Jane E Koehler, MD
Professor
Medicine
School of Medicine

quintana are fastidious, gram-negative bacteria that cause bacillary angiomatosis lesions, which are unique, potentially lethal, vascular proliferative lesions affecting HIV-infected patients. Relapsing and/or persistent bloodstream infection is a more frequent manifestation of Bartonella infection. We are investigating the molecular mechanisms associated with two virulence phenotypes of Bartonella: relapsing and persistent bloodstream infection; and hemin (iron)-regulation of gene expression. Finally, we are characterizing the mechanisms involved in differential transcription of virulence genes in the two environmental niches encountered by Bartonella, e.g., in the gut of the poikilothermic body louse vector, and in the bloodstream of the homeothermic mammalian host.

1) Mechanisms of Persistent Bloodstream Infection Bartonellae can persist in the bloodstream of some mammalian hosts indefinitely (even years in humans) and reach levels of 106 cfu/ml blood, often with minimal apparent systemic effects. Our animal model made possible the analysis of serial Bartonella bloodstream isolates, to detect sequential alteration(s) in surface structural components of Bartonella that confer the ability to adapt and persist in the host. We evaluated outer membrane proteins (OMP) from blood isolates over time as infection persisted/relapsed, and observed a family of three OMP that were present in the inoculum strain, but which were absent in later bloodstream isolates from the same animal.

We determined that these variably-expressed OMP (Vomp) are chromosomally encoded by four tandemly arranged, highly homologous genes that undergo phase variation, gene duplication or deletion, and high frequency recombination. The Vomp are members of the newly described family of trimeric autotransporter adhesins and are associated with several critical virulence properties, including host cell adhesion and autoaggregation. Each Vomp binds a different, unique substrate; binding specificity is determined by the major variable sequence at the tip of each Vomp adhesin. We are currently investigating the Vomp architecture (homotrimeric vs. heterotrimeric) on the surface of Bartonella, and the mechanisms involved in transport of the Vomp to the bacterial surface. The Vomp are essential virulence factors (the vomp null mutant is avirulent in vivo), and understanding the function and structure of the Vomp will provide important clues about the interactions between the host and Bartonella, including the mechanisms of persistence in the human bloodstream.

2) Regulation of Virulence Gene Expression by Environmental Cues A second research emphasis in my laboratory is the regulation of virulence gene expression by environmental cues. BQ is a Gram-negative bacillus that occupies two very disparate niches: the bloodstream of the homeothermic human reservoir (37°C, very low hemin/Fe level), and the gut of the poikilothermic body louse arthropod vector (28°C, toxic hemin level). The ability of BQ to survive in the body louse is essential for transmission from the body louse vector to humans, the only known host. We identified genes that are up regulated only at the lower temperature of the body louse, including several genes that control iron acquisition by Bartonella.

a) Virtually all bacteria protect themselves from environmental stressors by activating a general stress response (GSR). After BQ is taken up during a blood meal, the bacterium utilizes a unique system of transcriptional regulation to survive the decreased temperature (28°C) and heme-toxic (10 mM) gut in the body louse. We identified an alternative RNA polymerase sigma subunit that is central to the Bartonella GSR that is elicited at body louse temperature. The mechanism of GSR activation has been studied at the molecular level in a collaboration between the SSGCID at U WA. In collaboration with Dr. John Clark at UMass, we also began studying the regulation of BQ gene expression in wild type lice from a colony that can be fed a blood meal spiked with BQ wild type and mutant strains. This has enabled us to identify the signal cascade that activates the GSR after uptake of BQ into the body louse, as well as to identify genes that are critical for BQ survival in the arthropod host. Studying BQ virulence gene expression and regulation in the body louse enables us to define critical interactions between arthropod vector and bacterium that ultimately could provide targets for interrupting the transmission cycle to humans.

