Faculty ProfilesJane E Koehler, MD
513 Parnassus Ave
San Francisco, CA 94143
Research in my laboratory is focused on defining the clinical spectrum, microbiology, and molecular pathogenesis of the emerging pathogen Bartonella. Our research encompasses both translational and basic investigation. B. henselae and B. 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.
Education and Training
|Location||Degree or Training||Specialty||Date|
|University of California, San Francisco||Research Post-Doc Fellow||Infectious Diseases||1992|
|University of California, San Francisco||Clinical Fellow||Infectious Diseases||1988|
|University of California, San Francisco||Intern and Resident||Internal Medicine||1987|
|George Washington University||M.D.||School of Medicine||1984|
|University of California, Berkeley||M.A.||Microbiology and Immunology||1978|
Bartonella virulence gene expression and regulation, identification of new Bartonella speciesAwards and Honors
Elected Fellow, Infectious Diseases Society of America, 2012
Essential Core Teaching Award for Outstanding Lecture, UCSF School of Medicine Class of 2014, 2012
Walter E. Stamm Mentor Award, Infectious Diseases Society of America, 2011
Chancellor’s Award for the Advancement of Women, UCSF, 2008
Smadel Lecturer (named scientific award lecture), Infectious Diseases Society of America, 2008
Clinical Scientist Award in Translational Research, Burroughs Wellcome Fund, 2003-2008
Fellow, Executive Leadership in Academic Medicine (ELAM), Executive Leadership in Academic Medicine (ELAM), 2002-2003
Ann Sullivan Baker Visiting Professorship, Massachusetts General Hospital, Harvard Medical School, 2001
Elected Member, American Society for Clinical Investigation, American Society for Clinical Investigation, 1997
ICAAC Young Investigator Award, American Society for Microbiology, 1994
Pew Scholar in the Biomedical Sciences, Pew Biomedical Scholars Program, 1994-1998
Marilyn Coward Memorial Inaugural Lecturer, American Society for Microbiology, No CA, 1993
Scholarship Achievement Citation, American Medical Women's Association, 1984
Hyman R. Posin Prize in Neurology, George Washington University School of Medicine, 1984
Huron W. Lawson Award in Obstetrics and Gynecology, George Washington University School of Medicine, 1984
Graduation with Distinction, George Washington University School of Medicine, 1984
Alpha Omega Alpha Honor Medical Society, Junior Year Initiate, Alpha Omega Alpha Honor Medical Society, George Washington University School of Medicine, 1983
Related Web Sites
|Project Title||Project Number||Fiscal Year|
|California National Primate Research Center||P51RR000169||2015|
Huwyler C, Heiniger N, Chomel BB, Kim M, Kasten RW, Koehler JE. Dynamics of Co-Infection with Bartonella henselae Genotypes I and II in Naturally Infected Cats: Implications for Feline Vaccine Development. Microb Ecol. 2017 Aug; 74(2):474-484.
Kim JH, Previte DJ, Yoon KS, Murenzi E, Koehler JE, Pittendrigh BR, Lee SH, Clark JM. Comparison of the proliferation and excretion of Bartonella quintana between body and head lice following oral challenge. Insect Mol Biol. 2017 Jun; 26(3):266-276.
Molia S, Kasten RW, Stuckey MJ, Boulouis HJ, Allen J, Borgo GM, Koehler JE, Chang CC, Chomel BB. 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. Epidemiol Infect. 2016 Nov; 144(15):3237-3243.
Chomel BB, Molia S, Kasten RW, Borgo GM, Stuckey MJ, Maruyama S, Chang CC, Haddad N, Koehler JE. Isolation of Bartonella henselae and Two New Bartonella Subspecies, Bartonellakoehlerae Subspecies boulouisii subsp. nov. and Bartonella koehlerae Subspecies bothieri subsp. nov. from Free-Ranging Californian Mountain Lions and Bobcats. PLoS One. 2016; 11(3):e0148299.
Lee SA, Plett SK, Luetkemeyer AF, Borgo GM, Ohliger MA, Conrad MB, Cookson BT, Sengupta DJ, Koehler JE. Bartonella quintana Aortitis in a Man with AIDS, Diagnosed by Needle Biopsy and 16S rRNA Gene Amplification. J Clin Microbiol. 2015 Aug; 53(8):2773-6.
Gandhi, T.N., L.N. Slater, D.F. Welch, and J.E. Koehler. 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; 2649-2663 .
Chomel BB, Kasten RW, Stuckey MJ, Breitschwerdt EB, Maggi RG, Henn JB, Koehler JE, Chang CC. Experimental infection of cats with Afipia felis and various Bartonella species or subspecies. Vet Microbiol. 2014 Aug 27; 172(3-4):505-10.
