Biochemical stratagem for obligate parasitism of eukaryotic cells by Coxiella burnetii.

Abstract

Coxiella burnetti, the etiologic agent of Q fever, is an oligate intracellular parasite of eukaryotes. Unlike the majority of successful bacterial parasites, which escape the bactericidal environment of the phagolysosome by various means, C. burnetii multiplies only in the phagolysosome. In view of the relatively harsh environment inhabited by C. burnetii, we have examined (i) the in vitro metabolism of glucose and glutamate by whole cells of C. burnetii under conditions designed to approximate the pH within the phagolysosome and (ii) the effect of manipulation of the phagolysosomal pH by lysosomotropic amines on the replication of C. burnetii in chicken embryo fibroblasts. The transport, catabolism, and incorporation of both glucose and glutamate were found to be highly stimulated by acidic conditions, whereas at pH 7.0 metabolism of these substrates was minimal. The transport processes were shown to be energy dependent and highly sensitive to inhibition by uncouplers of oxidative phosphorylation. Increasing the phagolysosomal pH ofinfected chicken embryo fibroblasts by use of the lysosomotropic agents chloroquine, methylamine, or ammonium chloride inhibited the multiplication of C. burnetii, thus demonstrating the in vivo requirement for the acidic conditions ofthe phagolysosome. This apparent dependence upon phagosome-lysosome fusion to generate pH conditions favorable to C. burnetii replication suggests a unique biochemical mechanism of parasite activation. A pathogenic mechanism based on regulation of microbial metabolism by H+-dependent stimulation of cell function is proposed.

Interaction between autophagic vesicles and the Coxiella-containing vacuole requires CLTC (clathrin heavy chain)

“…Additionally, the effector Lpg1137 has recently been reported to proteolytically cleave STX17, a protein involved in the fusion of autophagosomes with the lysosome, and a further effector LpSpI, inhibits autophagy through its ability to target host sphingosine biosynthesis [38,39]. In contrast, rather than being bactericidal, the lysosome provides the appropriate environment to induce metabolic activity of Coxiella and promote intracellular replication [8]. Hence, autophagy induction and autophagosomal fusion is in this pathogen’s favor.…”

“…Features of the CCV, such as a low pH of approximately 4.8 and the presence of proteolytic and degradative enzymes, are closely aligned to those of lysosomes [7]. This environment is essential for the metabolic activity of Coxiella and the biogenesis of the replicative CCV [8,9]. Over a period of several days the pathogen directs the expansion of the CCV such that it can occupy the majority of the host cytoplasm.…”

Is Q Fever an emerging or re-emerging zoonosis?

“…burnetii is a small pleomorphic Gramnegative bacterium. C. burnetii is an obligate intracellular bacterium that replicates to high numbers, although with an estimated slow doubling time (12-20 h), within the phagolysosome of the eukaryotic phagocyte [53,187]. The sequence of the complete genome of C. burnetii Nine Mile phase I RSA493 has been analyzed and suggests a circular topology for the chromosome.…”

Coxiella burnetiiSurvival in THP-1 Monocytes Involves the Impairment of Phagosome Maturation: IFN-γ Mediates its Restoration and Bacterial Killing

“…The selective use of phagocytic receptors is an active process based on interference with complement receptor type 3-mediated phagocytosis (3). Once internalized, C. burnetii survives and replicates in an acidic environment (4,5), which is needed for bacterial metabolism (6,7). This low pH also accounts for the relative inefficiency of antibiotics toward C. burnetii (1).…”