HTNV-induced upregulation of miR-146a in HUVECs promotes viral infection by modulating pro-inflammatory cytokine release

Chen, Qingzhou; Luo, Fengguang; Lu, Mingxiang; Li, Ning; Teng, Yan; Huang, Qiuling; Zhu, Ni; Wang, Guanyi; Yue, Ming; Zhang, Yun; Feng, Yong; Xiong, Hairong; Hou, Wei

doi:10.1016/j.bbrc.2017.08.073

Cited by 13 publications

(5 citation statements)

References 35 publications

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“…Indeed, we found that A. agrarius mice lung tissue was more susceptible to HTNV infection rather than liver or kidney (marked by the asterisk, Figure S3A), which was consistent with previous studies (Kim et al, 2016; and insured the authenticity of our testing system. Elevated production of six in ammatory cytokines was observed in HIES than HINS, namely TNFα, IFNα, IL-1β, IP-10, MCP-1, and IL-10 (Figure 2B), which were also upregulated in HFRS patients (Figure 1G) and reported as pathogenic factors during hantaviral infection (Angulo et al, 2017;Chen et al, 2017a;Khaiboullina et al, 2014;Niikura et al, 2004).…”

Section: Resultsmentioning

confidence: 87%

“…To note, the regulation process and function of NF-κB signaling seem to be controversial during hantaviral infection. Some research pointed out that HTNV triggered TLR4-dependent and p65-mediated production of in ammatory cytokines or chemokines, which was responsible for endothelium dysfunction and viral pathogenicity (Chen et al, 2017a;Yu et al, 2014;Yu et al, 2012;Zhang et al, 2014a;Zhang et al, 2015). Nevertheless, other studies suggested that HTNV NP might bind to the karyopherin importin α and block the nucleus translocation of p65 induced by TNFα, hence possibly assisting virus replication by suppressing host immunity (Au et al, 2010;Taylor et al, 2009a;Taylor et al, 2009b).…”

Section: Introductionmentioning

confidence: 99%

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Differential Macrophage Phenotype Rewired by Hantaan Virus Constrains the Magnitude of Inflammatory Responses in Murine versus Humans

zhang

Yang

et al. 2022

Preprint

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Hantaan virus (HTNV) is principally maintained and transmitted by rodents in nature, the infection of which is non-pathogenic in the field or laboratory mouse, but can cause hemorrhagic fever with renal syndrome (HFRS) in human beings, a severe systemic inflammatory disease with high mortality. It remains obscure how HTNV infection leads to disparate outcomes in distinct species. Here, we revealed a differential immune status in murine versus humans post HTNV infection, which was orchestrated by the macrophage reprogramming process and characterized by late-phase inactivation of NF-κB signaling. In HFRS patients, the immoderate and continuous activation of inflammatory monocyte/macrophage (M1) launched TNFα-centered cytokine storm and aggravated host immunopathologic injury, which can be life-threatening; however, in field or laboratory mice, the M1 activation and TNFα release were significantly suppressed at the late infection stage of HTNV, restricting excessive inflammation and blocking viral disease process, which also protected mice from secondary LPS challenge or polymicrobial sepsis. Mechanistically, we found that murine macrophage phenotype was dynamically manipulated by HTNV via the Notch-lncRNA-p65 axis. At the early stage of HTNV infection, the intracellular domain of Notch receptor (NICD) was activated by viral nucleocapsid (NP) stimulation and potentiated the NF-κB pathway by associating with and facilitating the interaction between IKKβ and p65. At the late stage, Notch signaling launched the expression of diverse murine-specific long non-coding RNAs (lncRNAs) and attenuated M1 polarization. Among them, lncRNA 30740.1 (termed as lnc-ip65, an inhibitor of p65) bound to p65 and hindered its phosphorylation, exerting negative feedback on the NF-κB pathway. Genetic ablation of lnc-ip65 shifted the balance of macrophage polarization from a pro-resolution to an inﬂammatory phenotype, leading to superabundant production of pro-inﬂammatory cytokines and increasing mice susceptibility to HTNV infection or bacterial sepsis. Collectively, our findings identify an immune braking function and mechanism for murine lncRNAs in inhibiting p65-mediated M1 activation, opening a novel therapeutic avenue of controlling the magnitude of immune responses for HFRS and other inflammatory diseases.