Previte D, Olds BP, Yoon K, Sun W, Muir W, Paige KN, Lee SH, Clark J, Koehler JE, Pittendrigh BR. Differential gene expression in laboratory strains of human head and body lice when challenged with Bartonella quintana, a pathogenic bacterium. Insect Mol Biol. 2014 Apr; 23(2):244-54.
Abromaitis S, Koehler JE. The Bartonella quintana extracytoplasmic function sigma factor RpoE has a role in bacterial adaptation to the arthropod vector environment. J Bacteriol. 2013 Jun; 195(11):2662-74.
Koehler, J.E.. 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; 421-432.
Doyon JB, Sutton DA, Theodore P, Dhillon G, Jones KD, Thompson EH, Fu J, Wickes BL, Koehler JE, Schwartz BS. Rasamsonia argillacea pulmonary and aortic graft infection in an immune-competent patient. J Clin Microbiol. 2013 Feb; 51(2):719-22.
Roden JA, Wells DH, Chomel BB, Kasten RW, Koehler JE. Hemin binding protein C is found in outer membrane vesicles and protects Bartonella henselae against toxic concentrations of hemin. Infect Immun. 2012 Mar; 80(3):929-42.
Vigil A, Ortega R, Jain A, Nakajima-Sasaki R, Tan X, Chomel BB, Kasten RW, Koehler JE, Felgner PL. Identification of the feline humoral immune response to Bartonella henselae infection by protein microarray. PLoS One. 2010 Jul 06; 5(7):e11447.
Koehler, J.E. and D.A. Relman. Antimicrobial Therapy and Vaccines (Yu, V.L., R. Weber and D. Raoult, Eds). Bartonella species. 2010.
Chomel BB, Henn JB, Kasten RW, Nieto NC, Foley J, Papageorgiou S, Allen C, Koehler JE. Dogs are more permissive than cats or guinea pigs to experimental infection with a human isolate of Bartonella rochalimae. Vet Res. 2009 Jul-Aug; 40(4):27.
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. Molecular epidemiology of feline and human Bartonella henselae isolates. Emerg Infect Dis. 2009 May; 15(5):813-6.
Chomel BB, Boulouis HJ, Breitschwerdt EB, Kasten RW, Vayssier-Taussat M, Birtles RJ, Koehler JE, Dehio C. Ecological fitness and strategies of adaptation of Bartonella species to their hosts and vectors. Vet Res. 2009 Mar-Apr; 40(2):29.
Henn JB, Gabriel MW, Kasten RW, Brown RN, Koehler JE, MacDonald KA, Kittleson MD, Thomas WP, Chomel BB. Infective endocarditis in a dog and the phylogenetic relationship of the associated "Bartonella rochalimae" strain with isolates from dogs, gray foxes, and a human. J Clin Microbiol. 2009 Mar; 47(3):787-90.
Koehler, J.E.. 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; 425-436.
Koehler, J.E. AIDS Therapy (Dolin, R., H. Masur and M. Saag, Eds). Bartonellosis. 2008; 757-764.
MacKichan JK, Gerns HL, Chen YT, Zhang P, Koehler JE. A SacB mutagenesis strategy reveals that the Bartonella quintana variably expressed outer membrane proteins are required for bloodstream infection of the host. Infect Immun. 2008 Feb; 76(2):788-95.
Eremeeva ME, Gerns HL, Lydy SL, Goo JS, Ryan ET, Mathew SS, Ferraro MJ, Holden JM, Nicholson WL, Dasch GA, Koehler JE. Bacteremia, fever, and splenomegaly caused by a newly recognized bartonella species. N Engl J Med. 2007 Jun 07; 356(23):2381-7.
Boonjakuakul JK, Gerns HL, Chen YT, Hicks LD, Minnick MF, Dixon SE, Hall SC, Koehler JE. Proteomic and immunoblot analyses of Bartonella quintana total membrane proteins identify antigens recognized by sera from infected patients. Infect Immun. 2007 May; 75(5):2548-61.
Zhang P, Chomel BB, Schau MK, Goo JS, Droz S, Kelminson KL, George SS, Lerche NW, Koehler JE. A family of variably expressed outer-membrane proteins (Vomp) mediates adhesion and autoaggregation in Bartonella quintana. Proc Natl Acad Sci U S A. 2004 Sep 14; 101(37):13630-5.
