaccharide. J Clin Invest 69:742‑749, 1982.
35. Harriman GR, Podack ER, Braude AI, Corbeil LB, Esser AF, Curd JG: Activation of complement by serum‑resistant Neisseria gonorrhoeae: Assembly of the membrane attach complex without subsequent cell death. J Exp Med 156:1235‑1249, 1982.