b) Iron is an essential growth factor for virtually all bacteria, and the ability to acquire iron from the environment governs potential virulence and pathogenicity in many bacterial organisms (e.g., iron influences the expression of the diphtheria toxin by Corynebacterium diphtheriae). Acquisition of iron and expression of many virulence factors are under transcriptional regulation by the fur gene product, the ferric uptake regulation (Fur) protein, and its homodimeric complex. At sufficient intracellular iron levels, the co-repressors Fur and Fe2+ bind a consensus sequence in the promoter region of genes regulated by Fur, controlling expression of genes encoding iron-scavenging proteins and toxins. Bartonella is a hemophilic bacterium that is not free-living but is restricted to two alternate niches: the iron-rich gut of obligately hematophagous arthropods, or the severely iron-restricted bloodstream of mammals. Iron availability provides a signal to Bartonella indicating which niche (arthropod vector or mammalian reservoir) it occupies, and it is probable that the Fur protein is responsible for global regulation of genes required in each specific host environment. These studies will enable us to characterize the vector- and host-induced responses that facilitate the infection and persistence of Bartonella in humans.

• Copycat.
  The New England journal of medicine 2021 Dietz BW, Winston LG, Koehler JE, Margaretten M
• Bartonella type IV secretion effector BepC induces stress fiber formation through activation of GEF-H1.
  PLoS pathogens 2021 Wang C, Zhang H, Fu J, Wang M, Cai Y, Ding T, Jiang J, Koehler JE, Liu X, Yuan C
• Bartonella quintana type IV secretion effector BepE-induced selective autophagy by conjugation with K63 polyubiquitin chain.
  Cellular microbiology 2018 Wang C, Fu J, Wang M, Cai Y, Hua X, Du Y, Yang Z, Li Y, Wang Z, Sheng H, Yin N, Liu X, Koehler JE, Yuan C
• Comparison of the proliferation and excretion of Bartonella quintana between body and head lice following oral challenge.
  Insect molecular biology 2017 Kim JH, Previte DJ, Yoon KS, Murenzi E, Koehler JE, Pittendrigh BR, Lee SH, Clark JM
• Isolation of Bartonella henselae, Bartonella koehlerae subsp. koehlerae, Bartonella koehlerae subsp. bothieri and a new subspecies of B. koehlerae from free-ranging lions (Panthera leo) from South Africa, cheetahs (Acinonyx jubatus) from Namibia and captive cheetahs from California.
  Epidemiology and infection 2016 Molia S, Kasten RW, Stuckey MJ, Boulouis HJ, Allen J, Borgo GM, Koehler JE, Chang CC, Chomel BB
• Bartonella quintana Aortitis in a Man with AIDS, Diagnosed by Needle Biopsy and 16S rRNA Gene Amplification.
  Journal of clinical microbiology 2015 Lee SA, Plett SK, Luetkemeyer AF, Borgo GM, Ohliger MA, Conrad MB, Cookson BT, Sengupta DJ, Koehler JE
• Mandell, Douglas, and Bennett's Principles and Practice of Infectious Disease (Bennett, J.E., R. Dolin, and M.J. Blaser, Eds)
  Chapter 236: Bartonella, including cat-scratch disease 2015 Gandhi, T.N., L.N. Slater, D.F. Welch, and J.E. Koehler
• Experimental infection of cats with Afipia felis and various Bartonella species or subspecies.
  Veterinary microbiology 2014 Chomel BB, Kasten RW, Stuckey MJ, Breitschwerdt EB, Maggi RG, Henn JB, Koehler JE, Chang CC
• Sande's HIV/AIDS Medicine: Medical Management of AIDS 2013 (Volberding, P.A., W.C. Greene, and J.M.A. Lange, Eds)
  Bartonella infections in HIV-infected individuals 2013 Koehler, J.E.
• Rasamsonia argillacea pulmonary and aortic graft infection in an immune-competent patient.
  Journal of clinical microbiology 2012 Doyon JB, Sutton DA, Theodore P, Dhillon G, Jones KD, Thompson EH, Fu J, Wickes BL, Koehler JE, Schwartz BS
• Chapter 33 Bartonella infections in HIV-infected individuals.
