Resistance to Innate Immunity Contributes to Colonization of the Insect Gut by Yersinia pestis

Abstract

Yersinia pestis, the causative agent of bubonic and pneumonic plague, is typically a zoonotic vector-borne disease of wild rodents. Bacterial biofilm formation in the proventriculus of the flea contributes to chronic infection of fleas and facilitates efficient disease transmission. However prior to biofilm formation, ingested bacteria must survive within the flea midgut, and yet little is known about vector-pathogen interactions that are required for flea gut colonization. Here we establish a Drosophila melanogaster model system to gain insight into Y. pestis colonization of the insect vector. We show that Y. pestis establishes a stable infection in the anterior midgut of fly larvae, and we used this model system to study the roles of genes involved in biofilm production and/or resistance to gut immunity stressors. We find that PhoP and GmhA both contribute to colonization and resistance to antimicrobial peptides in flies, and furthermore, the data suggest biofilm formation may afford protection against antimicrobial peptides. Production of reactive oxygen species in the fly gut, as in fleas, also serves to limit bacterial infection, and OxyR mediates Y. pestis survival in both insect models. Overall, our data establish the fruit fly as an informative model to elucidate the relationship between Y. pestis and its flea vector.

A Single Amino Acid Change in the Response Regulator PhoP, Acquired during Yersinia pestis Evolution, Affects PhoP Target Gene Transcription and Polymyxin B Susceptibility

“…To our knowledge, this is the first study that directly indicated a potential role of phoP in the survival of Y. pestis within the flea digestive tract. Our results are consistent with the finding in a Drosophila melanogaster model for the Y. pestis colonization of insect vectors that the loss of phoP results in decreased colonization of the midgut of fly larvae (39). Although the mechanism by which phoP promotes bacterial survival in the fleas is unclear, it may be a subtle role that is not easily detected in a single-strain infection assay.…”

“…A recent study reported that Y. pestis lacking other genes in the lipid A modification pathway (galU and arnB) is defective in colonizing the flea midgut (40). In addition, the aforementioned Drosophila model of Y. pestis colonization showed that the decreased colonization of fly larvae by the phoP mutant strain can be rescued by the inactivation of the host imd, the gene that drives the production of antimicrobial peptides (39). Therefore, we cannot rule out the possibility that the lipid A modification and the resistance to antimicrobial peptide play some role in Y. pestis survival in the flea.…”

Options and Limitations in Clinical Investigation of Bacterial Biofilms

“…; it was identified that Providencia sneebia is lethal while propagating in the fly but elicits a mild immune response (282). Moreover, a chronic gut Yersinia pestis infection was established in the anterior fly larva midgut to mimic and dissect the relationships between biofilm-associated genes (PhoP, GmhA, and OxyR), the gut immune system, and antimicrobial peptides (283).…”

Regulated Control of the Assembly and Diversity of LPS by Noncoding sRNAs

“…RybB-mediated repression of WaaR could as well contribute to bacterial adhesion and phagocytosis as discussed earlier. Severe defects in LPS or lack of PhoP have been shown to cause defects in colonization, biofilm formation, and sensitivity to antimicrobial peptides in many pathogenic bacteria such as Yersinia pestis [ 83 ].…”