Plague is a flea-borne zoonotic disease characterized by sylvatic cycles in wild rodent populations and their associated fleas. These sylvatic cycles are composed of an epizootic phase, which increases the risk of transmission and human disease, and an enzootic/quiescent stage in which the causative bacterium, Yersinia pestis, persists and maintains the reservoir. While epizootics can be supported by a biofilm-mediated gut blockage transmission mechanism, the basis of the enzootic/quiescent stage is unknown. We propose that this quiescence is mediated by a 'dormant'form of the bacterium which sustains persistence within the flea but can then revert to a transmissible infection upon favorable conditions. Understanding the molecular underpinnings of Y. pestis persistence during inter-epizootic periods would resolve a significant gap in knowledge and may lead to identification of new targets to prevent flea-borne transmission and epizootics. Our recent comparative transcriptional profiling of a Yersinia pestis ?phoP mutant versus a wildtype strain supports the presence of an alternate dormant survival state in the ?phoP mutant within the flea gut. Among other supporting phenomena descriptive of dormancy, numerous toxin:antitoxin (TA) modules that are responsible for dormant persister cell formation by downregulating essential cellular processes have exclusively elevated expression in the ?phoP mutant. This lead to the hypothesis that Y. pestis transitions into the self-protective survival state of dormancy which allows it to persist in the flea host, and that this phenotype is reversible and driven by TA module expression. The goal of the R21 exploratory research is to determine whether dormancy is a function of persistence and whether expression of TA modules are responsible for driving dormancy and reactivation of the biological biofilm gut blockage transmissible infection in Y. pestis. Experimentally this will be achieved by establishing whether dormancy is phenotypically and mechanistically a function of persistence by assessing the prolonged survivability and high tolerance to antibiotics, respectively of the dormant Y. pestis ?phoP mutant in the flea gut. Next, by creating a conditionally inducible phoP strain we will test whether dormant cells can be reactivated to cause a transmissible infection. Finally we will specifically test the role of TA modules in driving the dormant and reactivated gut blocked transmitting phenotypes of Y. pestis by creating conditionally inducible toxin expressing strains and assaying them for long term survival, antibiotic tolerance and biofilm gut blockage. This research is consistent with the exploratory/developmental nature of the R21 mechanism (as described in PA-10-069) because it explores uncharacterized molecular mechanisms that drive persistence of Y. pestis in the flea vector, which may lead to identification of new targets to prevent flea-borne transmission and epizootics.

Public Health Relevance

Bubonic plague has re-emerged as a public health problem and is a bioweapons threat, in both events due to transmission by infected fleas. The objective of the research is to characterize whether dormancy drives persistence of Yersinia pestis in the flea vector and to define the molecular mechanisms responsible for this persistence during inter-epizootic periods. This may lead to identification of new targets to prevent flea-borne transmission and epizootics/epidemics.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Vector Biology Study Section (VB)
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Mukhopadhyay, Suman
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Washington State University
Veterinary Sciences
Schools of Veterinary Medicine
United States
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Vadyvaloo, Viveka; Viall, Austin K; Jarrett, Clayton O et al. (2015) Role of the PhoP-PhoQ gene regulatory system in adaptation of Yersinia pestis to environmental stress in the flea digestive tract. Microbiology 161:1198-1210
Bobrov, Alexander G; Kirillina, Olga; Vadyvaloo, Viveka et al. (2015) The Yersinia pestis?HmsCDE regulatory system is essential for blockage of the oriental rat flea (Xenopsylla cheopis), a classic plague vector. Environ Microbiol 17:947-59
Martínez, Luary C; Vadyvaloo, Viveka (2014) Mechanisms of post-transcriptional gene regulation in bacterial biofilms. Front Cell Infect Microbiol 4:38