  Sande\u0027s HIV/AIDS Medicine 2012 Jane E. Koehler
• Antimicrobial Therapy and Vaccines (Yu, V.L., R. Weber and D. Raoult, Eds)
  Bartonella species 2010 Koehler, J.E. and D.A. Relman
• Dogs are more permissive than cats or guinea pigs to experimental infection with a human isolate of Bartonella rochalimae.
  Veterinary research 2009 Chomel BB, Henn JB, Kasten RW, Nieto NC, Foley J, Papageorgiou S, Allen C, Koehler JE
• Molecular epidemiology of feline and human Bartonella henselae isolates.
  Emerging infectious diseases 2009 Bouchouicha R, Durand B, Monteil M, Chomel BB, Berrich M, Arvand M, Birtles RJ, Breitschwerdt EB, Koehler JE, Maggi R, Maruyama S, Kasten R, Petit E, Boulouis HJ, Haddad N
• Ecological fitness and strategies of adaptation of Bartonella species to their hosts and vectors.
  Veterinary research 2009 Chomel BB, Boulouis HJ, Breitschwerdt EB, Kasten RW, Vayssier-Taussat M, Birtles RJ, Koehler JE, Dehio C
• Infective endocarditis in a dog and the phylogenetic relationship of the associated "Bartonella rochalimae" strain with isolates from dogs, gray foxes, and a human.
  Journal of clinical microbiology 2008 Henn JB, Gabriel MW, Kasten RW, Brown RN, Koehler JE, MacDonald KA, Kittleson MD, Thomas WP, Chomel BB
• A survey of veterinarian involvement in zoonotic disease prevention practices.
  Journal of the American Veterinary Medical Association 2008 Lipton BA, Hopkins SG, Koehler JE, DiGiacomo RF
• AIDS Therapy (Dolin, R., H. Masur and M. Saag, Eds)
  Bartonellosis 2008 Koehler, J.E
• CHAPTER 38 Bartonella Infections in HIV-infected Individuals.
  Global HIV/AIDS Medicine 2008 Jane E. Koehler
• Global HIV/AIDS Medicine (P.A. Volberding, P.A., M.A. Sande, W.C. Greene, and J.M.A. Lange, Eds)
  Bartonella infections in HIV-infected individuals 2008 Koehler, J.E.
• Proteomic and immunoblot analyses of Bartonella quintana total membrane proteins identify antigens recognized by sera from infected patients.
  Infection and immunity 2007 Boonjakuakul JK, Gerns HL, Chen YT, Hicks LD, Minnick MF, Dixon SE, Hall SC, Koehler JE
• Infection and re-infection of domestic cats with various Bartonella species or types: B. henselae type I is protective against heterologous challenge with B. henselae type II.
  Veterinary microbiology 2003 Yamamoto K, Chomel BB, Kasten RW, Hew CM, Weber DK, Lee WI, Koehler JE, Pedersen NC
• AIDS Therapy (Dolin, R., H. Masur and M.S. Saag, Eds)
  Bartonellosis 2003 Koehler, J.E.
• HIV Clinical Manual (Singh, N., R.W. Shafer and S. Swindells, Eds)
  Bartonella species 2003 Koehler, J.E. and D.A. Relman
• Molecular epidemiology of Bartonella henselae infection in human immunodeficiency virus-infected patients and their cat contacts, using pulsed-field gel electrophoresis and genotyping.
  The Journal of infectious diseases 2002 Chang CC, Chomel BB, Kasten RW, Tappero JW, Sanchez MA, Koehler JE
• Experimental infection of domestic cats with Bartonella koehlerae and comparison of protein and DNA profiles with those of other Bartonella species infecting felines.
  Journal of clinical microbiology 2002 Yamamoto K, Chomel BB, Kasten RW, Hew CM, Weber DK, Lee WI, Droz S, Koehler JE
• Antimicrobial Therapy and Vaccines (Yu, V.L., R. Weber and D. Raoult, Eds)
  Bartonella species 2002 Koehler, J.E., Relman, D.A.
• Ocular bartonellosis.
