Stephen W. Barthold, D.V.M., Ph.D.
Dr. Barthold is a board-certified veterinary pathologist with expertise in experimental pathology of infectious disease, and pathology of laboratory animals, with special interest in mouse pathology. His laboratory is engaged in research on host-agent interactions during the course of persistent infections with Borrelia burgdorferi (the agent of Lyme disease),. His group utilizes mouse models and a multidisciplinary approach toward accomplishing its research aims, including molecular biology, microbiology, immunology and pathology.
Lyme disease is a tick-borne infectious disease of humans and animals. Inoculation of Borrelia burgdorferi into laboratory mice results in development of arthritis, carditis and neurologic disease within the first few weeks of infection. Arthritis and carditis resolve and recur episodically over the course of persistent infection. These are also key features of Lyme disease in humans, numerous species of laboratory animals, and some domestic animals (dogs, horses, etc.). Despite persistent infection, infected mice (and other species) develop protective and disease-resolving immune responses that are strongly B cell-mediated and T cell-independent. Using the mouse model, Dr. Barthold’s group has discovered that B. burgdorferi up-regulates several key antigens within the feeding tick and in vivo during the course of infection, and these antigens are the principal targets for protective and disease-resolving immune responses. Because these biologically relevant immune responses are strongly B cell-mediated, serum from infected mice has been used to screen a B. burgdorferi genomic expression library, resulting in incrimination, cloning and expression of key antigens that elicit either protective immunity or arthritis-resolving immunity. In addition, the group is investigating unique mechanisms by which B. burgdorferi evades immune clearance through sequestration within collagen. In the past, Dr. Barthold has utilized the mouse model to develop and test a recombinant outer surface protein A (OspA) vaccine that has been proven to be efficacious in mice, dogs and humans.
The mouse model has been used to prove that persistence of B. burgdorferi is the rule, rather the norm, for this infection, which has also been shown with numerous other animal models. This fact poses a challenge to antibiotic therapy for Lyme disease, as antibiotics act by eliminating the majority of microbes, but require the host to “mop up” the remainder. This approach works for conventional bacteria, but B. burgdorferi’s persistent behavior may preclude this approach. With this in mind, the mouse model has been used to show that following antibiotic treatment, mice remain infected with slowly dividing but genetically intact spirochetes which can be acquired and transmitted by ticks to other mice, or by allograft transmission from treated mice to naïve recipients. Ongoing studies are investigating if these “persisters” revert to fully pathogenic, dividing forms or die out. The model is being used to test efficacy of new antimicrobial drugs and alternate treatment regimens with the goal of optimizing treatment of humans and animals with Lyme disease.
Studies in the mouse model have demonstrated that the host antibody response is the main mediator of protective immunity and disease resolution during the course of infection. These responses are vigorous, as demonstrated by passive transfer of antibody to naïve animals, but they are incapable of eliminating persistent infection. Studies suggest that B. burgdorferi specific B cells provide antibody responses by short-lived plasma cells at the expense of higher affinity B cells and long-lived plasma cells due to a lack of helper T cell activation. These events are being examined because of the apparent lack of immunologic memory (repeated susceptibility to infection) and as a possible mechanism of disease exacerbation during persistent infection. Understanding the humoral immune response will elucidate mechanisms that lead to the failure of a vigorous but ultimately deficient B cell response to facilitate clearance from B. burgdorferi infection.
In addition to serving as Director of the CCM, Dr. Barthold was the inaugural Director of the UCD Mouse Biology Program (see Mouse Biology Program), which is administered by the CCM. As the program grew, Dr. Barthold transferred directorship to Dr. K.C. Kent Lloyd, a CCM Core Faculty Member and Associate Dean of Research in the School of Veterinary Medicine. Dr. Barthold continues to provide administrative and professional guidance to the Program, and pathology expertise.
Barthold SW, Cadavid D, Philipp M. Animal Models of Borreliosis. In: Borrelia: Molecular and Cellular Biology. S. Samuels and J. Radolf (eds), Horizon Press, in press, 2009.
Hodzic E, Feng S, Holden K, Freet KJ, Barthold SW. Persistence of Borrelia burgdorferi following antibiotic treatment in mice. Antimicrob Agents Chemother, 52:1728-1736, 2008. PMID: 18316520
Selected Book, Chapter
Perscy DH, Barthold SW. Pathology of Laboratory Rodents and Rabbits. Third Edition, Blackwell Publishing, Ames, Iowa, 2007.
Strother KO, Hodzic E, Barthold SW, de Silva AM. Infection of mice with Lyme disease spirochetes constitutively producing outer surface proteins A and B. Infect Immun, 75:2786-2794, 2007. PMID: 17371860
Barthold SW, Hodzic E, Feng S. Antibody-mediated disease remission in the mouse model of Lyme borreliosis. Infect Immun, 74:4817-4825, 2006.
Holden K, Hodzic E, Feng S, Freet KJ, Lefebvre R, Barthold SW. Coinfection with Anaplasma phagocytophilum alters Borrelia burgdorferi population distribution in C3H/HeN mice. Infect Immun, 73:3440-3444, 2005.
Hodzic E, Tunev S, Feng S, Freet KJ, Barthold SW. Immunoglobulin-regulated expression of Borrelia burgdorferi outer surface protein A in vivo. Infect Immun, 73:3313-3321, 2005.
Hodzic E, Feng S, Freet KJ, Barthold SW. Borrelia burgdorferi population dynamics and prototype gene expression during infection of immunocompetent and immunodeficient mice. Infect Immun 71:5042-5055, 2003.
Feng S, Hodzic E, Freet K, Barthold SW. Immunogenicity of Borrelia burgdorferi arthritis-related protein. Infect Immun, 71:7211-7214, 2003.
Hodzic E, Feng S, Freet K, Borjesson D, Barthold SW. Borrelia burgdorferi population kinetics and selected gene expression at the host-agent interface. Infect Immun, 70:3382-3388, 2002.
Hodzic E, Borjesson D, Feng S, Barthold SW. Acquisition dynamics of Borrelia burgdorferi and the agent of human granulocytic ehrlichiosis at the host-vector interface. Vector Borne & Zoonotic Diseases, 1:149-158, 2001.
Director, Center for Comparative Medicine
Member, School of Medicine Basic Sciences Council
Member, School of Veterinary Medicine Academic Council
Member, Research Advisory Committee, California National Primate Research Center
Member, Admissions Advisory Committee, School of Veterinary Medicine
UC Davis Comparative Pathology Graduate Group
UC Davis Microbiology Graduate Group
UC Davis Immunology Graduate Group
Director, NIH (RR-07038) Comparative Medical Science Training Program
Faculty of Discussants, C.L. Davis Foundation
Chair, Institute for Laboratory Animal Research Council, NRC
Member, Institute of Medicine, National Academies
Current Research Support
RO1 AI26815. Mouse Model of Lyme Borreliosis 07/01/88-11/30/12
R01 AI073911. Humoral Responses to Lyme Borreliosis: A Mouse Model. 02/01/08-01/31013
National Research Fund for Tick-Borne Diseases: Borrelia burgdorferi Persistence Following Anibiotic Treatment. 05/01/09-04/30/10