Ruth Montgomery, Ph.D.

Senior Research Scientist
Rheumatology

Research Activities

The focus of our lab’s research is on innate immunity, specifically the interaction of macrophages, neutrophils, and dendritic cells with pathogens (including the agent of Lyme disease, Borrelia burgdorferi, and West Nile virus), and the effect of aging and immunosuppression on the expression and efficiency of Toll-Like receptors. In our studies from a large cohort of human subjects, we have shown that older donors express lower levels of certain TLRs.

In Lyme disease, our comprehensive examination of phagocyte killing mechanisms has shown site-specific activation of macrophages, no global impairment of macrophage function in the infected host, and inefficient spirochetal clearance by PMN in the early innate immune response. Many PMN components are effective against B. burgdorferi, including granule contents and the abundant cytosolic protein, calprotectin, which is present in inflamed joint fluids at levels sufficient to block killing of spirochetes by certain antibiotics. We are also examining the effects of vector saliva on phagocyte function. Ixodes tick saliva is a potent immune modulator and we have shown one mechanism for its inhibition of PMN function is down-regulation of leukocyte integrins.

Our studies on West Nile virus (WNV) have shown that infection attenuates the activation of macrophages and interferes with intracellular signaling pathways. We have shown dysregulation of TLR3 in macrophages from older donors infected with WNV that leads to higher expression of cytokines and which may contribute to more severe infection in the elderly. We have evaluated the contribution of macrophages and innate immunity in several murine models of WNV infection, and in a genome-wide RNAi screen to identify host factors involved in anti-viral responses.

In addition to quantitative biochemical and molecular methods to address these questions, we use high-resolution confocal imaging. I am the Director of the Confocal Microscopy facility, which houses a Zeiss 510 META confocal microscope. In addition to our studies on phagocytes, we have imaged entire Ixodes ticks (J. Exp. Med. cover image, June 2006), and intact salivary glands to demonstrate expression of a novel tick receptor for spirochete outer surface protein A, and efficient down-regulation of salivary anti-coagulants by RNAi.

Selected Publications

• Montgomery RR, Lusitani DL, Chevance A, Malawista SE (2002) Human phagocytic cells in the early innate immune response to Borrelia burgdorferi. J Infect Dis 185:1773-9 .
• Lusitani DL, Malawista SE, and Montgomery RR (2003) Calprotectin, an abundant cytosolic protein from human polymorphonuclear leukocytes, inhibits the growth of B. burgdorferi. Infect Immun 71:4711-4716.
• Narasimhan S, Montgomery RR, Deponte K, Marcantonio N, Tschudi C, Anderson JF, Cappello M, Kantor FS, and Fikrig E (2004) Disruption of Ixodes scapularis anticoagulation pathways using RNA interference. Proc Natl Acad Sci USA 101:1141-1146.
• Montgomery RR, Lusitani D, de Boisfleury Chevance A, and Malawista SE (2004) Tick saliva reduces adherence and area of human neutrophils. Infect Immun 72:2989-2994.
• Montgomery, RR, Schreck, K, Wang, X, and Malawista, SE 2006. Human neutrophil calprotectin reduces the susceptibility of Borrelia burgdorferi to Penicillin. Infect. Immun 74:2468-2472.
• van Duin, D, Thomas, V, Mohanty, S, Montgomery, RR, Ginter, S, Fikrig, E, Allore, HG, Medzhitov, R, and Shaw, AC 2007. Age-associated Defect in Human TLR1 Function and Expression. J. Immunol. 178:970-975.
• Arjona, A., Foellmer, H., Town, T., Leng, L., McDonald, C., Wong, S., Montgomery, R.R., Fikrig, E., and Bucala, R. 2007. Abrogation of Macrophage Migration Inhibitory Factor Decreases West Nile Virus Lethality by Limiting Viral Neuroinvasion. J. Clin. Invest. 117:3059-3066.
• Kong, K.-F., Wang, X., Anderson, J.F., Fikrig, E., and Montgomery, R.R. 2008. West Nile virus attenuates activation of primary human macrophages. Viral Immunol 21:78-82.
• Kong, K.-f., Delroux, K., Wang, X., Qian, F., Arjona, A., Malawista, S.E., Fikrig, E., and Montgomery, R.R. 2008. Dysregulation of TLR3 impairs the innate immune response to West Nile virus in the elderly. J. Virol. 82:7613-7623.
• Wang, P., J. Dai, F. Bai, K. F. Kong, S. J. Wong, R. R. Montgomery, J. A. Madri, and E. Fikrig. 2008. Matrix metalloproteinase 9 facilitates West Nile Virus entry into the brain. J. Virol. 82:8978-8985.
• Krishnan, M. N., Ng, A., Sukumaran, B., Gilfoy, F. D., Uchil, P. D., Sultana, H., Brass, A. L, Adametz, R., Tsui, M., Qian, F., Montgomery, R. R., Lev, S., Mason, P. W., Koski, R. A., Elledge, S. J., Xavier, R. J., Agaisse, H,.and Fikrig,. E. 2008. RNA interference screen for human genes associated with West Nile virus infection. Nature 455:242-245.

Lab Members

Postdoctoral Associates
Feng Qian, Ph.D.	(203) 785-6955
Research Associates
Xiao-mei Wang	(203) 785-6955
Lin Zhang	(203) 785-6955

Contact

Campus Address
300 Cedar Street
TAC S-413

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

E-mail
ruth.montgomery@yale.edu

Office Phone
(203) 785-7039

Fax
(203) 785-7053