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The Mechanisms of Disease


Yersinia pseudotuberculosis and Yersinia pestis are highly related and yet cause different diseases. Y. pseudotuberculosis leads to a gastrointestinal disease while Y. pestis causes plague, a strain of which was likely the cause of Europe's Black Death pandemic. Northwestern University's Wyndham Lathem is studying how these species cause disease, with a particular focus on how small RNAs regulate virulence. Genome Technology's Ciara Curtin caught up with Lathem to discuss his work, which was recently published in PNAS. What follows is an excerpt of their conversation, edited for space.

Genome Technology: Why did you set out to do a global survey of small RNAs in Yersinia pseudotuberculosis?

Wyndham Lathem: My laboratory is interested in understanding the molecular mechanisms by which the Yersinia species cause disease in mammals and we had undertaken a study previously that had determined that a chaperone for small regulatory RNAs called Hfq is required for full virulence of Yersinia pseudotuberculosis. It's not a virulence factor per se, but what it does is mediate the interaction of these small noncoding RNAs with target messenger RNA, and it allows the small RNAs to regulate, post-transcriptionally, that messenger RNA.

Without this protein Hfq, small RNAs can't function properly. We have shown that Hfq is required for the full virulence, so that told us that one or more small RNAs are required for the full virulence of Yersinia.

GT: Why did you take a deep sequencing approach to identifying small RNAs in Yersinia?

WL: We had considered multiple approaches. If you look in the literature, there have been many different ways by which people go about identifying small RNAs. Some of them are based on co-immunoprecipitation with proteins, some use tiling microarrays, but recently deep sequencing has become a preferred approach. One of the reasons for that is it allowed us to mine the transcriptome of Yersinia to an extent that would not have been possible with other approaches. The sensitivity by which deep sequencing was able to reveal low abundance, low abundantly expressed RNAs was far superior than what we would find with other approaches.

GT: Why were most of the small RNAs you found unique to Yersinia?

WL: We identified 150 small RNAs that not been previously identified in Yersinia, and so when we took that list and compared them to the genomes of other bacteria, we found that about 80 percent of those small RNAs are unique to Yersinia species, meaning that we could not find homologous sequences in E. coli or Salmonella or even more closely related species to Yersinia, such as Photorhabdus. That was actually quite a surprise.

Not only were there a large number of small RNAs that Yersinia have that these others don't, but we also found that Yersinia lacks many small RNAs that these other species do have. ... That begs the question: How does Yersinia regulate those targets if it doesn't have those same small RNAs?

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GT: You focused on two small RNAs, Ysr29 and Ysr35. How do they affect virulence?

WL: We were interested in Ysr29 because, not only was it specific to Yersinia, but it was unique to Yersinia pseudotuberculosis, meaning that Yersinia pestis — the most closely related species to Yersinia pseudotuberculosis — does not have this small RNA. We wondered whether there was something about this small RNA that endowed Yersinia pseudotuberculosis to be virulent through the fecal-oral route of infection. Ysr35, we were interested in because it was a small RNA that is shared between both Yersinia pestis and Yersinia pseudotuberculosis and we wanted to know whether conservation of small RNA was important for virulence of the genus as a whole.

For the case of Ysr29 for Yersinia pseudotuberculosis, we found significant attenuation of virulence [in mice infected with bacteria lacking Ysr29]. And then we have found the same for Ysr35 for both Yersinia pseudotuberculosis and Yersinia pestis. Now interestingly — and this was kind of a relief to us — not every small RNA we studied had an effect on virulence.

GT: How do you think your findings could be used to help either treat or prevent disease?

WL: I think that there are a couple of approaches. ... If we identify small RNAs that are required for virulence, we can then identify the regulated targets of those small RNAs, which would imply that those targets are also required for virulence. ... The idea is now that we know that those proteins are involved potentially in virulence, we might be able to target them for either vaccine development or therapeutics that would help treat the potential infection. The second way that I think is quite appealing is by targeting the small RNA machinery itself. I mentioned Hfq as a factor that's absolutely essential for virulence. Well, humans and mammals don't have this protein, so if there was a way that you could find a therapeutic or a small molecule or something like that, that could specifically target Hfq and render it inactive or nonfunctional, then you would disrupt the small RNA machinery of the bacteria, which would render the bacteria highly attenuated, if not avirulent, which would allow the body to clear the infection.

GT: What's your next step?

WL: What we're primarily interested in is, based on our results, understanding how bacterial pathogens evolve. One of the most interesting findings that came out of this study was that Yersinia pseudotuberculosis and Yersinia pestis, although they are so genetically closely related, cause completely separate diseases. ... Some of these differences in diseases might be attributable to changes in small RNA content or expression. What was published in this report is that we found six small RNAs that Yersinia pseudotuberculosis produces that Yersinia pestis does not. We've since expanded this study to do the same global analysis of small RNAs in Yersinia pestis. We haven't published that work, but we've already identified multiple small RNAs that Yersinia pestis contains that Yersinia pseudotuberculosis doesn't. We are very interested in understanding how the gain or loss of any of those small RNAs might have contributed to the evolution of Yersinia pseudotuberculosis, which causes this mild, self-limiting disease versus Yersinia pestis, which causes acute, highly pathogenic infection.

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