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Title: Primary structural variation in anaplasma marginale Msp2 efficiently generates immune escape variants

item GRACA, TELMO - Washington State University
item PARADISO, LYDIA - Washington State University
item BROSCHAT, SHIRA - Washington State University
item Noh, Susan
item PALMER, GUY - Washington State University

Submitted to: Infection and Immunity
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/4/2015
Publication Date: 8/10/2015
Citation: Graca, T., Paradiso, L., Broschat, S.L., Noh, S.M., Palmer, G.H. 2015. Primary structural variation in anaplasma marginale Msp2 efficiently generates immune escape variants. Infection and Immunity. 83(11):4178-84.

Interpretive Summary: Microbial pathogens use diverse mechanisms to persist in their mammalian hosts, evolutionarily driven to increase the likelihood of onward transmission and propagation of self. Antigenic variation is one strategy used by pathogens ranging from RNA viruses to protozoa. For example, bacterial pathogens in the genera Anaplasma, Borrelia, Mycoplasma, Neisseria, and Treponema use a variety of silent alleles that can be inserted into expression sites such that unique antigenic and structural variants are made. The donor alleles are under long-term selective pressure to provide a template for expressing a variant that is sufficiently unique to avoid the immune system, but also retains a functional structure. In this study, the authors use A. marginale, the most prevalent tick borne pathogen of cattle, to determine the minimum amount of change required in an antigenically variable protein that will allow the pathogen to evade the host immune response. The authors found that a significant loss of antibody binding to a structural variant occurred with only a single amino acid insertion, thus demonstrating how minimal change can result in a new antigenic variant. Overall this and other studies suggest that relatively small genetic changes, predominantly insertions and deletions, can generate antigenic variants and, when maintained in the genome as a novel allele, could provide the basis for emergence of a new strain with the ability to evade the host immune system and be transmitted to other hosts.

Technical Abstract: Antigenic variation allows microbial pathogens to evade immune clearance and establish persistent infection. Anaplasma marginale utilizes gene conversion of a repertoire of silent msp2 alleles into a single active expression site to encode unique Msp2 variants. As the genomic complement of msp2 alleles alone is insufficient to generate the number of variants required for persistence, A. marginale uses segmental gene conversion, in which oligonucleotide segments from multiple alleles are recombined into the expression site to generate a novel msp2 mosaic, not represented elsewhere in the genome. Whether these segmental changes are sufficient to evade a broad antibody response is unknown. We addressed this question by identifying Msp2 variants that differed in primary structure within the immunogenic hypervariable region microdomains and tested whether these represented true antigenic variants. The minimal primary structural difference between variants was a single amino acid resulting from a codon insertion and overall the amino acid identity among paired microdomains ranged from 27-92%. Collectively, 89% of the expressed structural variants were also antigenic variants across all biological replicates, independent of a specific host major histocompatibility complex (MHC) haplotype. Biologic relevance is supported by the following: i) all structural variants were expressed during infection of a natural host; ii) the structural variation observed in the microdomains corresponded to the mean length of variants generated by segmental gene conversion; and iii) antigenic variants were identified using a broad antibody response that developed during infection of a natural host. The findings demonstrate that segmental gene conversion efficiently generates Msp2 antigenic variants.