Dr. Tim Sparer

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Major Research Interests

My major focus of my laboratory is the role of the viral chemokines from cytomegaloviruses in dissemination and pathogenesis.   We have recently branched out into the fields of cancer research looking at the role of chemokine receptors in tumorigenesis.  We currently have three main areas of research in my lab.

Viral Chemokines and CMV Pathogenesis

Human cytomegalovirus (HCMV) infections are a major cause of morbidity and mortality in immunocompromised hosts. HCMV infection/reactivation is a significant factor in graft rejection in solid organ trans-plants, graft vs. host disease in bone marrow transplants, and has been implicated in the development of coronary disease in heart transplant patients. Additionally, primary cytomegalovirus infection during pregnancy can lead to hearing loss, mild learning disabilities or mental retardation. Because of these long-term detrimental effects, the Institute of Medicine has made a vaccine for HCMV a top priority. Understanding the pathogenesis and dissemination of HCMV will provide valuable information for developing safe and effective vaccines or therapeutics. Cytomegaloviruses, as well as other herpesviruses, have evolved mechanisms for altering both the innate and the adaptive arms of the immune response. Their co-evolution with the host allows an intimate interrelationship between these viruses and the immune system. Dissecting how herpesviruses subvert and usurp the immune system will not only reveal important information about viral pathogenesis but may also unveil unique immunological pathways. Both murine and human cytomegaloviruses encode proteins with sequence homology to known chemokines. Chemokines are small chemotactic cytokines that are important in controlling leukocyte trafficking during innate, inflammatory, and adaptive immune responses. Chemokines fall into two major groups based on the spacing of the amino terminal cysteines: CXC chemokines function mostly on neutrophils, while CC chemokines function on a much broader array of cell types (immune and non-immune cell types). Murine CMV produces a CC chemokine homologue, while HCMV has two homologues to CXC chemokines. My work focuses on both human and murine cytomegaloviruses, investigating how these viruses use viral chemokines to alter the trafficking of immune cells for the viruses' benefit.

References

• Functional characterization of chimpanzee cytomegalovirus chemokine, vCXCL-1(CCMV)
• Cytomegalovirus MCK-2 controls mobilization and recruitment of myeloid progenitor cells to facilitate dissemination
• Expression of human CXCR2 in murine neutrophils as a model for assessing cytomegalovirus chemokine vCXCL-1 function in vivo
• Murine cytomegalovirus CC chemokine homolog MCK-2 (m131-129) is a determinant of dissemination that increases inflammation at initial sites of infection

Viral Chemokines and Atherosclerosis

Human cytomegaloviruses (CMVs) have been implicated as a risk factor for the development of atherosclerosis.  Because of their species specificity, infection of mice with murine CMVs  has been used as a model for human viral pathogenesis.  In the murine model of atherosclerosis (apolipoprotein E (ApoE) knockout (KO) mice), murine CMV has been associated with exacerbated atherosclerosis.  Because inflammation is a hallmark of atherosclerosis initiation, chemokines (chemoattractant cytokines) must play a role in atherogenesis.  Both human and murine CMVs produce novel chemokines that function like host chemokines (i.e. attract leukocytes). We are currently investigating whether these chemokines and specific cell types contribute to CMV induced atherosclerosis.

This project is currently funded through the American Heart Association.

Chemokine Receptors and Cancers

The numbers for melanomas are quite impressive: 80% of all skin cancer deaths are due to melanomas.  For patients with metastatic melanomas, only 14% survive after five years.  1 in 65 Americans will develop an invasive melanoma.  Identification of abnormally functioning chemokine receptors and understanding their contribution to the biology of metastatic melanomas will open the door to new avenues for drug development.  Chemokines and their receptors normally function in inflammatory, developmental, and homeostatic processes.  Deregulation of this system is associated with the development of cancers and metastasis.  Chemokine receptors are members of the G protein coupled receptors (GPCR ) family of membrane receptors.  Chemokine receptors such as CXCR2 that continually induce a signal within a cell in the absence of ligand often lead to cellular transformation, the first steps in cancer development. We are currently investigating the important residues of CXCR2 responsible for activation.  These discoveries may lead to the development of drugs to shutoff CXCR2s thus providing doctors with another weapon in their arsenal to treat melanomas or to decrease their metastatic potential.

This project is currently funded through a grant from the Elsa U. Pardee foundation.

Dr. Tim Sparer

Assistant Professor
M409 Walters Life Sciences
Knoxville, TN 37996-0845

Phone: 865-974-3800
Fax: 865-974-4007
Email: tsparer@utk.edu

Education

Assistant Professor of Microbiology, 2003-present

Walter and Idun Berry
Postdoctoral Fellow, Stanford University, 1999-2003

Wellcome Trust Postdoctoral Fellow, Imperial College, London, UK 1996-1999

Ph.D. Emory University School of Medicine, 1996

BA Northwestern University, 1989