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Infection and Immunity, April 2003, p. 1706-1718, Vol. 71, No. 4
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.4.1706-1718.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Expression of Multiple Outer Membrane Protein Sequence Variants from a Single Genomic Locus of Anaplasma phagocytophilum

A. F. Barbet,1* P. F. M. Meeus,1 M. Bélanger,1,{dagger} M. V. Bowie,1,{ddagger} J. Yi,1 A. M. Lundgren,1 A. R. Alleman,2 S. J. Wong,3 F. K. Chu,3 U. G. Munderloh,4 and S. D. Jauron4,§

Departments of Pathobiology,1 Physiological Sciences, University of Florida, Gainesville, Florida 32611,2 Wadsworth Center, New York State Department of Health, Albany, New York 12201,3 Department of Entomology, University of Minnesota, St. Paul, Minnesota 551084

Received 23 October 2002/ Returned for modification 26 November 2002/ Accepted 8 January 2003

Anaplasma phagocytophilum is the causative agent of an emerging tick-borne zoonosis in the United States and Europe. The organism causes a febrile illness accompanied by other nonspecific symptoms and can be fatal, especially if treatment is delayed. Persistence of A. phagocytophilum within mammalian reservoir hosts is important for ensuring continued disease transmission. In the related organism Anaplasma marginale, persistence is associated with antigenic variation of the immunoprotective outer membrane protein MSP2. Extensive diversity of MSP2 is achieved by combinatorial gene conversion of a genomic expression site by truncated pseudogenes. The major outer membrane protein of A. phagocytophilum, MSP2(P44), is homologous to MSP2 of A. marginale, has a similar organization of conserved and variable regions, and is also encoded by a multigene family containing some truncated gene copies. This suggests that the two organisms could use similar mechanisms to generate diversity in outer membrane proteins from their small genomes. We define here a genomic expression site for MSP2(P44) in A. phagocytophilum. As in A. marginale, the msp2(p44) gene in this expression site is polymorphic in all populations of organisms we have examined, whether organisms are obtained from in vitro culture in human HL-60 cells, from culture in the tick cell line ISE6, or from infected human blood. Changes in culture conditions were found to favor the growth and predominance of certain msp2(p44) variants. Insertions, deletions, and substitutions in the region of the genomic expression site encoding the central hypervariable region matched sequence polymorphisms in msp2(p44) mRNA. These data suggest that, similarly to A. marginale, A. phagocytophilum uses combinatorial mechanisms to generate a large array of outer membrane protein variants. Such gene polymorphism has profound implications for the design of vaccines, diagnostic tests, and therapy.

* Corresponding author. Mailing address: Department of Pathobiology, College of Veterinary Medicine, University of Florida, P.O. Box 110880, Gainesville, FL 32611-0880. Phone: (352) 392-4700. Fax: (352) 392-9704. E-mail: barbeta{at}mail.vetmed.ufl.edu.

Editor: J. T. Barbieri

{dagger} Present address: Department of Oral Biology, University of Florida, Gainesville, FL 32611.

{ddagger} Present address: College of Education, University of Florida, Gainesville, FL 32611.

§ Present address: Office of Medical Education, Flinders University School of Medicine, Adelaide, Australia.

Infection and Immunity, April 2003, p. 1706-1718, Vol. 71, No. 4
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.4.1706-1718.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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