Stephen W. Barthold, DVM, PhD
Distinguished Professor Emeritus
SVM: Veterinary Pathology, Microbiology and Immunology
SOM: Medical Pathology and Laboratory Medicine
University of California, Davis
County Rd. 98 & Hutchison Dr.
Davis, CA 95616
Phone: (530) 752-7913
Research interest: Borrelia burgdorferi
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 was engaged in research on host-agent interactions during the course of persistent infections with Borrelia burgdorferi (the agent of Lyme disease),. His group utilized 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.
Antibiotic Tolerance of Borrelia burgdorferi
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.
Humoral Responses to Lyme Borreliosis
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 Former 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.
Hastey CJ, Ochoa J, Olsen KJ, Barthold SW, Baumgarth N. MyD88- and TRIF-independent induction of type I interferon drives naive B cell accumulation but not loss of lymph node architecture in Lyme disease. Infect Immun. 2014 Apr;82(4):1548-58. doi: 10.1128/IAI.00969-13. Epub 2014 Jan 22. PubMed PMID: 24452685; PubMed Central PMCID: PMC3993384.
Hodzic E, Imai D, Feng S, Barthold SW. Resurgence of persisting non-cultivable Borrelia burgdorferi following antibiotic treatment in mice. PLoS One. 2014 Jan 23;9(1):e86907. doi: 10.1371/journal.pone.0086907. eCollection 2014. PubMed PMID: 24466286; PubMed Central PMCID: PMC3900665.
Hodzic E, Feng S, Barthold SW. Assessment of transcriptional activity of Borrelia burgdorferi and host cytokine genes during early and late infection in a mouse model. Vector Borne Zoonotic Dis. 2013 Oct;13(10):694-711. doi: 10.1089/vbz.2012.1189. Epub 2013 Aug 9. PubMed PMID: 23930938; PubMed Central PMCID: PMC3787468.
Imai DM, Feng S, Hodzic E, Barthold SW. Dynamics of connective-tissue localization during chronic Borrelia burgdorferi infection. Lab Invest. 2013 Aug;93(8):900-10. doi: 10.1038/labinvest.2013.81. Epub 2013 Jun 24. PubMed PMID: 23797360.
Whary et al. The Laboratory Mouse. In: Laboratory Animal Medicine. 3rd Edition, in press, 2014.
Dr. Barthold is currently retired. Please contact him via email to inquire as to past laboratory staff members.