Stephen Malawista, M.D.

Professor of Medicine
Rheumatology

Research Activities

My laboratory is devoted primarily to two general areas of investigation - motile functions of leukocytes that bear on aspects of the inflammatory response, and the continued elucidation of Lyme disease, which we discovered in 1975.

The leukocyte work is particularly aimed at the relationships among specific but overlapping areas of leukocyte activity: adherence, locomotion, target recognition, chemotaxis, penetration of endothelial monolayers, ingestion, the increased metabolic activity that ordinarily accompanies phagocytosis or other cell-triggering reactions, degranulation of lysosomal structures, and intracellular killing. The ways in which these activities can be separated from one another may distinguish obligate interactions from mere concomitance, and may reveal the specific pathways by which cell function is altered. The experimental approach is through various agents and situations in which one or more of these activities appear to be altered, including 1) leukocytes treated in a variety of ways to produce granule-poor anucleate fragments (cytoplasts) that retain motile and/or respiratory functions of the parent cell, 2) cytoplasts or leukocytes treated with agents that affect their killing capacity for microorganisms, 3) cytoplasts or leukocytes treated with molecules and particles that initiate or inhibit calcium fluxes, activation of protein kinase C or of adenylate cyclase, protein phosphorylation, polymerization of microtubules and microfilaments, and rearrangements or altered expression of specific cell-surface receptors, 4) leukocytes treated with controlled brief heat to alter their respiratory burst oxidase activity, 5) leukocytes from patients with chronic granulomatous disease, leukocyte adhesion deficiency, or other disorders of leukocyte structure and function, and 6) cytoplasts, leukocytes, or cell lines treated with substances that produce ultrastructural alterations in fibrillar elements, such as the metaphase-arresting agents, colchicine, vinblastine and griseofulvin (affecting microtubules), and cytochalasins (affecting microfilaments).

The elucidation of Lyme disease has been irresistible by virtue of its linkage of inflammatory rheumatology to infectious disease. We have addressed its natural history, antiquity, immunopathogenesis, etiology, molecular biology, diagnosis, treatment, and prevention. Current work is especially aimed at how the causative spirochete, Borrelia burgdorferi, may persist in certain patients even though these agents are killed quickly and efficiently by phagocytic cells in vitro.

Selected Publications

Malawista, S.E., Van Blaricom, G., and Breitenstein, M.G. 1989. Cryopreservable neutrophil surrogates: Stored cytoplasts from human polymorphonuclear leukocytes retain chemotactic, phagocytic, and microbicidal function. J. Clin. Invest. 83: 728-732.

di Giovine, F., Malawista, S.E., Thornton, E. and Duff, G. 1991. Urate crystals stimulate production of tumor necrosis factor alpha from human blood monocytes and synovial cells: Cytokine mRNA and protein kinetics, and cellular distribution. J. Clin. Invest. 87:1375-1381.

Malawista, S.E., R. R. Montgomery, and G. Van Blaricom. 1992. Evidence for reactive nitrogen intermediates in killing of Staphylococci by human neutrophil cytoplasts: A new microbicidal pathway for polymorphonuclear leukocytes. J. Clin. Invest. 90:631-636.

Malawista, S.E. and A. de Boisfleury Chevance. 1997. Random locomotion and chemotaxis of human blood polymorphonuclear leukocytes in the presence of EDTA: PMN in close quarters require neither leukocyte integrins nor external divalent cations. Proc. Natl. Acad. Sci. USA 94:11577-11582.

Malawista, S.E., A. de Boisfleury Chevance, and L.A. Boxer. 2000.Random locomotion and chemotaxis of human blood polymorphonuclear leukocytes from a patient with Leukocyte Adhesion Deficiency-1: Normal displacement in close quarters via chimneying. Cell Motil. Cytoskel. 46:183-189.

Malawista, S.E. 2000. Resolution of Lyme arthritis, acute or prolonged: A new look. Inflammation 24: 493-503.

Malawista, S.E., J. Van Damme, J.I. Smallwood, and A. de Boisfleury Chevance. 2002. Chemotactic activity of human blood leukocytes in plasma treated with EDTA: Chemoattraction of neutrophils about monocytes is mediated by the generation of NAP-2. J. Leuk. Biol. 72:175-182.

Lusitani, D.D., S. E. Malawista, and R.R. Montgomery. 2002. Borrelia burgdorferi are susceptible to killing by a variety of human PMN components. J. Infect. Dis. 185:797-804.

Montgomery, R.R., Schreck, K., Wang, X., and Malawista, S.E. 2006. Human neutrophil calprotectin reduces the susceptibility of Borrelia burgdorferi to Penicillin. Infect. Immun. 74:2468-2472.

Malawista, S.E., Smith, E.O., and Seibyl, J.P. 2006. Cryopreservable neutrophil surrogates: Granule-poor, motile cytoplasts from PMN home to inflammatory lesions in vivo. Cell. Motil. Cytoskel. 63:254-257.

Lab Members

Research Assistants

Swapna Samantha
Anne de Boisfleury Chevance (Paris)

Clinical Research Nurse

Donna Carrano

Contact

Campus Address
300 Cedar Street
TAC S-525D

Mailing Address
Yale University School of Medicine
P.O. Box 208031
New Haven, CT 06520-8031

E-mail
stephen.malawista@yale.edu

Office Phone
(203) 785-2453

Fax
(203) 785-7053