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Mark Wooten, Ph.D.

Media Release:

Dr. Wooten's laboratory is interested in the host/pathogen interactions that lead to the development of two different infectious diseases: Lyme disease and melioidosis.

Lyme diseaseÌý(i.e. Lyme borreliosis) is a particularly interesting and complicated malady that involves two major events: 1) persistent infection of the host by the spirochetal bacteriumÌýBorrelia burgdorferiÌýand 2) the response of the host's innate immune defenses to the organism, which produces the inflammation that leads to the symptoms of Lyme disease.ÌýB. burgdorferiÌýis a highly infectious tick-borne obligate parasite that is especially adept at evading host defenses, disseminating widely via spirochetal motility through dense tissues, and persisting long-term within almost any tissue of the body. The infected host mounts a vigorous immune response to these spirochetes, as evidenced by the production of inflammatory soluble mediators and large quantities ofÌýB. burgdorferi-specific antibodies. Although passive transfer ofÌýB. burgdorferi-specific antiserum can prevent naive mice from subsequent infection, the immune response elicited during natural infection is usually unable to clear the infection, resulting in a persisting bacterial reservoir that can re-emerge under various conditions. This persistence in target tissues promotes prolonged stimulation of the host's innate defenses via interaction with endogenous bacterial lipoproteins, resulting in activation of immune pathways that appear to mediate much of the inflammatory pathology indicative of Lyme disease. Based on these dynamics, we are interested in utilizing the well-established murine model of Lyme disease to address the following areas:

• Identification of host immune cell types and mediators that are important in controlling the abilities ofÌýB. burgdorferiÌýto infect, invade, and persist in mammalian host tissues.
• Identification of host signaling pathways that modulate the inflammatory pathology that is characteristic for Lyme disease.
• Development of intravital microscopy techniques that allow direct visualization of the interactions betweenÌýB. burgdorferiÌýand different immune cell populations within the intact skin of infected mice.
• Assessment of the importance ofÌýB. burgdorferiÌýmotility and chemotaxis mechanisms for establishing acute and persistent infection in vertebrate and invertebrate hosts.

MelioidosisÌýis a human and animal disease that is caused by infection withÌýBurkholderia pseudomallei, which is endemic within different tropical and subtropical regions worldwide. Acute disease can lead to fulminant septicemia with mortality rates of 40-90%, even with vigorous antibiotic and supportive therapy. Chronic disease can also develop, with recrudescence occurring months to years after initial exposure. While there are some predisposing factors that make certain human populations more susceptible to developing this disease (e.g. diabetes, alcohol abuse, renal disease, etc.), exposure toÌýB. pseudomallei-containing aerosols is reported to have an LD₅₀Ìý≤100 organisms in mice. Based on these properties, B. pseudomallei is considered a Tier 1 select agent with the highest potential for misuse as a biological weapon. This organism is also quite resistant to many classes of antibiotics and there is currently no vaccine. Thus there is great interest in identifying targets for preventative and/or curative treatments for these infections.

Persistence within macrophages and other cell types appears to be central to the development of melioidosis, providing them an environment where they can proliferate and spread cell-to-cell via actin polymerization, thus enabling the bacteria to spread and evade humoral immune mediators. Relatively little is known about the molecular basis forÌýB. pseudomalleiÌývirulence, but it appears that these bacteria quickly escape the phagosome and evade intracellular killing, preventing bacterial clearance and generation of an effective adaptive immune response. A better understanding of the basic biology of macrophage/phagocyte subversion by this bacterium would greatly facilitate the development of preventative and curative treatments. We are interested in utilizing the recently-developed murine model of melioidosis to address the following areas:

• Identification of mechanisms that virulentÌýB. pseudomalleiÌýstrains utilize to circumvent efficient clearance by macrophages/neutrophils.
• Identification of outer membrane proteins expressed byÌýB. pseudomalleiÌýthat might serve as virulence factors/vaccine candidates.
• Testing vaccines in animal models to assess effectiveness and identify immune correlates of clearance.

