B.S., (Honors), University of Dhaka
M.S., University of Dhaka
PhD, Osaka University
Lyme disease is the most prevalent arthropod borne, emerging infectious disease. The disease is caused by the spirochete Borrelia burgdorferi, which is transmitted to humans via infected Ixodes ticks (Ixodes scapularis; commonly known as deer ticks). Lyme disease is a multiple-systemic disorder with various clinical symptoms including: erythema migrans rash, arthritis, cardiac, musculoskeletal and neurological manifestations. In the United States, approximately 60% of untreated patients develop Lyme arthritis, and more than 10% of these patients become treatment-resistant for unknown reasons. In addition, 4-10% of the untreated Lyme patients develop carditis. Currently, no vaccines are available to prevent Lyme disease.
When a tick feeds, the spirochetes migrate from the tick midgut to its salivary glands and then into the mammalian host. Borrelia burgdorferi is highly invasive: After deposition in the skin by a tick bite, spirochetes traverse the intracellular matrix, penetrate the vascular endothelial cell lining, and are disseminated to large joints, ears, heart and other tissues. However, the mechanisms involved in this invasive process, and how the organisms migrate from the tick midgut to the salivary glands, are unknown.
Borrelia burgdorferi has a wave-like morphology and unique means of motility. The organelles for motility, periplasmic flagella, are located in the periplasmic space within the outer membrane sheath and cell cylinder. These spirochetes are able to swim in highly viscous, gel-like environments such as joints, connective tissues and brain where most externally-flagellated bacteria move slowly or stop swimming. Periplasmic flagella are essential for both motility and morphology of Borrelia burgdorferi, as mutations in the gene encoding the major periplasmic flagellar protein results in cells that are rod-shaped and non motile.
Bacterial pathogens are highly adapted, with survival strategies that require multiplication and living in hosts. Chemotaxis two-component phosphorelay systems are fundamental to many adaptive responses and are often essential for virulence in host organisms. While motility and chemotaxis are critical for many pathogenic organisms to colonize and/or cause disease, the role of these processes in Borrelia burgdorferi-mediated pathogenesis has not been determined.
One of our immediate goals is to determine the extent to which motility and chemotaxis in Borrelia burgdorferi is involved in transmission and disease progression. Our long term goal is to identify a molecule or a pathway (e.g., chemotaxis signal transduction pathway) in the organism for which a novel pharmacological agent can be developed to better treat or prevent the multi-systemic Lyme disease.
Sultan S.Z, Sekar P, Zhao X, Manne A, Liu J, Wooten R.M, Motaleb M. A. Motor rotation is essential for the formation of the periplasmic flagellar ribbon, cellular morphology, and Borrelia burgdorferi persistence within Ixodes tick and murine hosts. Infection & Immunity. 83(5); 2015. PMID: 25690096
Zhao X, Zhang K, Boquoi T, Hu B, Motaleb MA, Miller KA, James ME, Charon NW, Manson MD, Norris SJ, Li C, Liu J. Cryoelectron tomography reveals the sequential assembly of bacterial flagella in Borrelia burgdorferi. Proc. Natl. Acad. Sci., USA. Aug 12, 2013. PMID: 23940315.
S. Z. Sultan, A. Manne, P. E. Stewart, A. Bestor, P. A. Rosa, N. W. Charon and M. A. Motaleb. Motility is crucial for the infectious life cycle of Borrelia burgdorferi. Infection & Immunity. 81:2012-2021, 2013. PMID: 23529620. Editors Spotlight article. Journal Cover illustration.
S. Sultan, J. Pitzer, T. Boquoi, G. Hobbs, M. Miller and M. Motaleb. Analysis of the HD-GYP domain phosphodiesterase reveals a role in motility and enzootic life cycle of Borrelia burgdorferi. Infection & Immunity. 79: 3273-3283, 2011. PMID: 21670168.
M. A. Motaleb, S. Sultan, M. R. Miller, C. Li, and N. W. Charon. CheY3 of Borrelia burgdorferi is the key response regulator essential for chemotaxis and forms a long-lived phosphorylated intermediate. Journal of Bacteriology. 193: 3332-3341, 2011. PMID: 21531807.
M. Motaleb, J. Pitzer, S. Sultan and J. Liu. A novel gene inactivation system reveals an altered periplasmic flagellar orientation in a Borrelia burgdorferi fliL mutant. Journal of Bacteriology. 193: 3324-3331, 2011. PMID: 21441522. Journal cover illustration.
J. Pitzer, S. Sultan, Y. Hayakawa, G. Hobbs, M. Miller and M. Motaleb. Analysis of the Borrelia burgdorferi cyclic-di-GMP binding protein PlzA reveals a role in motility and virulence. Infection & Immunity. 79: 1815-25, 2011. PMID: 21357718.
S. Z. Sultan, J. E. Pitzer, M. R. Miller and M. A. Motaleb. Analysis of a Borrelia burgdorferi phosphodiesterase demonstrates a role for cyclic-di-GMP in motility and virulence. Molecular Microbiology. 77: 128-42, 2010. PMID: 20444101.
Y. Pazy, M. A. Motaleb, M. T. Guarnieri, N.W. Charon, R. Zhao and Silversmith, R. E. Identical phosphatase mechanisms achieved through distinct modes of binding phosphoprotein substrate. Proc. Natl. Acad. Sci. USA. 107: 1924-9, 2010. PMCID: PMC2836628.
M. A. Motaleb, M. R. Miller, C. Li, R. G. Bakker, S. F. Goldstein, R. E. Silversmith, R. B. Bourret, and N. W. Charon. CheX is a phosphorylated CheY phosphatase essential for Borrelia burgdorferi chemotaxis. Journal of Bacteriology. 187: 7963-7969, 2005. PMCID: PMC1291287.
C. Li, R.G. Bakker, M.A. Motaleb, M.L. Sartakova, F.C. Cabello and N.W. Charon. Asymmetrical flagellar rotation in Borrelia burgdorferi nonchemotactic mutants. Proc. Natl. Acad. Sci. USA. 99: 6169-74, 2002. PMCID: PMC122921.
M. A. Motaleb, L. Corum, J. L. Bono, A. F. Elias, P. Rosa, D. S. Samuels, N. W. Charon. Borrelia burgdorferi periplasmic flagella have both skeletal and motility functions. Proc. Natl. Acad. Sci. USA. 97:10899-904, 2000. PMCID: PMC27121.