Abstract:Human C-type lectin member 18A (CLEC18A) is ubiquitously expressed in human, and highest expression levels are found in human myeloid cells and liver. In contrast, mouse CLEC18A (mCLEC18A) is only expressed in brain, kidney and heart. However, the biological functions of CLEC18A are still unclear. We have shown that a single amino acid change (S339 →R339) in CTLD domain has profound effect in their binding to polysaccharides and house dust mite allergens. In this study, we further demonstrate that CLEC18A and … Show more
“…A mouse model has also demonstrated that human CLEC18A associates with TLR3 and dsRNA in endosomes to enhance TLR3-mediated IFN expression (49). In mosquitoes, CLEC18A may also associate with a Toll or DENV/Toll receptor to enhance innate immune signaling cascades and AMPs expression.…”
Section: Discussionmentioning
confidence: 98%
“…C-type lectins act as important components of many innate immune systems, and are known to act as PRRs of several viruses (including DENV). In mice, transgenic expression of human CLEC18A enhances BMDM IFN-α/β expression following DENV exposure (49). CLEC18A may thus interact with DENV directly to enhance cellular response levels.…”
Section: Human Clec18a Associates With Dengue Prm-e and Virus Particlesmentioning
confidence: 99%
“…Beyond hepatocytes, this isoform can also be secreted from monocytes, dendritic cells, and macrophages, suggesting that CLEC18A may be related to the innate immune system, and therefore may possibly participate in combatting viral infection (47). A mouse model study has demonstrated that the presence of CLEC18A increases type-I interferon expression (49), could leading to reduction in DENV infection and replication. Despite these promising results however, CLEC18A has not yet been expressed in mosquitoes.…”
The C-type lectins, one family of lectins featuring carbohydrate binding domains which participate in a variety of bioprocesses in both humans and mosquitoes, including immune response, are known to target DENV. A human C-type lectin protein CLEC18A in particular shows extensive glycan binding abilities and correlates with type-I interferon expression, making CLEC18A a potential player in innate immune responses to DENV infection; this potential may provide additional regulatory point in improving mosquito immunity. Here, we established for the first time a transgenic Aedes aegypti line that expresses human CLEC18A. This expression enhanced the Toll immune pathway responses to DENV infection. Furthermore, viral genome and virus titers were reduced by 70% in the midgut of transgenic mosquitoes. We found significant changes in the composition of the midgut microbiome in CLEC18A expressing mosquitoes, which may result from the Toll pathway enhancement and contribute to DENV inhibition. Transgenic mosquito lines offer a compelling option for studying DENV pathogenesis, and our analyses indicate that modifying the mosquito immune system via expression of a human immune gene can significantly reduce DENV infection.
“…A mouse model has also demonstrated that human CLEC18A associates with TLR3 and dsRNA in endosomes to enhance TLR3-mediated IFN expression (49). In mosquitoes, CLEC18A may also associate with a Toll or DENV/Toll receptor to enhance innate immune signaling cascades and AMPs expression.…”
Section: Discussionmentioning
confidence: 98%
“…C-type lectins act as important components of many innate immune systems, and are known to act as PRRs of several viruses (including DENV). In mice, transgenic expression of human CLEC18A enhances BMDM IFN-α/β expression following DENV exposure (49). CLEC18A may thus interact with DENV directly to enhance cellular response levels.…”
Section: Human Clec18a Associates With Dengue Prm-e and Virus Particlesmentioning
confidence: 99%
“…Beyond hepatocytes, this isoform can also be secreted from monocytes, dendritic cells, and macrophages, suggesting that CLEC18A may be related to the innate immune system, and therefore may possibly participate in combatting viral infection (47). A mouse model study has demonstrated that the presence of CLEC18A increases type-I interferon expression (49), could leading to reduction in DENV infection and replication. Despite these promising results however, CLEC18A has not yet been expressed in mosquitoes.…”
The C-type lectins, one family of lectins featuring carbohydrate binding domains which participate in a variety of bioprocesses in both humans and mosquitoes, including immune response, are known to target DENV. A human C-type lectin protein CLEC18A in particular shows extensive glycan binding abilities and correlates with type-I interferon expression, making CLEC18A a potential player in innate immune responses to DENV infection; this potential may provide additional regulatory point in improving mosquito immunity. Here, we established for the first time a transgenic Aedes aegypti line that expresses human CLEC18A. This expression enhanced the Toll immune pathway responses to DENV infection. Furthermore, viral genome and virus titers were reduced by 70% in the midgut of transgenic mosquitoes. We found significant changes in the composition of the midgut microbiome in CLEC18A expressing mosquitoes, which may result from the Toll pathway enhancement and contribute to DENV inhibition. Transgenic mosquito lines offer a compelling option for studying DENV pathogenesis, and our analyses indicate that modifying the mosquito immune system via expression of a human immune gene can significantly reduce DENV infection.
