Long Noncoding RNAs in Host-Pathogen Interactions

Abstract

Long noncoding RNAs (lncRNAs) are key molecules that regulate gene expression in a variety of organisms. LncRNAs can drive different transcriptional and post-transcriptional events that impact cellular functions. Recent studies have identified many lncRNAs associated with immune cell development and activation; however, an understanding of their functional role in host immunity to infection is just emerging. Here, we provide a detailed and updated review of the functional roles of lncRNAs in regulating mammalian immune responses during host-pathogen interactions, because these functions may be either beneficial or detrimental to the host. With increased mechanistic insight into the roles of lncRNAs, it may be possible to design and/or improve lncRNA-based therapies to treat a variety of infectious and inflammatory diseases.

Figure 1.. Location of Mammalian LncRNAs Relative to Nearby Protein-Coding Genes.

Mammalian LncRNAs are classified depending on their genomic location. Intergenic lncRNAs and bidirectional lncRNAs do not overlap with other genes. Intergenic lncRNAs are situated between two protein-coding genes, at least 1 kb away from them; bidirectional lncRNAs are oriented head to head with a protein-coding gene within 1kb. Intronic lncRNAs and NATs show some degree of overlap with other genes [9]. Intronic lncRNAs arise from the intronic regions of protein-coding genes; NATs are lncRNAs complementary to protein-coding genes and may be categorized as cis-NATs, complementary to a protein-coding gene located in their same genomic location; and trans-NATs, arising in a different genomic location [89, 99]. Arrows show transcriptional direction.

Figure 2.. Examples of Known Mammalian LncRNAs Implicated in Immune Responses against Microbial Components.

(A) In murine macrophages, lincRNA-Cox2 is upregulated in response to LPS and Pam3CSK4 [25]. In murine macrophages and in response to Pam3CSK4, lincRNA-Cox2 binds hnRNPA/B and hnRNPA2/B1 leading to both activation and repression of different classes of genes [25]; in murine macrophages and in response to LPS, lincRNA-Cox2 can bind the SWI/SNF complex, leading to late inflammatory gene activation [26]. In human monocytes, IL-1β-RBT46 is upregulated following LPS stimulation, and enhances LPS-induced expression and release of proinflammatory mediators IL-1β and CXCL8 [28]. In murine macrophages, lincRNA-EPS is downregulated following LPS stimulation and at a steady state, lincRNA-EPS restrains IRG activation by interacting with hnRNPL [29]. However, after LPS-induced downregulation of lincRNA-EPS, its inhibitory function no longer appears to be exerted, leading to the upregulation of IRGs both in vitro and in vivo in mice [29]. (B) In HeLa cells, NEAT1 is upregulated in response to ISD and binds HEXIM1, DNAPK and paraspeckle components, thus forming the HDP-RNP complex [33]. Upon stimulation with ISD, the HDP-RNP is remodeled in its composition, with recruitment of STING, release of paraspeckle components, and phosphorylation of IRF3 [33]. Abbreviations: DNAPK, DNA-dependent protein kinase; MAL, MyD88 adapter-like; MyD88, myeloid differentiation primary response 88; pIRF3, phosphorylated interferon regulatory factor 3; STING, stimulator of interferon genes; TLR, Toll-like receptor; TRAM, TRIF-related adaptor molecule; TRIF, TIR-domain-containing adapter-inducing interferon-β.

Figure 3.. Examples of Known Mammalian Host-Derived LncRNAs Implicated in Host Defense Against Bacterial Infections.

(A) In human CD8⁺ T cells, lncRNA-CD244 is upregulated during Mycobacterium tuberculosis infection in a CD244-dependent manner [52]. LncRNA-CD244 interacts with the chromatin modification enzyme EZH2, leading to trimethylation of H3K27 at the TNFA and IFNG loci [52]. LncRNA-CD244 represses the expression of these two genes and promotes bacterial replication in human CD8⁺ T cells [52]. (B) In THP-1 cells, MEG3 is downregulated after M. bovis BCG infection [70]. In THP-1 cells, MEG3 affects autophagy by increasing LC3A/B conversion and blocking lysosomal degradation, thus eliminating intracellular M. bovis BCG [70]. (C) In HeLa cells, NEAT1 is upregulated upon Salmonella enterica Typhimurium [37]. The bacterium induces loss of MTR4 and RRP6, where NEAT1 is no longer degraded by the exosome, promoting the transcription of immune genes as well as bacterial clearance [37]. Abbreviations: EZH2, enhancer of zeste homolog 2.

Figure 4.. Examples of Known Mammalian Host-Derived LncRNAs Implicated in Host Defense Against Viral Infections.

(A) In human hepatocytes, lncRNA-IFI6 is upregulated in response to HCV. It specifically regulates IFI6 expression, leading to the regulation of H3K4me3 and H3K27me3 marks at the IFI6 promoter, promoting HCV infection in human hepatocytes [64]. In human hepatocytes, EGOT is upregulated upon HCV and SFV infection through the RIG-I and PKR pathways. In human hepatocytes, EGOT increases the expression of several ISGs, negatively affecting the antiviral response [35]. (B) In murine macrophages, lncRNA-ACOD1 is upregulated following VSV infection in an NF-κB-dependent manner. In murine macrophages, lncRNA-ACOD1 binds GOT2, increasing its catalytic activity and production of its metabolites, facilitating viral replication [36]. In murine macrophages, lncRNA-Lmsb3b is a type I IFN-dependent lncRNA induced in response to VSV and SeV [78]. At a late stage of infection, lncRNA-Lms3b binds the RIG-1 CTD, competing with RIG-I ligands; it also maintains RIG-I in a repressed state and prevents RIG-I oligomerization [78]. This inhibits RIG-I signaling and promotes viral replication in murine macrophages [78]. Abbreviations: CARDs, caspase recruitment domains; H3K27me3, trimethylation of lysine 27 on histone H3; H3K4me3, trimethylation of lysine 4 on histone H3; PKR, protein kinase R; RIG-I, retinoic acid-inducible.