  American journal of ophthalmology 2000 Cunningham ET, Koehler JE
• Bartonella Species.
  2000 Jane E. Koehler
• Persistent Bacterial Infections (Nataro, J.P., M.J. Blaser and S. Cunningham-Rundles, Eds)
  Bartonella Species 2000 Koehler, J.E.
• Identification of Bartonella species directly in clinical specimens by PCR-restriction fragment length polymorphism analysis of a 16S rRNA gene fragment.
  Journal of clinical microbiology 1999 Matar GM, Koehler JE, Malcolm G, Lambert-Fair MA, Tappero J, Hunter SB, Swaminathan B
• AIDS Therapy (Dolin, R., H. Masur and M.S. Saag, Eds)
  Bartonellosis 1999 Koehler, J.E.
• Antimicrobial Therapy and Vaccines (Yu, V.L., T.C. Merigan, Jr. and S.L. Barriere, Eds)
  Bartonella species 1999 Koehler, J.E., Relman, D.A.
• The AIDS Knowledge Base (Cohen, P.T., M.A. Sande and P.A. Volberding, Eds)
  Bartonella: Bacillary angiomatosis and bacillary peliosis agents 1999 Koehler, J.E.
• The Medical Management of AIDS (Sande, M.A. and P.A. Volberding, Eds)
  Bacillary angiomatosis and other unusual infections in HIV-infected individuals 1999 Koehler, J.E.
• Detection of Bartonella henselae by polymerase chain reaction in brain tissue of an immunocompromised patient with multiple enhancing lesions. Case report and review of the literature.
  Journal of neurosurgery 1998 George TI, Manley G, Koehler JE, Hung VS, McDermott M, Bollen A
• Use of retinal biopsy to diagnose Bartonella (formerly Rochalimaea) henselae retinitis in an HIV-infected patient.
  Archives of ophthalmology (Chicago, Ill. : 1960) 1998 Warren K, Goldstein E, Hung VS, Koehler JE, Richardson W
• Bartonella-associated infections.
  Infectious disease clinics of North America 1998 Spach DH, Koehler JE
• Emerging Infections I (Scheld, W.M., D. Armstrong and J.M. Hughes, Eds)
  Bartonella: An emerging human pathogen 1998 Koehler, J.E.
• Infectious Disease Clinics of North America: Emerging Infectious Diseases (Conte, J. and J.M. Hughes, Eds)
  Bartonella-associated infections 1998 Spach, D.H., Koehler, J.E.
• Bartonella: an Emerging Human Pathogen.
  1997 Jane E. Koehler
• Bacillary angiomatosis associated with myositis in a patient infected with human immunodeficiency virus.
  Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 1997 Whitfeld MJ, Kaveh S, Koehler JE, Mead P, Berger TG
• Experimental and natural infection with Bartonella henselae in domestic cats.
  Comparative immunology, microbiology and infectious diseases 1997 Abbott RC, Chomel BB, Kasten RW, Floyd-Hawkins KA, Kikuchi Y, Koehler JE, Pedersen NC
• The Medical Management of AIDS (Sande, M.A. and P.A. Volberding, Eds)
  Bacillary angiomatosis and other unusual infections in HIV infected individuals 1997 Koehler, J.E.
• Bacillary angiomatosis of the cervix and vulva in a patient with AIDS.
  Obstetrics and gynecology 1996 Long SR, Whitfeld MJ, Eades C, Koehler JE, Korn AP, Zaloudek CJ
• Granulomatous hepatitis and necrotizing splenitis due to Bartonella henselae in a patient with cancer: case report and review of hepatosplenic manifestations of bartonella infection.
  Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 1996 Liston TE, Koehler JE
• Advances in Pediatric Infectious Diseases (Aronoff, S.C., W.T. Hughes, S. Kohl, W.T. Speck and E.R. Wald, Eds)
  Bartonella infections 1996 Koehler, J.E.
• Bartonella infections.
