Human Cytomegalovirus Encoded miR-US25-1-5p Attenuates CD147/EMMPRIN-Mediated Early Antiviral Response

Abstract

Cellular receptor-mediated signaling pathways play critical roles during the initial immune response to Human Cytomegalovirus (HCMV) infection. However, the involvement of type-I transmembrane glycoprotein CD147/EMMPRIN (extracellular matrix metalloproteinase inducer) in the antiviral response to HCMV infection is still unknown. Here, we demonstrated the specific knockdown of CD147 significantly decreased HCMV-induced activation of NF-κB and Interferon-beta (IFN-β), which contribute to the cellular antiviral responses. Next, we confirmed that HCMV-encoded miR-US25-1-5p could target the 3′ UTR (Untranslated Region) of CD147 mRNA, and thus facilitate HCMV lytic propagation at a low multiplicity of infection (MOI). The expression and secretion of Cyclophilin A (sCyPA), as a ligand for CD147 and a proinflammatory cytokine, were up-regulated in response to HCMV stimuli. Finally, we confirmed that CD147 mediated HCMV-triggered antiviral signaling via the sCyPA-CD147-ERK (extracellular regulated protein kinases)/NF-κB axis signaling pathway. These findings reveal an important HCMV mechanism for evading antiviral innate immunity through its encoded microRNA by targeting transmembrane glycoprotein CD147, and a potential cause of HCMV inflammatory disorders due to the secretion of proinflammatory cytokine CyPA.

Altered human cytomegalovirus-encoded miRNAs in host circulation: novel disease biomarkers and potential aetiological agents

“…Additionally, miR-UL148D was found to target ACVR1B and limited pro-inflammatory cytokine secretion in HCMV latent infected primary myeloid cells [66]. Besides miR-UL112-1 and miR-UL148D, a very recent work confirmed that miR-US25-1-5p could attenuate the expression of CD147, which can mediate HCMV-triggered antiviral signaling, and induce HCMV lytic propagation at a low multiplicity of infection [67].…”

“…Essential hypertension has been recognized as a critical risk factor for cardiovascular diseases and the main cause of chronic renal failure. Existing studies have documented that essential hypertension may be induced by specific environmental and genetic factors, nevertheless, the precise cause of [27], [49] IL-32 Immune evasion [50] hcmv-miR-US4-1 ERAP1 Immune evasion [29] hcmv-miR-UL112-5p ERAP1 Immune evasion [51] hcmv-miR-UL112-3p IE72 Virus replication [24] UL114 Virus replication [52] hcmv-miR-US25-2 Undetermined Virus replication [52] hcmv-miR-US25-1 Undetermined Virus replication [52] hcmv-miR-US25-2 eIF4A1 Virus replication [53] hcmv-miR-US25-1 ATP6V0C Virus replication [54] hcmv-miR-US25-1 YWHAE, UBB, NPM1, HSP90AA1 Virus replication [55] hcmv-miR-US33-5p STX3 Virus replication [56] hcmv-miR-US5-1 Geminin Virus replication [57] hcmv-miR-UL112-3p IE1 HCMV latency [59] IE72 HCMV latency [60] hcmv-miR-UL148D IER5 HCMV latency [61] hcmv-miR-UL112-3p Type I IFNs Host secretory pathway [62] TLR2 Host secretory pathway [63] hcmv-miR-UL148D RANTES Host secretory pathway [65] ACVR1B Host secretory pathway [66] hcmv-miR-US25-1 CD147 Host secretory pathway [67] hcmv-miR-UL148D IEX-1 Host cell apoptosis [68] ERN1 Host cell apoptosis [70] hcmv-miR-UL36-5p ANT3 Host cell apoptosis [73] hcmv-miR-US4-1 QARS Host cell apoptosis [74] hcmv-miR-US25-1 BRCC 3 Host cell apoptosis [75] hcmv-miR-UL112-3p MAPK, Chemokine Host cell growth and proliferation [31] hcmv-miR-US25-1-5p, hcmv-miR-US25-2-5p Plasma Congenital CMV infection Upregulation [84] hcmv-miR-US33-5p Plasma Acute aortic dissection Upregulation [86] hcmv-miR-US4-1, hcmv-miR-UL-148D Serum IFNα treatment non-responsive chronic hepatitis B Upregulation [87] hcmv-miR-UL112-3p, hcmv-miR-UL22a-5p, hcmv-miR-UL148d, hcmv-miR-UL36-5p, hcmv-miR-UL59…”

The Interplay Between Viral-Derived miRNAs and Host Immunity During Infection

“…miR-UL112, US25-2-3p, and US4-1 modulate immune recognition by cytotoxic T lymphocyte (CTL) and natural killer (NK) cells (64)(65)(66)(67). Similarly, the HCMV miRs UL112-3p, US5-1, UL112-1, US25-1-5p, and UL148D target multiple host inflammatory genes and result in reduced inflammatory response (53,54,(68)(69)(70)(71). Also, UL148D and UL36-5p are found to inhibit programmed cell death by repressing the expression of cellular genes involved in the regulation of apoptosis (72)(73)(74).…”

MicroRNAs expressed by human cytomegalovirus

“…In recent years, primary myeloid cells have been receiving much attention due to the high ranges of latency-associated HCMV transcripts including miRNAs measured in this cell model, while much work on the potential targets of these HCMV miRNAs has been carried out [30,31,49]. Various experiments have been performed to elucidate the expression and functions of miRNAs during latency using primary myeloid cells infected with mutant viruses [21,27,31,51,52]. The mutation include altering the expression of a specific miRNA or removing the miRNA binding site.…”