Koehler JE, Sanchez MA, Tye S, Garrido-Rowland CS, Chen FM, Maurer T, Cooper JL, Olson JG, Reingold AL, Hadley WK, Regnery RR, Tappero JW. Prevalence of Bartonella infection among human immunodeficiency virus-infected patients with fever. Clin Infect Dis. 2003 Aug 15; 37(4):559-66.
Yamamoto K, Chomel BB, Kasten RW, Hew CM, Weber DK, Lee WI, Koehler JE, Pedersen NC. 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. Vet Microbiol. 2003 Mar 20; 92(1-2):73-86.
Koehler, J.E. and D.A. Relman. HIV Clinical Manual (Singh, N., R.W. Shafer and S. Swindells, Eds). Bartonella species. 2003; 278-281.
Koehler, J.E.. AIDS Therapy (Dolin, R., H. Masur and M.S. Saag, Eds). Bartonellosis. 2003; 491-497.
Chang CC, Chomel BB, Kasten RW, Tappero JW, Sanchez MA, Koehler JE. Molecular epidemiology of Bartonella henselae infection in human immunodeficiency virus-infected patients and their cat contacts, using pulsed-field gel electrophoresis and genotyping. J Infect Dis. 2002 Dec 15; 186(12):1733-9.
Yamamoto K, Chomel BB, Kasten RW, Hew CM, Weber DK, Lee WI, Droz S, 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. J Clin Microbiol. 2002 Feb; 40(2):466-74.
Koehler, J.E., Relman, D.A.. Antimicrobial Therapy and Vaccines (Yu, V.L., R. Weber and D. Raoult, Eds). Bartonella species. 2002; 925-931.
Park SY, Kelminson KL, Lee AK, Zhang P, Warner RE, Rehkopf DH, Calderwood SB, Koehler JE. Identification, characterization, and functional analysis of a gene encoding the ferric uptake regulation protein in Bartonella species. J Bacteriol. 2001 Oct; 183(19):5751-5.
Koehler, J.E.. Persistent Bacterial Infections (Nataro, J.P., M.J. Blaser and S. Cunningham-Rundles, Eds). Bartonella Species. 2000; 339-353.
Matar GM, Koehler JE, Malcolm G, Lambert-Fair MA, Tappero J, Hunter SB, Swaminathan B. Identification of Bartonella species directly in clinical specimens by PCR-restriction fragment length polymorphism analysis of a 16S rRNA gene fragment. J Clin Microbiol. 1999 Dec; 37(12):4045-7.
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; 411-428.
Koehler, J.E.. AIDS Therapy (Dolin, R., H. Masur and M.S. Saag, Eds). Bartonellosis. 1999.
Koehler, J.E.. The AIDS Knowledge Base (Cohen, P.T., M.A. Sande and P.A. Volberding, Eds). Bartonella: Bacillary angiomatosis and bacillary peliosis agents. 1999; 625-635 .
Koehler, J.E., Relman, D.A.. Antimicrobial Therapy and Vaccines (Yu, V.L., T.C. Merigan, Jr. and S.L. Barriere, Eds). Bartonella species. 1999; 578-583.
George TI, Manley G, Koehler JE, Hung VS, McDermott M, Bollen A. 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. J Neurosurg. 1998 Oct; 89(4):640-4.
Warren K, Goldstein E, Hung VS, Koehler JE, Richardson W. Use of retinal biopsy to diagnose Bartonella (formerly Rochalimaea) henselae retinitis in an HIV-infected patient. Arch Ophthalmol. 1998 Jul; 116(7):937-40.
Spach, D.H., Koehler, J.E.. Infectious Disease Clinics of North America: Emerging Infectious Diseases (Conte, J. and J.M. Hughes, Eds). Bartonella-associated infections. 1998; 137-155.
Koehler, J.E.. Emerging Infections I (Scheld, W.M., D. Armstrong and J.M. Hughes, Eds). Bartonella: An emerging human pathogen. 1998; 147-163.
Koehler JE, Sanchez MA, Garrido CS, Whitfeld MJ, Chen FM, Berger TG, Rodriguez-Barradas MC, LeBoit PE, Tappero JW. Molecular epidemiology of bartonella infections in patients with bacillary angiomatosis-peliosis. N Engl J Med. 1997 Dec 25; 337(26):1876-83.
Abbott RC, Chomel BB, Kasten RW, Floyd-Hawkins KA, Kikuchi Y, Koehler JE, Pedersen NC. Experimental and natural infection with Bartonella henselae in domestic cats. Comp Immunol Microbiol Infect Dis. 1997 Jan; 20(1):41-51.
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. 1997; 363-380.
