Long Non-Coding RNA FGD5-AS1 Induced by Chlamydia trachomatis Infection Inhibits Apoptosis via Wnt/β-Catenin Signaling Pathway

Abstract

BackgroundChlamydia trachomatis (Ct) is one of the most common bacterial sexually transmitted infection (STI) pathogens in the world, but the exact pathogenic mechanism still needs to be further elucidated. Long non-coding RNAs (lncRNAs) have become vital regulators in many biological processes. Their role in the interaction between Ct and host cells has not been reported.MethodsMicroarrays were used to study the expression profiles of lncRNAs and mRNAs in HeLa cells at 12, 24, and 40 h post-infection (hpi). Differentially expressed lncRNAs and mRNAs were verified by RT-qPCR. Coding-non-coding (CNC) network analysis showed co-expression molecules of selected lncRNA. Western blot, flow cytometry, and indirect immunofluorescence were used to detect the effect of lncRNA FGD5-AS1 on apoptosis during Ct infection.ResultsCompared with the uninfected group, the number of differential lncRNAs were 2,130, 1,081, and 1,101 at 12, 24, and 40 hpi, and the number of differential mRNAs was 1,998, 1,129, and 1,330, respectively. Ct induced differential expression of large amounts of lncRNAs and mRNAs in HeLa cells, indicating that lncRNAs may play roles in the pathogenesis of Ct. RT-qPCR verified six differential lncRNAs and six differential mRNAs, confirming the reliability of the microarray. Among these molecules, lncRNA FGD5-AS1 was found to be upregulated at 12 and 24 hpi. Coding-non-coding (CNC) network analysis showed that co-expressed differential molecules of FGD5-AS1 at 12 and 24 hpi were enriched in the DNA replication and Wnt signaling pathway. The downregulation of FGD5-AS1 decreased the expression of β-catenin and inhibited the translocation of β-catenin and the DNA replication, while it promoted apoptosis of the host cells.ConclusionsDNA replication and apoptosis of host cells were affected by upregulating FGD5-AS1 via Wnt/β-catenin pathway during Ct infection. This study provides evidence that lncRNAs are involved in the coaction between Ct and hosts, and provides new insights into the study of lncRNAs that regulate chlamydial infection.

Persistence in Chlamydia

“…Expression of many ncRNAs is altered during growth stress stimuli that induce persistent growth, particularly IFN-γ and carbenicillin [92]. Recent findings provided evidence that lncRNAs are involved in regulating apoptosis pathways in Chlamydia [93,94]. The anti-apoptotic activity of the lncRNAs includes modulation of the DNA replication and apoptosis of host cells via Wnt/β-catenin pathway [93] or downregulation of the Bcl-2/Bax ratio with a marked release of cytochrome c, resulting in a significantly elevated level of caspase-3 activation [94].…”

“…Recent findings provided evidence that lncRNAs are involved in regulating apoptosis pathways in Chlamydia [93,94]. The anti-apoptotic activity of the lncRNAs includes modulation of the DNA replication and apoptosis of host cells via Wnt/β-catenin pathway [93] or downregulation of the Bcl-2/Bax ratio with a marked release of cytochrome c, resulting in a significantly elevated level of caspase-3 activation [94]. One of the Chlamydial targeted lncRNA (MIAT) was involved in regulating Chlamydial development during the persistent infection [94].…”

The emerging roles of long non-coding RNA in host immune response and intracellular bacterial infections

“…LncRNAs are either host-derived or expressed by pathogens and their response may play a crucial role in modulating bacterial infections. The general outcome of intracellular pathogenic infection may depend upon how these lncRNAs modulate target (Wen et al, 2021) genes to either promote or restrict the pathogens' replication inside host (Agliano et al, 2019).…”

“…Gene ontology analysis showed they enriched for DNA replication and Wnt signaling pathway. FGD5-AS1 positively regulated the expression of the Wnt/b-Catenin pathway (Figure 4C), inhibiting apoptosis and promoting intracellular replication of Ct in host (Wen et al, 2021).…”

Targeting lncRNA/Wnt axis by flavonoids: A promising therapeutic approach for colorectal cancer

“…Thus, a better understanding of lncRNAs molecular targeting and delivery systems may facilitate to develop new CRC diagnostic, prognostic, and therapeutic strategies. To date, numerous convincing studies show that lncRNAs target multiple signaling pathways (such as TGF/Smad, Hippo, Notch, MAPK/ERK, PI3K/Akt/mTOR pathway), especially Wnt/β‐Catenin signaling pathway (Sun, Zhang, & Liu, 2018; Ji et al, 2013; Wen et al, 2021; Yu, Rong, et al, 2021). Indeed, lncRNAs can interact with multiple components of Wnt/β‐Catenin signaling pathway to regulate the expression of Wnt target genes in cancers, which significantly contribute to establishing the well‐accepted concept of lncRNA/Wnt axis.…”