“…The results may explain in part why the deficiency of CMPK2 only affected DENV-induced IFN but not pro-inflammatory cytokine production. A recently published report demonstrating that C-type lectin member 18A (CLEC18A) enhances the production of type I and type III IFNs, but not proinflammatory cytokines, in response to H5N1 influenza A virus infection may serve as another example ( Huang et al., 2021 ). Figure 3 Effects of CMPK2 knockout in the context of DENV infection (A−G) Four THP-1 CMPK2-KO clones were generated with CRISPR-Cas9 approaches as described in experimental procedures (A).…”
Summary
Mitochondria regulate the immune response after dengue virus (DENV) infection. Microarray analysis of genes identified the upregulation of mitochondrial cytidine/uridine monophosphate kinase 2 (CMPK2) by DENV infection. We used small interfering RNA-mediated knockdown (KD) and CRISPR-Cas9 knockout (KO) approaches, to investigate the role of CMPK2 in mouse and human cells. The results showed that CMPK2 was critical in DENV-induced antiviral cytokine release and mitochondrial oxidative stress and mitochondrial DNA release to the cytosol. The DENV-induced activation of Toll-like receptor (TLR)-9, inflammasome pathway, and cell migration was suppressed by CMPK2 depletion; however, viral production increased under CMPK2 deficiency. Examining mouse bone marrow-derived dendritic cells from interferon-alpha (IFN-α) receptor-KO mice and signal transducer and activator of transcription 1 (STAT1)-KO mice, we confirmed that CMPK2-mediated antiviral activity occurred in IFN-dependent and IFN-independent manners. In sum, CMPK2 is a critical factor in DENV-induced immune responses to determine innate immunity.
“…TLRs family members localize to cell surface and endosomes, among which TLR3, TLR7 and TLR8 function as RNA sensors. TLR3 recognizes double-stranded RNA (dsRNA) of various viral genome or replication intermediates, and boosts host immune response to viral infection [ 6 , 7 ], whereas TLR7 and TLR8 recognize guanosine and uridine-containing single-stranded RNA (ssRNA) motifs in viral RNA [ 8 ]. When combined with RNA, the RNA sensors of TLRs switch through conformational changes, recruit adaptor protein TRIF for TLR3 and MyD88 for TLR7/TLR8, causing IRF3/7 phosphorylation and IFN-β secretion [ 9 ].…”
RNA sensors detect foreign and endogenous RNAs to protect the host by initiating innate and adaptive immune response. In tumor microenvironment (TME), activation of RNA sensors induces tumor-inhibitory cytotoxic T lymphocyte responses and inhibits the activity of immunosuppressive cells though stimulating type I IFN signaling pathway. These characteristics allow RNA sensors to be prospective targets in tumor immunotherapy. Therefore, a comprehensive understanding of the roles of RNA sensors in TME could provide new insight into the antitumor immunotherapy. Moreover, RNA sensors could be prominent triggering targets to synergize with immunotherapies. In this review, we highlight the diverse mechanisms of RNA sensors in cancer immunity and their emerging contributions in cancer immunotherapy, including monotherapy with RNA sensor agonists, as well as combination with chemotherapy, radiotherapy, immune checkpoint blockade or cancer vaccine.
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