Abstract

ABSTRACTRickettsia species are obligate intracellular bacteria with both conserved and lineage-specific strategies for invading and surviving within eukaryotic cells. One variable component of Rickettsia biology involves arthropod vectors: for instance, typhus group rickettsiae are principally vectored by insects (i.e., lice and fleas), whereas spotted fever group rickettsiae are exclusively vectored by ticks. For flea-borne Rickettsia typhi, the etiological agent of murine typhus, research on vertebrate host biology is facilitated using cell lines and animal models. However, due to the lack of any stable flea cell line or a published flea genome sequence, little is known regarding R. typhi biology in flea vectors that, importantly, do not suffer lethality due to R. typhi infection. To address if fleas combat rickettsial infection, we characterized the cat flea (Ctenocephalides felis) innate immune response to R. typhi. Initially, we determined that R. typhi infects Drosophila cells and increases antimicrobial peptide (AMP) gene expression, indicating immune pathway activation. While bioinformatics analysis of the C. felis transcriptome identified homologs to all of the Drosophila immune deficiency (IMD) and Toll pathway components, an AMP gene expression profile in Drosophila cells indicated IMD pathway activation upon rickettsial infection. Accordingly, we assessed R. typhi-mediated flea IMD pathway activation in vivo using small interfering RNA (siRNA)-mediated knockdown. Knockdown of Relish and Imd increased R. typhi infection levels, implicating the IMD pathway as a critical regulator of R. typhi burden in C. felis. These data suggest that targeting the IMD pathway could minimize the spread of R. typhi, and potentially other human pathogens, vectored by fleas.

Highlights

  • Rickettsia species are obligate intracellular bacteria with both conserved and lineage-specific strategies for invading and surviving within eukaryotic cells

  • We tested whether R. typhi could infect the Drosophila hemocyte-like KC167 and S2Rϩ cell lines, which can elicit an immune response upon microbial infection and induce antimicrobial peptide (AMP) gene expression [31]

  • A significant increase in R. typhi infection was observed between 1 and 24 h postinfection, followed by a decrease in R. typhi between 24 and 48 h postinfection for both KC167 and S2Rϩ cells. These results indicate that R. typhi is able to infect Drosophila KC167 and S2Rϩ cells and that these cell lines could serve as a model for studying activation of flea innate immunity by R. typhi

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Summary

Introduction

Rickettsia species are obligate intracellular bacteria with both conserved and lineage-specific strategies for invading and surviving within eukaryotic cells. Knockdown of Relish and Imd increased R. typhi infection levels, implicating the IMD pathway as a critical regulator of R. typhi burden in C. felis These data suggest that targeting the IMD pathway could minimize the spread of R. typhi, and potentially other human pathogens, vectored by fleas. One emergent method to control the spread of vectorborne pathogens is genetic modification of the vector immune response to prevent pathogen survival and transmission Such an approach requires in-depth knowledge of the host’s immune system, which for arthropod vectors is becoming increasingly more realized [5]. It has been demonstrated that upon taking a blood meal, the cat flea, Ctenocephalides felis, upregulates the expression of genes associated with immune defense [17] Pathogen evasion of this antibacterial response is likely required for optimal vector colonization and disease transmission. Characterizing flea innate immune pathways may illuminate targets for prevention of pathogen transmission

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