Emir Hodzic, DVM, MSc, PhD
Director, Real-Time PCR Research & Diagnostics Core Facility
School of Veterinary Medicine
Department of Medicine and Epidemiology
University of California, Davis, CA
Post-treatment persistence of antimicrobial tolerant replicatively-attenuated Borrelia burgdorferi in a mouse model
Dr. Hodzic graduated in 1978 from the School of Veterinary Medicine at University of Sarajevo, Bosnia and Herzegovina, then received Master (1984) and PhD (1990) degrees from the same university in the area of Microbiology and Molecular biology. In 1992, his career was abruptly stopped for two years as a result of the war in his home country of Bosnia and Herzegovina. After resettlement to the U.S., Dr. Hodzic earned a position at Yale University as a postdoctoral fellow. In 1997, he was awarded a faculty position at the Center for Comparative Medicine, at UC Davis. Currently, Dr. Hodzic is the Director of the Real-time PCR Research and Diagnostics Core Facility at UC Davis. After relocating to the U.S., his research has focused on using animal models to investigate the interaction of Borrelia burgdorferi, the agent of Lyme borreliosis, and Anaplasma phagocytophilum, the agent of human granulocytic anaplasmosis, with tick vectors and mammalian hosts. He developed a mouse model of Anaplasma infection that mimics many of the same aspects as seen in humans. While working on B. burgdorferi persistence, Dr. Hodzic revealed groundbreaking evidence of B. burgdorferi in collagenous tissues after antimicrobial therapy. Most recent findings confirmed previous studies, in which B. burgdorferi could not be cultured from tissues, but B. burgdorferi DNA (BbDNA) was detectable in tissues months, and even a year after completion of treatment. In addition, there was a resurgence of spirochete BbDNA in multiple tissues at 12 months, with BbDNA copy levels nearly equivalent to those found in saline-treated mice. Despite the continued non-cultivable state, RNA transcription of multiple B. burgdorferi genes was detected in host tissues, BbDNA was acquired by xenodiagnostic ticks, and spirochetal forms could be visualized within ticks and mouse tissues by. During his career, Dr. Hodzic has collaborated with other researchers and produced numerous peer-reviewed publications from each project.
Conference Lecture Summary
A basic feature of infection caused by Borrelia burgdorferi, the etiological agent of Lyme borreliosis, is that persistent infection is the rule in its many hosts. The ability to persist and evade host immune clearance poses a challenge to effective antimicrobial treatment. A link between therapy failure and the presence of persister cells has started to emerge. There is growing experimental evidence that viable, but non-cultivable spirochetes persist following treatment with several different antimicrobial agents. In earlier studies, we have detected a population of B. burgdorferi in tissues after antimicrobial therapy in mice treated with ceftriaxone, doxycycline, or tigecycline at various intervals of infection, and tissues were tested at intervals after treatment. Specific BbDNA was consistently detected in tissues of mice at late at 12 months after treatment, but culture was consistently negative. Spirochetes could be visualized by immunohistochemistry in tissues rich in collagen of mice after treatment. Antimicrobial-tolerant persistent spirochetes could be acquired by larval ticks; after blood meal ticks molt into next life stage, nymps and adults, which remained BbDNA-positive; nymphs transmitted BbDNA to recipient immunocompromised mice with multiple tissues PCR-positive, with no obvious inflammation being observed; and allografts from treated mice transplanted into recipient immunocompromised mice transferred BbDNA to recipient mice. Transcriptional activity of BbDNA-positive tissues was detected for several target genes, suggesting their viability. In the next study we detected the subpopulation of viable, antimicrobial-tolerant, but slow dividing and persistent spirochetes of B. burgdorferi resurged in mice 12 months after treatment and re-disseminated into multiple tissues. Isolation of these spirochetes has been unsuccessful. In the most current study, we utilized a disease-susceptible (C3H/HeN) and disease-resistant (C57BL/6) mouse strain infected with B. burgdorferi strains N40 and B31, to confirm the generality of this phenomena as well as to assess the persisters’ clinical relevance. The status of infection was evaluated at 12 and 18-months after treatment. The results demonstrated that persistent spirochetes remain viable for up to 18 months following treatment, as well as being non-cultivable. The clinical relevance of persistent spirochetes and their resurgence beyond 18 months following antimicrobial treatment compels further studies utilizing other animal models.