The goal of the proposed research is determine how competition at the level of host population immunity and transmission fitness drives genetic diversification of microbial pathogens-changes that underlie shifts in disease pattern and are fundamental to the understanding of how new pathogens emerge. Specifically, we are focused on microbial pathogens that employ gene conversion as a mechanism to generate antigenic variants, evade clearance by the immune system, and persist within mammalian host reservoirs-pathogens that can be broadly diverse in taxon (e.g. the bacterium Borrelia versus the protozoa Trypanosoma) but united by these common persistence and variant evolution mechanisms. These pathogens generate within- host antigenic variants using genomic complements of variant donor alleles. There is strong selective pressure for sufficient diversity among the variant alleles in the genome to evade clearance and persist, as within host persistence dramatically increases the likelihood of successful ongoing transmission. This pressure alone would lead to strain homogeneity as defined by the allelic repertoire within a pathogen species rather than the emergence and heterogeneity. In our work, we identified strain superinfection as an opposing selective pressure that drives allelic diversification among strains of a pathogen, strain emergence, and heterogeneity. Penetration of a new strain into a region with a high prevalence of infection and consequent broad immunity against the variants encoded by an existing endemic strain requires that the new strain encode variants that will be immunologically novel and allow establishment of infection. This pressure is hypothesized to favor continual genetic probing for selective advantage and to result in the genetic change that underlies shifts in transmission and disease patterns. Understanding how this occurs in bacteria and protozoa, complex pathogens that cannot rely on mutation and the large progeny burst size as do viruses, and the consequences for transmission within endemic zones is the goal. Using Anaplasma marginale as a model in which we can study pathogen infectivity and transmission in a natural mammalian host, we determine how the two contrasting selective pressures mold strain structure and test the kinetics of new strain emergence in the host population. Importantly, we link the effect of strain emergence, defined by expression of a novel variant-encoding allele, on its transmission fitness and persistence and expansion in the host population. This knowledge of the kinetics of pathogen emergence is critically important to understand how new genomically complex pathogens fail or succeed in changing disease patterns.

Public Health Relevance

Understanding how microbial pathogens undergo genetic change under natural selective pressures represents a major gap in knowledge in emerging infectious diseases research and is specifically relevant to public health as genetic change underlies shifts in disease phenotype, including new patterns of transmission, gain or loss of virulence, and adaptation to new host species.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Perdue, Samuel S
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Washington State University
Veterinary Sciences
Schools of Veterinary Medicine
United States
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Pierlé, Sebastián Aguilar; Rosshandler, Ivan Imaz; Kerudin, Ammielle Akim et al. (2014) Genetic Diversity of Tick-Borne Rickettsial Pathogens; Insights Gained from Distant Strains. Pathogens 3:57-72
Mercado-Curiel, Ricardo F; Ávila-Ramírez, María L; Palmer, Guy H et al. (2014) Identification of Rhipicephalus microplus genes that modulate the infection rate of the rickettsia Anaplasma marginale. PLoS One 9:e91062
Vallejo Esquerra, Eduardo; Herndon, David R; Alpirez Mendoza, Francisco et al. (2014) Anaplasma marginale superinfection attributable to pathogen strains with distinct genomic backgrounds. Infect Immun 82:5286-92
Hammac, G Kenitra; Pierlé, Sebastián Aguilar; Cheng, Xiaoya et al. (2014) Global transcriptional analysis reveals surface remodeling of Anaplasma marginale in the tick vector. Parasit Vectors 7:193
Herndon, David R; Ueti, Massaro W; Reif, Kathryn E et al. (2013) Identification of multilocus genetic heterogeneity in Anaplasma marginale subsp. centrale and its restriction following tick-borne transmission. Infect Immun 81:1852-8
Palmer, Guy H; Brayton, Kelly A (2013) Antigenic variation and transmission fitness as drivers of bacterial strain structure. Cell Microbiol 15:1969-75
Pierle, Sebastian Aguilar; Hammac, Gena Kenitra; Palmer, Guy H et al. (2013) Transcriptional pathways associated with the slow growth phenotype of transformed Anaplasma marginale. BMC Genomics 14:272
Noh, Susan M; Turse, Joshua E; Brown, Wendy C et al. (2013) Linkage between Anaplasma marginale outer membrane proteins enhances immunogenicity but is not required for protection from challenge. Clin Vaccine Immunol 20:651-6
Palmer, Guy H; Brown, Wendy C; Noh, Susan M et al. (2012) Genome-wide screening and identification of antigens for rickettsial vaccine development. FEMS Immunol Med Microbiol 64:115-9
Agnes, Joseph T; Brayton, Kelly A; LaFollett, Megan et al. (2011) Identification of Anaplasma marginale outer membrane protein antigens conserved between A. marginale sensu stricto strains and the live A. marginale subsp. centrale vaccine. Infect Immun 79:1311-8

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