Overview of the Francisella tularensis subsp. holarctica clades, B.6 and B.12, regarding their phenotypic and pathogenic characteristics

Francisella tularensis is the causative agent of the zoonotic disease tularemia and is classified as a Category A select agent for bioterrorism. Tularemia can affect a broad range of animals predominantly rabbits and rodents. In humans the clinical manifestation varies from flu-like symptoms to severe pneumonia with a lethality rate of up to 60 %. In Europe, tularemia is caused by F. tularensis subsp. holarctica (Fth) which is further classified into two clades (B.6 and B.12) using canonical Single Nucleotide Polymorphism (canSNP) typing and whole genome SNP typing. These clades also represent two biovars according to their resistance to erythromycin (I: B.6 sensitive; II: B.12 resistant). Fth strains belonging to the B.6 clade are primarily isolated in Western Europe, whereas B.12 strains are mainly found in Northern, Central and Eastern Europe. In Germany, both clades are present with a comparable geographical distribution. For a long time, it was not clear if the genetic differences result in clade-specific phenotypes including a different pathogenic potential. Recently, we have demonstrated that Fth strains show a clade-specific growth pattern in media and a distinct protein expression profile reflecting the phylogenetic relation. Data from wild animals might reveal a more severe course of disease caused by B.6 strains suggesting a higher pathogenic potential of the B.6 clade. In humans, more cases of pneumonia caused by B.6 strains are found, but too less data are currently available to statistically confirm this assumption. Moreover, the proteomic data showed that known virulence factors, like the pathogenicity determinant protein PdpA1, Fe(2+) transporter FeoB, Biotin synthase BioB and Catalase-peroxidase KatG, are differently expressed in both clades. Using Drosophila S2 cells, B.6 strains showed a faster replication capacity during the first hours, but a reduced survival at later stages of infection, which corresponds with the decreased expression of ribosomal proteins observed in B.6 strains. So far, the available data do not allow a general conclusion about the putative different pathogenicity of the Fth genotypes; therefore, more research is needed.