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Secretion System May Not Be Culprit in Rickettsia Pathogenesis

NEW YORK (GenomeWeb News) – New research suggests a molecular secretion system that contributes to the virulence of some bacterial species, including the plant pathogen Agrobacterium tumefaciens, is evolutionarily conserved in Rickettsia species. But, as researchers reported online this week in PLoS ONE, the system turned up in both pathogenic and non-pathogenic Rickettsia species, suggesting it may not be involved in Rickettsia-related pathogenesis, as commonly presumed.

Researchers from Virginia Tech and the Universities of Maryland and Louisville used bioinformatics to find components of a type IV secretion system or in more than a dozen species of Rickettsia, a group of obligate intracellular bacteria that include the causative agents for epidemic typhus and Rocky Mountain spotted fever. Their findings suggest T4SS genes are well-conserved in the Rickettsia species and appear to be functional, though the results failed to link T4SS function to Rickettsia virulence.

"Virulent species of Rickettsia are of great interest both as emerging agents of infectious disease and potential bio-terror agents. However, a lot of intense laboratory work has failed to provide information that characterizes their virulence factors," co-senior author Bruno Sobral, the former executive and scientific director of the Virginia Bioinformatics Institute at Virginia Tech, said in a statement.

"Our comparative genomics approach sheds light on the evolution of Rickettsia virulence and provides a solid foundation for the future laboratory assessment of the function of the Rickettsia type IV secretion system," he added.

The T4SS appears to contribute to the virulence of a range of bacterial species, including those involved in everything from Legionnaires' disease and whooping cough to Q fever and cat-scratch disease. The system, best characterized in Agrobacterium, can deliver virulence factors to host cells via a membrane-spanning transport system.

A dozen T4SS genes have been identified in Agrobacterium. Prior to the latest study, only six had been found in Rickettsia, though some appeared to be highly duplicated in otherwise-streamlined Rickettsia genomes.

To learn more about the nature of T4SS in Rickettsia, the researchers started with genes from other bacteria and used Blast to search 13 fully-sequenced Rickettsia species' genomes, also taking into account other information, including T4SS structural and functional findings from previous studies.

While some of the genes had been identified using automated annotation, others remained undiscovered in the genome, lead author Joseph Gillespie, a Virginia Bioinformatics Institute at Virginia Tech bioinformatician, told GenomeWeb Daily News. "We found three genes that were being missed by these automated searches," he said.

Based on their results, the team concluded that the T4SS is well-conserved in the Rickettsia species, though there were subtle differences between the T4SS genes and their location from one species to the next.

"Altogether, phylogeny estimation supports a single inheritance of the 18 Vir components from the Rickettsia ancestor, with one gene loss, one split gene, three major gene rearrangements, and several minor switches of coding strand," the authors wrote.

And in contrast to Agrobacterium, where all of the T4SS genes are lined up "like ducks in a row," Gillespie noted, the team found that T4SS genes were "clustered but scattered" all over the Rickettsia genomes they examined.

The new results also challenge the assumption that the T4SS contributes to Rickettsia species' pathogenesis, Gillespie explained, since both pathogenic and apparently non-pathogenic Rickettsia species house a complete T4SS.

"These secretion systems don't always contribute to pathogenesis," Gillespie said, noting that in other studied bacterial species the T4SS is involved in other biological functions such as mating, dumping DNA into the environment, and DNA uptake.

In the future, Gillespie and his team plan to sequence the genomes of symbiotic Rickettsia species to determine whether or not these bugs have a similar T4SS gene complement as species investigated in this study. Gillespie is also in the process of transplanting T4SS genes into bacteria that resemble Rickettsia but that are free-living rather than an obligate intracellular species.

For his part, Gillespie intends to find out one way or another whether T4SS is involved in Rickettsia pathogenesis or not. "A lot of people are making assumptions," he said. But he emphasized the importance of doing the research to actually test those ideas — particularly since some may see T4SS as a viable target for drug design and discovery. "You don't want to target something that's not involved in pathogenesis," he said.