Charles R. Brown
Associate Professor

  • PhD, University of Chicago

    • BrownChar@missouri.edu

    Research emphasis: Dr. Brown's research interests: Immunopathogenesis of Lyme disease.

    Lyme borreliosis is a multisystemic disease caused by infection with the spirochete Borrelia burgdorferi. This tick-transmitted disease is the most common vector-borne illness in the United States with more than 18,000 new cases reported each year. Untreated, Lyme disease can result in a variety of clinical syndromes affecting the joints (Lyme arthritis), heart, skin, and nervous system. The mechanisms underlying the development of disease in this infection are currently unknown.

    My lab is focused on defining the immunological mechanisms responsible for either resistance or susceptibility to arthritis or carditis development following infection with B. burgdorferi. We use a mouse model of experimental infection in which C3H/He mice are susceptible, and C57BL/6 or DBA/2 mice are resistant to disease development. We have previously shown that although live spirochetes are required, differences within the host immune response are likely responsible for the development of pathology and lie within the innate immune response.

    There are two current projects in the lab:

    1. We have demonstrated that the recruitment of neutrophils into the infected joints is required for the development of Lyme arthritis. The chemokine KC is a neutrophil chemoattractant and is produced in high amounts in the joints of susceptible but not resistant mouse strains following infection with B. burgdorferi. Infection of mice deficient in the receptor for KC (CXCR2) does not result in development of arthritis, thus implicating KC-mediated recruitment of neutrophils in disease pathogenesis. Current experiments are exploring this further by: specifically blocking KC activity in susceptible mice using anti-KC antiserum; attempting to induce neutrophil recruitment in resistant mice by treating them with recombinant KC; and determining the cellular source of KC in joint tissue and why there is differential production of KC between different mouse strains in response to B. burgdorferi infection.

    2. Lyme arthritis is an inflammatory disease with periods of inflammation and resolution. Eicosanoids are powerful lipid mediators of inflammatory responses which may be involved in disease processes. Cyclooxygenase-2 (COX-2) is upregulated during injury or infection and catalyzes the production of prostaglandins from arachidonic acid. Several commercially available drugs block this response (celebrex, vioxx) and act to suppress the symptoms of chronic inflammation (pain and swelling), but their effect on underlying disease processes is currently unknown. Treatment of mice infected with B. burgdorferi with these compounds does not inhibit their ability to develop Lyme arthritis, but it does prevent its natural resolution. Current experiments are exploring the mechanism for this examining: altered prostaglandin production; increased leukotriene production; and decreased lipoxin production.

    Teaching: Veterinary Immunology, Mechanisms of Disease, Immunology (MMI), Advanced Immunology (MMI)

    Selected publications:

    Brown, C.R., and S.L. Reiner. 2000. Bone-marrow chimeras reveal hemopoietic and nonhemo-poietic control of resistance to experimental Lyme arthritis. J. Immunol. 165:1446-1452.

    Brown, C.R., and S.L. Reiner. 2000. Genes outside the major histocompatability complex control resistance and susceptibility to development of experimental Lyme arthritis. Med. Microbiol. Immunol. 198:85-90.

    Johnson, J.J., C.W. Roberts, C. Pope, F. Roberts, M.J. Kirisits, R. Estes, E. Mui, T. Krieger, C.R. Brown, J. Forman, and R. McLeod. 2002. In vitro correlates of Ld restricted resistance to Toxoplasmic encephalitis and their critical dependence on parasite strain. J. Immunol. 169:966-973.

    Brown, C.R., V.A. Blaho, and C.M. Loiacono. 2003. Susceptibility to experimental Lyme arthritis correlates with KC and MCP-1 production in joints and requires neutrophil recruitment via CXCR2. J. Immunol. 171:893-901.

    Brown, C.R., V.A. Blaho, and C.M. Loiacono. 2004. Treatment of mice with the neutrophil-depleting antibody RB6-8C5 results in early development of experimental Lyme arthritis via the recruitment of Gr-1- PMN-like cells. Infect. Immun. 72:4956-4965. (Selected for Faculty of 1000)

    Ray, A., D. Kumar, A. Shakya, C.R. Brown, and B.K. Ray. 2004. Serum amyloid A-activating factor-1 (SAF-1) transgenic mice are prone to develop a severe form of inflammation-induced arthritis. J. Immunol. 173:4684-4691.

    Wilson, A.P., J.J. Thelen, J. Lakritz, C.R. Brown, and A.E. Marsh. 2004. The identification of a sequence related to apicomplexan enolase from Sarcocystis neurona. Parasitol. Res. 94:354-360.

    Fritsche, K., R. Irons, L. Pompos, J. Janes, Z. Zheng, and C. Brown. 2005. Omega-3 poly-unsaturated fatty acid impairment of early host resistance against Listeria monocytogenes infection is independent of neutrophil infiltration and function. Cell. Immunol. 235:65-71.

    Brown, C.R., V.A. Blaho, K.L. Fritsche, and C.M. Loiacono. 2006. STAT1-deficiency exacerbates carditis but not arthritis during experimental Lyme borreliosis. J. Interferon Cytokine Res. 26:18-27. Journal cover, June 2006 and April 2007

    Montgomery, R.R., C. Booth, X. Wang, V.A. Blaho, S.E. Malawista, and C.R. Brown. 2007. Regulated recruitment of macrophages and PMN in Lyme carditis. Infect. Immun. 75:613-620.

    Xu, Q., S.V Seemanapalli, K.E. Reif, C.R. Brown, and F.T. Liang. 2007.Increasing the recruitment of neutrophils to the site of infection dramatically attenuates Borrelia burgdorferi infectivity. J. Immunol. 178:5109-5115.

    Blaho, V.A., W.J. Mitchell, and C.R. Brown. 2008. Arthritis develops but fails to resolve during inhibition of cyclooxygenase-2 in a murine model of Lyme disease. Arthritis Rheum. 58:1485-1495.

    Brown, C.R., A.Y-C. Lai, Callen, S.T., V.A. Blaho, J.M. Hughes, and W.J. Mitchell. 2008. Adenoviral delivery of IL-10 fails to attenuate experimental Lyme disease. Infect. Immun. 76:5500-5507.

    Blaho, V.A., M.W. Buczynski, C.R. Brown, and E.A. Dennis. 2009. Lipidomic analysis of dynamic eicosanoid responses during the induction and resolution of Lyme arthritis. J. Biol. Chem. 284:21599-21612.

    Blaho, V.A., M.W. Buczynski, E.A. Dennis, and C.R. Brown. 2009. Cyclooxygenase-1 orchestrates the humoral immune response via regulation of IL-17. J. Immunol.,183:5644-5653.