Killing me softly: chlamydial use of proteolysis for evading host defenses

Abstract

Chlamydial infections in humans cause severe health problems, including blinding trachoma and sexually transmitted diseases. Although the involved pathogenic mechanisms remain unclear, the ability to replicate and maintain long-term residence in the infected cells seems to significantly contribute to chlamydial pathogenicity. These obligate intracellular parasites maintain a delicate balance between exploiting and protecting their host: they occupy intracellular space and acquire nutrients from the infected cells, but at the same time they have to maintain the integrity of the host cells for the completion of their intracellular growth. For this purpose, chlamydiae hijack certain signaling pathways that prevent the host cells from undergoing apoptosis induced by intracellular stress and protect the infected cells from recognition and attack by host defenses. Interestingly, one of the strategies that chlamydiae use for these purposes is the induction of limited proteolysis of host proteins, which is the main focus of this article.

Figure 1

Chlamydial life cycle and the inflammatory processes associated. (i) Chlamydiae are obligate intracellular bacterial pathogens with a life cycle including two cell types: elementary bodies (EBs), which are infectious and invade the host cells, and reticular bodies (RBs), which are not infectious and undergo duplication inside a cytoplasmic vacuole (or inclusion). RBs differentiate back to EBs for exiting the infected cells and then enter adjacent new target cells, starting a new cycle of infection. This productive infection is observed in cell cultures . (ii) However, during infection in humans, chlamydiae can enter a persistent infection status in which RBs do not undergo rapid duplication, instead becoming enlarged bodies each with multiple nuclei. Although it is not known how the parasites enter or exit the infection status, it is believed that the persistent infection can significantly contribute to the inflammatory pathologies induced by chlamydiae . (iii) Both productively and persistently infected cells can release large amounts of inflammatory cytokines that can induce and sustain tissue damage and inflammatory responses at the site of infection , . The lysis of productively infected cells might further amplify the inflammation. Due to the inability of the inflammation to clear the intracellular infection, the net result may be tissue damage and fibrosis of the tissue, .

Figure 2

The role of host kinase pathways in chlamydial acquisition of lipids and induction of inflammation. Chlamydiae can acquire lipids from host cells by converting glycerophospholipids into lysophospholipids through activation of host Raf/MEK/ERK/cPLA2 pathway (i) , intercepting Golgi-derived exocytic vesicles by cleaving golgin-84 (ii) , activating kinases that are sensitive to rottlerin inhibition (iii) , inducing fusion with CD63-positive vesicles (iv) and recruiting lipid droplets (LD) (v) . U0126, an inhibitor of MEK1/2, can inhibit the ERK/cPLA2 pathway and the acquisition of glycerophospholipids by the microbe (vi) . The endoparasites modify host-derived glycerophospholipids by replacing the straight chain fatty acid with a branched chain fatty acid at the sn2 position (i, vii). They synthesize the branched fatty acid chain using glucose (GLC) to build the main carbon chain, and use the branched side chain of isoleucine (ILE) to seal the carbon chain. Thus, one can conveniently quantitate the acquisition of host glycerophospholipids by monitoring the incorporation of H³-labeled ILE into chlamydial lipids . Rottlerin (iii) is a plant-derived inhibitor targeting various mammalian kinases, including protein kinase C delta (PKCδ), and it can inhibit sphingomyelin trafficking from Golgi to the parasite inclusion . However, it is not known whether rottlerin exerts its inhibitory effect via inhibition of PKCδ. Importantly, rottlerin also blocks chlamydial replication. Since it is known that blocking sphingomyelin trafficking is not enough for inhibiting chlamydial growth, rottlerin must block multiple and redundant pathways; these might include the fusion with CD63-positive vesicles, the recruitment of lipid droplets, and cPLA2-catalyzed lysophospholipid generation. Interestingly, the activation of host kinases for acquisition of lipids might also contribute to the induction of inflammation. Many inflammatory cytokines including IL-8 and IL-6 are indeed produced by chlamydiae-infected cells , , . ERK1/2-mediated pathway might directly or indirectly (via promoting nuclear localization of Pro-IL-1α, precursor of IL-1α) participate in the activation of inflammatory genes, since U0126 can significantly inhibit the cytokine production (vi) . However, the effect of rottlerin on inflammation has not been investigated. In addition, the cleaved arachidonic acid can be converted into PGE2 by the action of COX2. PGE2 can further enhance inflammation by promoting the activation of inflammatory genes (viii) .