Interaction ofChlamydia trachomatisSerovar L2 with the Host Autophagic Pathway

Abstract

Chlamydiae are obligate intracellular pathogens that replicate within a membrane-bound compartment (the inclusion) and are associated with important human diseases, such as trachoma, pneumonia, and atherosclerosis. We have examined the interaction of the host autophagic pathway with Chlamydia trachomatis serovar L2 by using the specific autophagosomal stain monodansylcadaverine, antibodies to autophagosome-associated markers, and traditionally used autophagic inhibitors, particularly 3-methyladenine and amino acids. Chlamydial inclusions did not sequester monodansylcadaverine, suggesting absence of fusion with autophagosomes. Interestingly, exposure of cultures infected for 19 h to 3-methyladenine or single amino acids until the end of infection (44 h) caused various degrees of abnormalities in the inclusion maturation and in the progeny infectivity. Incubation of host cells with chemicals throughout the entire period of infection modulated the growth of Chlamydia even more dramatically. Remarkably, autophagosomal markers MAP-LC3 and calreticulin were redistributed to the inclusion of Chlamydia, a process that appears to be sensitive to 3-methyladenine and some amino acids. The present data indicate the lack of autophagosomal fusion with the inclusion because it was devoid of monodansylcadaverine and no distinct rim of autophagosomal protein-specific staining around the inclusion could be observed. However, high sensitivity of Chlamydia to conditions that could inhibit host autophagic pathway and the close association of MAP-LC3 and calreticulin with the inclusion membrane still suggest a potential role of host autophagy in the pathogenesis of Chlamydia.

Pathogens and autophagy: subverting to survive

“…14 Additionally, a potential role for host autophagy in Chlamydia trachomatis pathogenesis has been proposed. 15 Similar to the results obtained with P.gingivalis, exposing infected cultures to autophagy inhibitors -such as 3-methyladenine and amino acids -altered the inclusion maturation and Chlamydia growth. 15 Work from our own laboratory demonstrated that Coxiella burnetii, a gram-negative bacterium, replicates in a compartment labeled by the autophagosomal protein Atg8/LC3.…”

“…15 Similar to the results obtained with P.gingivalis, exposing infected cultures to autophagy inhibitors -such as 3-methyladenine and amino acids -altered the inclusion maturation and Chlamydia growth. 15 Work from our own laboratory demonstrated that Coxiella burnetii, a gram-negative bacterium, replicates in a compartment labeled by the autophagosomal protein Atg8/LC3. 16 Furthermore, we have recently shown that both physiologically and pharmacologically induced autophagy favor the development of the Coxiella replicative vacuole.…”

The autophagic pathway is a key component in the lysosomal dependent entry ofTrypanosoma cruziinto the host cell

“…Although in some cases the autophagic response functions as an innate immune response against pathogens like Mycobacterium tuberculosis, 22 Group A Streptococcus 23 and Listeria monocytogenes, 24 in other cases the microorganisms take advantage of this cellular process to favor the infection. [25][26][27] That is the case of Porphyromonas gingivalis, 26,27 Brucella abortus, 27 Coxiella burnetii, 28 Chlamydia 29 and Staphylococcus aureus. 30 The main difference between these two behaviors is not well understood to date, but is important to mention that some pathogens have the faculty to modulate the autophagic response in their own benefit.…”

Trafficking from CD63-positive late endocytic multivesicular bodies is essential for intracellular development of Chlamydia trachomatis

“…Autophagy is a major mechanism for degradation and recycling of intracellular macromolecules (Klionsky and Emr, 2000). Although studies have indicated a lack of autophagosomal fusion with the chlamydial inclusion, the intracellular bacteria were sensitive to 3-methyladenine and other traditional inhibitors of autophagy (Al-Younes et al, 2004). The autophagy pathway is thought to intersect MVBs prior to lysosomal delivery (Lucocq and Walker, 1997).…”

“…The PI 3-kinase inhibitor 3-methyladenine is also a modulator of autophagy (Seglen and Gordon, 1982); and in the pathogenesis of Chlamydia, a potential role of the host cell's autophagy pathway has been proposed (Al-Younes et al, 2004). Autophagy is a major mechanism for degradation and recycling of intracellular macromolecules (Klionsky and Emr, 2000).…”