Abstract
Coxiella burnetii is an intracellular, zoonotic pathogen that is the causative agent of Q fever. Infection most frequently occurs after inhalation of contaminated aerosols, which can lead to acute, self-limiting febrile illness or more serve chronic infections such as hepatitis or endocarditis. Macrophages are the principal target cells during infection where C. burnetii resides and replicates within a unique phagolysosome-like compartment, the Coxiella-containing vacuole (CCV). The first virulence determinant described as necessary for infection was full-length lipopolysaccarride (LPS); spontaneous rough mutants (phase II) arise after passage in immuno-incompetent hosts. Phase II C. burnetii are attenuated in immuno-competent animals, but are fully capable of infecting a variety of host cells in vitro. A clonal strain of the Nine Mile isolate (RSA439, clone 4), has a 26 KDa chromosomal deletion that includes LPS biosynthetic genes and is uniquely approved for use in BL2/ABL2 conditions. With the advances of axenic media and genetic tools for C. burnetii research, the characterization of novel virulence determinants is ongoing and almost exclusively performed using this attenuated clone. A major problem with predicting essential virulence loci with RSA439 is that, although some cell-autonomous phenotypes can be assessed in tissue culture, no animal model for assessing pathogenesis has been defined. Here we describe the use of SCID mice for predicting virulence factors of C. burnetii, in either independent or competitive infections. We propose that this model allows for the identification of mutations that are competent for intracellular replication in vitro, but attenuated for growth in vivo and predict essential innate immune responses modulated by the pathogen during infection as a central pathogenic strategy.
Highlights
Q fever is a zoonotic disease caused by the Gram-negative bacterium Coxiella burnetii, which most commonly causes asymptomatic or acute febrile illness but can lead to serious chronic infections including endocarditis in humans (van Schaik et al, 2013)
We observed that the mice do, mount a significant antigen specific CD4+ mediated immune response to IP challenge with C. burnetii Nine Mile II (NMII) (Figure 1B)
Further evidence to support this hypothesis is that Genome equivalents (GE) from heat killed NMII in SCID mice are not detectable after 14 days, the detection of GE in wild-type mice even after 28 days suggests that these bacteria are potentially still viable or would have been cleared especially considering wild-type mice mount a specific CD4+ Tcell response (Figure 1B)
Summary
Q fever is a zoonotic disease caused by the Gram-negative bacterium Coxiella burnetii, which most commonly causes asymptomatic or acute febrile illness but can lead to serious chronic infections including endocarditis in humans (van Schaik et al, 2013). Invasion of macrophages is through a passive mechanism after which the C. burnetii vacuole traffics through the default endocytic pathway to a phagolysosome-like compartment termed the CCV (Baca et al, 1993; Howe et al, 2010; van Schaik et al, 2013). This compartment becomes highly fusogenic and expands concomitant with C. burnetii replication (Howe et al, 2003; Coleman et al, 2004) while no apparent bactericidal mechanisms are inhibited. C. burnetii manipulates a variety of host pathways to create and maintain its unique intracellular replicative niche including endolysosomal trafficking, secretion, autophagy, and apoptosis (Larson et al, 2015)
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