Dr. Wooten received his Bachelors (Zoology/Chemistry; 1985) and Masters (Microbiology/Immunology; 1990) from the University of Arkansas (Fayetteville) under the supervision of Dr. Jim Saunders. He received his Ph.D. (Microbiology/Immunology; 1995) from the University of Mississippi Medical Center under the supervision of Dr. Jan Bly. He completed post-doctoral training at the University of Utah College of Medicine in the laboratory of Dr. Janis Weis. Dr. Wooten joined the Department of Medical Microbiology and Immunology at the University of Toledo College of Medicine in May 2001.

(Wooten Lab L-R: Laura Nejedlik, John Presloid, Caroline Lambert. Saad Moledina, Irum Syed, Dr. Mark Wooten)

Current Funding:

Development of an Attenuated Vaccine for the Prevention of Lyme Disease
USAMRAA (Department of Defense) Tick-Borne Disease Research Program
Period of support: 09/01/2021 - 08/31/2025
Principal Investigator: R. Mark Wooten

Factor H-Fc fusions as novel therapeutics for Burkholderia pseudomallei infections
National Institute of Allergy and Infectious Diseases (R41)
Period of Support: 08/01/23 - 07/31/25
Principal Investigator:Ìý R. Mark Wooten
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Representative Publications:

Breidenbach, J.D., B.W. French, T.T. Gordon, A.L Kleinhenz, F.K. Khalaf, J.C. Willey, J.R. Hammersley, R. M. Wooten, E. Crawford, N.N. Modyanov, D. Malhotra, S.T. Haller and D.J. Kennedy.Ìý Short-term, Low Dose Microcystin-LR Aerosol Induces Inflammatory Responses in Healthy Human Primary Airway Epithelium. In press

(2021). Microcystin-LR (MC-LR) triggers inflammatory responses in macrophages. Int J Mol Sci. 2021 Sep 14;22(18):9939. doi: 10.3390/ijms22189939. PMID:Ìý34576099.

(2021). Interactions between the pathogenic Burkholderia and the complement system: A review of potential immune evasion mechanisms.Ìý Front Cell Infect Microbiol. Ìý(2021) Sep 30;11:701362. doi: 10.3389/fcimb.2021.701362. PMID:Ìý34660335

(2020).Ìý Immune Response to Borrelia: Lessons from Lyme Disease Spirochetes. Curr Issues Mol Biol. DOI: 10.21775/cimb.042.145. PMID: 33289684.

. (2016).Ìý Borrelia burgdorferi CheY2 is dispensable for chemotaxis or motility but crucial for the enzootic life cycle of the spirochete.Ìý Infect Immun. 2016 Dec 29;85(1):e00264-16.doi:10.1128/IAI.00264-16

. (2016) TheÌýBorrelia burgdorferiÌýCheY3 response regulator is essential for chemotaxis and completion of its natural infection cycle.ÌýÌýMay 20. doi: 10.1111/cmi.12617

Ìý(2015) Spirochetal motility and chemotaxis in the natural enzootic cycle and development of Lyme disease. Curr Opin Microbiol 28: 106-113.

ÌýÌý(2015) ÌýMotor rotation is essential for the formation of the periplasmic flagellar ribbon, cellular morphology, and Borrelia burgdorferi persistence within Ixodes tick and murine hosts. ÌýInfect Immun. 2015 May;83(5):1765-77. doi: 10.1128/IAI.03097-14.

ÌýÌý(2014) ÌýDelineating the importance of serum opsonins and the bacterial capsule in affecting the uptake and killing of Burkholderia pseudomallei by murine neutrophils and macrohages. ÌýPLoS Negl Trop Dis. 2014 Aug 21;8(8):e2988. doi: 10.1371/journal.pntd.0002988.

ÌýÌý(2013) ÌýBorrelia burgdorferi elicited-IL-10 suppresses the production of inflammatory mediators, phagocytosis, and expression of co-stimulatory receptors by murine macrophages and/or dendritic cells. ÌýPLoS One. 2013 Dec 19;8(12):e84980. doi: 10.1371/journal.pone.0084980

Ìý (2013) ÌýSecretion of growth factors from macrophages when culture with microparticles. J. Biomed. Mater. Res., Part A. Nov; 101(11):3170-80.

