Chlamydia trachomatis-Induced Alterations in the Host Cell Proteome Are Required for Intracellular Growth

Abstract

Summary Intracellular pathogens directly alter host cells in order to replicate and survive. While infection-induced changes in host transcription can be readily assessed, post-transcriptional alterations are more difficult to catalog. We applied the global protein stability (GPS) platform, which assesses protein stability based on relative changes in an adjoining fluorescent tag, to identify changes in the host proteome following infection with the obligate intracellular bacteria Chlamydia trachomatis. Our results indicate that C. trachomatis profoundly remodels the host proteome independently of changes in transcription. Additionally, C. trachomatis replication depends on a subset of altered proteins, such as Pin1 and Men1, which regulate the host transcription factor AP-1 controlling host inflammation, stress, and cell survival. Furthermore, AP-1-dependent transcription is activated during infection, and required for efficient Chlamydia growth. In summary, this experimental approach revealed that C. trachomatis broadly alters host proteins and can be applied to examine host-pathogen interactions and develop host-based therapeutics.

Enhanced Direct Major Histocompatibility Complex Class I Self-Antigen Presentation Induced by Chlamydia Infection

“…Similar to our findings here (Fig. 3C), the levels of other proteins were diminished without appreciable alterations to the transcript levels (60). Future work will be needed to determine whether C. trachomatis reduces particular host proteins either because they are detrimental to the bacteria or simply because they provide self-peptides for antigen presentation, as demonstrated here.…”

“…Many times, this manifests itself in alterations to the transcriptome, which have been observed for a variety of Chlamydia species (57)(58)(59). However, a recent report demonstrated that C. trachomatis infection can alter the abundance of host proteins without altering levels of transcripts (60). In this way the bacterium was able to stabilize host components necessary for its survival.…”

AP-1 Transcription Factor Serves as a Molecular Switch between Chlamydia pneumoniae Replication and Persistence

“…Knockdown of the c-Jun protein altered C. pneumoniae infection, resulting in (i) 20% smaller inclusions, (ii) downregulation of MOMP, (iii) reduction of the chlamydial load, and (iv) a significant decrease in chlamydial recovery. Our findings indicate that growth conditions are suboptimal in the absence of the c-Jun protein and are in line with those described in the report of Olive et al, who found that c-Jun knockdown results in a significant reduction in the level of IFU production (25). In our study, the knockdown effect on infection was possibly limited, since the siRNA approach resulted in only a partial reduction in the level of the c-Jun protein.…”

“…In concordance with those findings, we demonstrated that proteins of the AP-1 family are regulated upon chlamydia infection. We found that C. pneumoniae regulates AP-1 proteins mainly at late time points during development, a finding in line with that from a recent study focusing on Chlamydia trachomatis (25). It was demonstrated that the phosphorylation of c-Jun and c-Fos with subsequent AP-1-dependent transcription is induced at a late developmental stage, suggesting that AP-1 is involved in replication or during the redifferentiation process.…”

“…A role for AP-1 upon infection with microbes or viruses has already been described (22,23). Indeed, AP-1 was regulated during C. pneumoniae infection in smooth vascular muscle cells, while for the sexually transmittable organism Chlamydia tracho-matis, AP-1 has been demonstrated to be crucial for bacterial growth and development (24,25).…”