PhD: Hershey Medical School, Penn State University
Postdoctoral Training: Harvard Medical School and
Dana-Farber Cancer Institute Department of Pharmacology

Joined the faculty: 1977

Affiliations: Center for Cardiovascular and Respiratory Sciences

Teaching: BIOC 339, BIOC 705, BIOC 531, BCMP 562

Office: 2286
Phone: (304) 293-7762
Fax: (304) 293-6846
Email: mmiller@hsc.wvu.edu  

Most of my research is devoted to studying various aspects of Lyme disease, caused by the spirochete Borrelia burgdorferi, which is described in more detail directly below. In an other area of research, I have been studying microorganisms that are present in scuba divers rinse tanks, addressed at the bottom of this page.

Lyme Disease: We are investigating various aspects of Lyme disease, which is caused by the spirochete Borrelia burgdorferi (Bb).Bb are transmitted to humans via tick bites; once in the skin Bb move through the dermis, often causing a characteristic “bulls eye” inflammation. Bb enter the vascular system where they are disseminated to other tissues, inducing inflammation. In collaboration with Dr. Nyles Charon (WVU Dept. Microbiology and Immunology) and Dr. Motaleb (East Carolina University Dept. Microbiology) we are studying the molecular mechanisms regulating chemotaxis and motility. Bb is unusual in that it contains periplasmic flagella which originate at each end of the organism and extend toward the other end, overlapping in the center of the spirochete (see Figure 1). Rotation of the flagella causes the spirochete to move. Bb can move toward attractants and away from repellents via complex chemotaxis mechanisms. The swimming pattern of Bb is also rather unusual, as demonstrated in Movie 1 – the spirochetes can ‘run’ or translate, ‘flex’ or stop running and ‘reverse’ or change directions. Mutation of some chemotaxis genes causes altered swimming behavior, illustrated in Movie 2 (constant running) and Movie 3 (constant flexing). We have identified several chemo-attractants (ref no. 2 & 3 below), and are characterizing the chemotaxis phospho-transfer system (ref no. 1 & 4 below).

In collaboration with Dr. Ping He (WVU Dept. Physiology and Pharmacology) we are studying the interaction of Bb with the vascular system. We have shown that “spent” medium from cultures of virulent Bb rapidly causes an inflammatory reaction in rat microvessels that is characterized by a transient increase in vessel permeability (Figure 2 and ref no. 6 below) and intracellular calcium. This inflammatory reaction is not caused by avirulent Bb, which has lost 8 of the 20 circular and linear plasmids associated with virulent Bb. We are characterizing this inflammatory reaction and the compound(s) responsible for this inflammation. In addition, we are studying, in real time and in vivo, the interaction of Bb with endothelial and blood cells in microvessels. When Bb are introduced into microvessels, they rapidly bundle to leukocytes, with many spirochetes bound to a single leukocyte (Figures 3 and 4 below). In Figure 3 endothelial nuclei are red, spindle shaped; leukocyte nuclei are red, round or polymorphonuclear shape; Bb are green.

Figure 4 is a cross section of a single leukocyte (not stained or colored), showing multiple Bb (green) bundled to it. Figure 5 shows that when Bb attach to endothelial cells (cell can’t be seen in this picture), one end or “head” attaches and the other end or “tail” remains free to move. From these studies we are observing, for the first time, in a living animal, how Bb interacts with cells in the vascular system and how the spirochete penetrates blood vessels.

  References:

• Md.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 CheY-P phosphatase essential for Borrelia burgdorferi chemotaxis” J. Bacteriology 187, 7963 – 7969 (2005).
   
• R. G. Bakker, C. LI, M. R. Miller,C. Cunningham, and N. W. Charon "Identification of specific chemoattractants and complementation of cheA2 of Borrelia burgdorferi: A flow cytometry-based capillary tube chemotaxis assay". Applied Env. Microbiol. 73, 1180-1188 (2007).
   
• Md. A. Motaleb, M. R. Miller, R. G. Bakker, C. Li and N. Charon "Isolation and Characterization of Chemotaxis Mutants of the Lyme Disease Spirochete Borrelia burgdorferi Using Allelic Exchange Mutagenesis, Flow Cytometry and Cell Tracking" Methods in Enzymology, 422, 421-437 (2007).
   
• Md. A. Motaleb, M. R. Miller, C. Li and N. W. Charon "Phosphorylation assays of chemotaxis two-component system proteins in Borrelia burgdorferi", Methods in Enzymology, 422, 438 – 447 (2007).
   
• A.M. Magro, A.D. Magro, C. Cunningham and M.R. Miller "Down-regulation of vinculin upon MK886-induced apoptosis in LN18 glioblastoma cells", Neoplasma, 54, 517 - 526 (2007).
   
• X. Zhou, M. R. Miller, Md. Motaleb, N. W. Charon, P. He “Spent culture medium from virulent Borrelia burgdorferi increases permeability of individually perfused microvessels of rat mesentery” PLoS ONE 3: e4101 (2008). http://dx.plos.org/10.1371/journal.pone.0004101.