Ìý (2012) ÌýCapsule influences the deposition of critical complement C3 levels required for the killing ofÌýBurkholderia pseudomalleiÌývia NADPH-oxidase induction by human neutrophils. PLoS One. 2012;7(12):e52276. doi: 10.1371/journal.pone.0052276.

, RG.Ìý (2012) ÌýHuman platelets efficiently kill IgG-opsonizedÌýE. coli. FEMS Immunol Med Microbiol. 65:78-83.

Ìý (2012) ÌýELISA-based measurement of antibody responses and PCR-based detection profiles can distinguish between active infection and early clearance ofÌýBorrelia burgdorferi. Clin Dev Immunol. 2012:138069.

, ER.Ìý (2010) Identification and characterization ofÌýBurkholderia malleiÌýandÌýB. pseudomalleiÌýadhesions for human respiratory epithelial cells. BMC Microbiol. 10:250-269.

.Ìý(2009) Roles for phagocytic cells and complement in controlling relapsing fever infection.Ìý J Leukoc Biol. 2009 Sep; 86(3):727-736.

Lazarus JJ, Kay MA, McCarter AL, Wooten RM.Ìý(2008) Viable Borrelia burgdorferi enhances interleukin-10 production and suppresses activation of murine macrophages.ÌýInfect Immun.ÌýMar;76:1153-1162.

*Ìý (2007)Ìý Borrelia burgdorferi binding of host complement regulator factor H is not required for efficient mammalian infection.Ìý Infect. Immun. 75:3131-3139.Ìý *These labs contributed equally to this manuscript.

Ìý(2007)Ìý The Moraxella catarrhalis autotransporter McaP is a conserved surface protein that mediates adherence to human epithelial cells through its N-terminal passenger domain.Ìý Infect. Immun.Ìý75:314-324.

Ìý(2006)Ìý Gene expression profiling reveals unique pathways associated with differential severity of lyme arthritis. ÌýJ. Immunol. 177:7930-7942.

Ìý(2006)Ìý IL-10 Deficiency promotes increased Borrelia burgdorferi clearance predominantly through enhanced innate immune responses.Ìý J Immunol. 177: 7076-7085.

(2006) Identification of aFrancisella tularensis LVS outer membrane protein that confers adherence to A549 human lung cells.Ìý FEMS Microbiol. Lett. 263:102-108.

Ìý(2004) Effects of vLsE Complementation on the Infectivity of Borrelia burgdorferi Lacking the Linear Plasmid Ip28-1. Infect. Immun., 72:6577-6585.

Ìý(2003) Effect of Complement Component C3 Deficiency on Experimental Lyme Borreliosis in Mice. Infect. Immun.,Ìý71:4432-4440.

Ìý(2003) Tripalmitoyl-S-Glyceryl-Cysteine-Dependent OspA Vaccination of Toll-Like Receptor 2-Deficient Mice Results in Effective Protection fromÌýBorrelia burgdorferiÌýChallenge. Infect. Immun.,Ìý71:3894-3900.

Ìý(2002) Toll-like receptor 2 plays a pivotal role in host defense and inflammatory response toÌýBorrelia burgdorferi. Vector Borne Zoonotic Dis,Ìý2:275-278.

. (2002) Toll-like receptor 2 is required for innate, but not acquired, host defense toÌýBorrelia burgdorferi. J. Immunol.,Ìý168:348-355.Ìý

Ìý(2001) Host-pathogen interactions promoting inflammatory Lyme arthritis: use of mouse models for dissection of disease processes. Curr. Opin. Micro.,Ìý4:274-279.Ìý

Ìý(2001) Resistance to Lyme disease in decorin-deficient mice. J. Clin. Invest.,Ìý107:845-852.Ìý

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Ìý(1999) Cutting Edge: Inflammatory signaling byÌýBorrelia burgdorferiÌýlipoproteins is mediated by toll-like receptor 2. J. Immunol.,Ìý163:2382-2386.Ìý

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