  Advances in pediatric infectious diseases 1996 Koehler JE
• Cutaneous Medicine and Surgery (Arndt, K.A., P.E. LeBoit, J.K. Robinson and B.U. Wintroub, Eds)
  Bacillary angiomatosis, cat scratch disease, and Bartonellosis 1996 Tappero, J.W., Koehler, J.E.
• Bartonella-associated infections in HIV-infected patients.
  AIDS clinical care 1995 Koehler JE
• Intra-abdominal mass associated with gastrointestinal hemorrhage: a new manifestation of bacillary angiomatosis.
  Gastroenterology 1995 Koehler JE, Cederberg L
• Genomic fingerprinting of Bartonella species by repetitive element PCR for distinguishing species and isolates.
  Journal of clinical microbiology 1995 Rodriguez-Barradas MC, Hamill RJ, Houston ED, Georghiou PR, Clarridge JE, Regnery RL, Koehler JE
• AIDS Commentary: Bacillary angiomatosis
  Clinical Infectious Diseases 1995 Koehler, J.E. and J.W. Tappero
• The Medical Management of AIDS (Sande, M.A. and P.A. Volberding, Eds)
  Bacillary angiomatosis and HIV infection 1995 Koehler, J.E.
• Bacillary angiomatosis: investigation of the unusual interactions between Rochalimaea bacilli and endothelial cells.
  The Journal of laboratory and clinical medicine 1994 Koehler JE
• Rochalimaea henselae Infection: A New Zoonosis With the Domestic Cat as Reservoir.
  JAMA 1994 Jane E. Koehler, Carol A. Glaser, Jordan W. Tappero
• The AIDS Knowledge Base (Cohen, P.T., M.A. Sande and P.A. Volberding, Eds)
  Infections associated with HIV Disease: Rochalimaea (bacillary angiomatosis and bacillary peliosis agents) 1994 Koehler, J.E., Tappero, J.W.
• Bacillary angiomatosis and bacillary peliosis in patients infected with human immunodeficiency virus.
  Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 1993 Koehler JE, Tappero JW
• Rochalimaea infections.
  Annals of internal medicine 1993 Tappero JW, Koehler JE
• Interaction between the Chlamydia trachomatis histone H1-like protein (Hc1) and DNA.
  Journal of bacteriology 1993 Christiansen G, Pedersen LB, Koehler JE, Lundemose AG, Birkelund S
• Bacillary angiomatosis.
  AIDS clinical review 1993 Berger TG, Koehler JE
• Foscarnet therapy for severe acyclovir-resistant herpes simplex virus type-2 infections in patients with the acquired immunodeficiency syndrome (AIDS). An uncontrolled trial.
  Annals of internal medicine 1989 Erlich KS, Jacobson MA, Koehler JE, Follansbee SE, Drennan DP, Gooze L, Safrin S, Mills J
• Opportunistic Infections in Patients with the Acquired Immunodeficiency Syndrome (Leoung, G. and J. Mills, Eds)
  Bacterial infections in acquired immunodeficiency syndrome 1989 Koehler, J.E., Chaisson, R.E.
• Attenuation of enkephalin activity in neuroblastoma X glioma NG108-15 hybrid cells by phospholipases.
  Journal of neurochemistry 1983 Law PY, Griffin MT, Koehler JE, Loh HH
• Comparison of opiate inhibition of adenylate cyclase activity in neuroblastoma N18tG2 and neuroblastoma x glioma NG108-15 hybrid cell lines.
  Molecular pharmacology 1982 Law PY, Koehler JE, Loh HH
• Potentiation of opiate action in neuroblastoma N18TG2 cells by lipid incorporation.
  Molecular pharmacology 1982 Law PY, Nicksic TD, O'Rourke MA, Koehler JE, Herz A, Loh HH
• Demonstration and characterization of opiate inhibition of the striatal adenylate cyclase.
  Journal of neurochemistry 1981 Law PY, Wu J, Koehler JE, Loh HH
• Enkephalin inhibition of the adenylate cyclase activity in neuroblastoma x glioma hybrid NG108-15 cells. Attenuation by phospholipase C
  Federation Proceedings 1980 Law, PY, JE Koehler, HH Loh