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Section: Resultsmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Differential Macrophage Phenotype Rewired by Hantaan Virus Constrains the Magnitude of Inflammatory Responses in Murine versus Humans

zhang

Yang

et al. 2022

Preprint

View full text Add to dashboard Cite

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“…Therefore, using miR-146a mimic could reduce the expression of pro-inflammatory cytokines, thus escaping the host immune response. It was also discovered that viral proteins (NP/GP) could increase the transcriptional activity of the miR-146a promoter ( Chen et al, 2017 ). Latest research reports that RNA sequencing of HTNV infection and mock infection HUVEC showed that in the process of HTNV infection, a total of 70 circRNAs, 66 miRNAs, and 788 mRNAs were differentially expressed by promoting or inhibiting virus replication ( Lu et al, 2020 ).…”

Section: Molecular Mechanisms Of Hantavirus To Evade Innate Antiviral Immune Responsesmentioning

confidence: 99%

Viruses Run: The Evasion Mechanisms of the Antiviral Innate Immunity by Hantavirus

Zhang

Wang

et al. 2021

Front. Microbiol.

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Hantavirus can cause hemorrhagic fever with renal syndrome (HFRS) in Eurasia and hantavirus pulmonary syndrome (HPS) in America, with high mortality and unknown mechanisms. Innate immunity is the host’s first-line defense to bridge the acquired immunity against viral infections. However, hantavirus has evolved various strategies in both molecular and cellular aspects to evade the host’s natural immune surveillance. The Interferon-I (IFN-I) signaling pathway, a central link of host defense, induces various antiviral proteins to control the infection. This paper summarizes the molecular mechanisms of hantavirus evasion mechanisms of the IFN signaling pathway and cellular processes such as regulated cell death and cell stress. Besides, hantavirus could also evade immune surveillance evasion through cellular mechanisms, such as upregulating immune checkpoint molecules interfering with viral infections. Understanding hantavirus’s antiviral immune evasion mechanisms will deepen our understanding of its pathogenesis and help us develop more effective methods to control and eliminate hantavirus.

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“…Previous studies have reported cytokine overexpression by macrophages, monocytes and lymphocytes, including interleukin (IL)-6, IL-8, tumour necrosis factor-α (TNF-α), interferon-β (IFN-β), and interferon-gamma-inducible protein (IP)-10, and this hypercytokinemia correlated with HFRS disease severity [ 5 , 6 ]. CD4 + T cells with broad antigenic repertoires possessing polyfunctional properties lead to less severe clinical outcomes, which may enhance the antiviral status of host cells and the cytotoxic effect of ThGranzyme B + cells [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

Rapid humoral immune responses are required for recovery from haemorrhagic fever with renal syndrome patients

Quan

Xing

et al. 2020

Emerging Microbes & Infections

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Haemorrhagic fever with renal syndrome (HFRS) following Hantaan virus (HTNV) infection displays variable clinical signs. Humoral responses elicited during HTNV infections are considered important, however, this process remains poorly understood. Herein, we have investigated the phenotype, temporal dynamics, and characteristics of B-cell receptor (BCR) repertoire in an HFRS cohort. The serological profiles were characterized by a lowered expression level of nucleoprotein (NP)-specific antibody in severe cases. Importantly, B-cell subsets were activated and proliferated within the first two weeks of symptom onset and moderate cases reacted more rapidly. BCR analysis in the recovery phase revealed a dramatic increase in the immunoglobulin gene diversity which was more significantly progressed in moderate infections. In severe cases, B-cell-related transcription was lower with inflammatory sets overactivated. Taken together, these data suggest the clinical signs and disease recovery in HFRS patients were positively impacted by rapid and efficacious humoral responses.

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HTNV-induced upregulation of miR-146a in HUVECs promotes viral infection by modulating pro-inflammatory cytokine release

Cited by 13 publications

References 35 publications

Differential Macrophage Phenotype Rewired by Hantaan Virus Constrains the Magnitude of Inflammatory Responses in Murine versus Humans

Differential Macrophage Phenotype Rewired by Hantaan Virus Constrains the Magnitude of Inflammatory Responses in Murine versus Humans

Viruses Run: The Evasion Mechanisms of the Antiviral Innate Immunity by Hantavirus

Rapid humoral immune responses are required for recovery from haemorrhagic fever with renal syndrome patients

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