Chomel BB, Kasten RW, Floyd-Hawkins K, Chi B, Yamamoto K, Roberts-Wilson J, Gurfield AN, Abbott RC, Pedersen NC, Koehler JE. Experimental transmission of Bartonella henselae by the cat flea. J Clin Microbiol. 1996 Aug; 34(8):1952-6.
Liston TE, Koehler JE. Granulomatous hepatitis and necrotizing splenitis due to Bartonella henselae in a patient with cancer: case report and review of hepatosplenic manifestations of bartonella infection. Clin Infect Dis. 1996 Jun; 22(6):951-7.
Mohle-Boetani JC, Koehler JE, Berger TG, LeBoit PE, Kemper CA, Reingold AL, Plikaytis BD, Wenger JD, Tappero JW. Bacillary angiomatosis and bacillary peliosis in patients infected with human immunodeficiency virus: clinical characteristics in a case-control study. Clin Infect Dis. 1996 May; 22(5):794-800.
Koehler, J.E.. Advances in Pediatric Infectious Diseases (Aronoff, S.C., W.T. Hughes, S. Kohl, W.T. Speck and E.R. Wald, Eds). Bartonella infections. 1996; 11:1-27.
Tappero, J.W., Koehler, J.E.. 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; 1023-1029.
Chomel BB, Abbott RC, Kasten RW, Floyd-Hawkins KA, Kass PH, Glaser CA, Pedersen NC, Koehler JE. Bartonella henselae prevalence in domestic cats in California: risk factors and association between bacteremia and antibody titers. J Clin Microbiol. 1995 Sep; 33(9):2445-50.
Rodriguez-Barradas MC, Hamill RJ, Houston ED, Georghiou PR, Clarridge JE, Regnery RL, Koehler JE. Genomic fingerprinting of Bartonella species by repetitive element PCR for distinguishing species and isolates. J Clin Microbiol. 1995 May; 33(5):1089-93.
Koehler, J.E. and J.W. Tappero. AIDS Commentary: Bacillary angiomatosis. Clinical Infectious Diseases. 1995; 17:97-102.
Koehler, J.E.. The Medical Management of AIDS (Sande, M.A. and P.A. Volberding, Eds). Bacillary angiomatosis and HIV infection. 1995; 494-511.
Koehler, J.E., Tappero, J.W.. 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; 6.3-1 to 6.3-17.
Tappero JW, Koehler JE, Berger TG, Cockerell CJ, Lee TH, Busch MP, Stites DP, Mohle-Boetani J, Reingold AL, LeBoit PE. Bacillary angiomatosis and bacillary splenitis in immunocompetent adults. Ann Intern Med. 1993 Mar 01; 118(5):363-5.
Tappero JW, Mohle-Boetani J, Koehler JE, Swaminathan B, Berger TG, LeBoit PE, Smith LL, Wenger JD, Pinner RW, Kemper CA. The epidemiology of bacillary angiomatosis and bacillary peliosis. JAMA. 1993 Feb 10; 269(6):770-5.
Koehler JE, Burgess RR, Thompson NE, Stephens RS. Chlamydia trachomatis RNA polymerase major sigma subunit. Sequence and structural comparison of conserved and unique regions with Escherichia coli sigma 70 and Bacillus subtilis sigma 43. J Biol Chem. 1990 Aug 05; 265(22):13206-14.
Erlich KS, Jacobson MA, Koehler JE, Follansbee SE, Drennan DP, Gooze L, Safrin S, Mills J. Foscarnet therapy for severe acyclovir-resistant herpes simplex virus type-2 infections in patients with the acquired immunodeficiency syndrome (AIDS). An uncontrolled trial. Ann Intern Med. 1989 May 01; 110(9):710-3.
Koehler, J.E., Chaisson, R.E.. Opportunistic Infections in Patients with the Acquired Immunodeficiency Syndrome (Leoung, G. and J. Mills, Eds). Bacterial infections in acquired immunodeficiency syndrome. 1989; 231-249.
Koehler JE, LeBoit PE, Egbert BM, Berger TG. Cutaneous vascular lesions and disseminated cat-scratch disease in patients with the acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. Ann Intern Med. 1988 Sep 15; 109(6):449-55.
Law PY, Koehler JE, Loh HH. Comparison of opiate inhibition of adenylate cyclase activity in neuroblastoma N18tG2 and neuroblastoma x glioma NG108-15 hybrid cell lines. Mol Pharmacol. 1982 Mar; 21(2):483-91.
Law, PY, JE Koehler, HH Loh. Enkephalin inhibition of the adenylate cyclase activity in neuroblastoma x glioma hybrid NG108-15 cells. Attenuation by phospholipase C. Federation Proceedings. 1980; 39:385.