Paramyxovirus Activation and Inhibition of Innate Immune Responses

Paramyxoviruses represent a remarkably diverse family of enveloped nonsegmented negative-strand RNA viruses, some of which are the most ubiquitous disease-causing viruses of humans and animals. This review focuses on paramyxovirus activation of innate immune pathways, the mechanisms by which these RNA viruses counteract these pathways, and the innate response to paramyxovirus infection of dendritic cells (DC). Paramyxoviruses are potent activators of extracellular complement pathways, a first line of defense that viruses must face during natural infections. We discuss mechanisms by which these viruses activate and combat complement to delay neutralization. Once cells are infected, virus replication drives type I interferon (IFN) synthesis that has the potential to induce a large number of antiviral genes. Here we describe four approaches by which paramyxoviruses limit IFN induction: by limiting synthesis of IFN-inducing aberrant viral RNAs, through targeted inhibition of RNA sensors, by providing viral decoy substrates for cellular kinase complexes, and through direct blocking of the IFN promoter. In addition, paramyxoviruses have evolved diverse mechanisms to disrupt IFN signaling pathways. We describe three general mechanisms, including targeted proteolysis of signaling factors, sequestering cellular factors, and upregulation of cellular inhibitors. DC are exceptional cells with the capacity to generate adaptive immunity through the coupling of innate immune signals and T cell activation. We discuss the importance of innate responses in DC following paramyxovirus infection and their consequences for the ability to mount and maintain antiviral T cells.     

Salicylic Acid Regulates Plasmodesmata Closure during Innate Immune Responses in Arabidopsis

In plants, mounting an effective innate immune strategy against microbial pathogens involves triggering local cell death within infected cells as well as boosting the immunity of the uninfected neighboring and systemically located cells. Although not much is known about this, it is evident that well-coordinated cell–cell signaling is critical in this process to confine infection to local tissue while allowing for the spread of systemic immune signals throughout the whole plant. In support of this notion, direct cell-to-cell communication was recently found to play a crucial role in plant defense. Here, we provide experimental evidence that salicylic acid (SA) is a critical hormonal signal that regulates cell-to-cell permeability during innate immune responses elicited by virulent bacterial infection in Arabidopsis thaliana. We show that direct exogenous application of SA or bacterial infection suppresses cell–cell coupling and that SA pathway mutants are impaired in this response. The SA- or infection-induced suppression of cell–cell coupling requires an ENHANCED DESEASE RESISTANCE1– and NONEXPRESSOR OF PATHOGENESIS-RELATED GENES1–dependent SA pathway in conjunction with the regulator of plasmodesmal gating PLASMODESMATA-LOCATED PROTEIN5. We discuss a model wherein the SA signaling pathway and plasmodesmata-mediated cell-to-cell communication converge under an intricate regulatory loop.     

SDF-1基因对HIV-1核酸疫苗诱导的免疫应答

研究SDF-1基因对HIV-1核酸疫苗诱导免疫应答的影响,以探求治疗性HIV-1核酸疫苗的新策略. 将pCI-neoGAG联合SDF-1基因或者pCI-neoGAG单独免疫Balb/c小鼠,采用ELISA检测免疫小鼠的特异性抗体和IFN-γ水平,用MTT比色法检测免疫小鼠脾淋巴细胞的增殖,用乳酸脱氢酶(LDH)试验检测小鼠特异性细胞毒性T淋巴细胞(CTL)的应答.研究结果提示 与pCI-neoGAG免疫组比较,pCI-neoGAG联合SDF-1基因免疫组小鼠血清的抗HIV-1p24抗体滴度降低,有显著性差异(p<0.01);而与pCI-neoGAG免疫组比较,pCI-neoGAG联合SDF-1基因免疫组小鼠血清的IFN-γ升高,差异显著(p<0.01);pCI-neoGAG联合SDF-1基因免疫组小鼠的脾淋巴细胞增殖实验刺激指数(SI)以及特异性CTL活性均高于pCI-neoGAG免疫组,有显著性差异(p<0.01).因此,SDF-1基因联合HIV-1核酸疫苗免疫小鼠,可能增强特异性Th1细胞和CTL反应,SDF-1基因对体液免疫有抑制作用.SDF-1基因对于治疗性HIV-1核酸疫苗是具有较好应用前景的免疫佐剂.     

IL-12基因对HIV-1核酸疫苗诱导的免疫应答的影响

研究白细胞介素 12(IL 12)基因对HIV 1核酸疫苗诱导免疫应答的影响,以探求治疗性 HIV 1 核酸疫苗的新策略。将 pCI neoGAG联合白细胞介素 12基因或者 pCI neoGAG单独免疫 Balb/c小鼠,通过 ELISA检测免疫小鼠的特异性抗体和 IFN γ,通过MTT实验检测免疫小鼠脾淋巴细胞增殖实验,通过乳酸脱氢酶(LDH)实验检测小鼠特异性细胞毒性T淋巴细胞(CTL)反应。与 pCI neoGAG免疫组比较,pCI neoGAG联合白细胞介素 12基因免疫组小鼠血清的抗 HIV 1p24 抗体滴度降低,有显著性差异(P< 0. 01);而与 pCI neoGAG 免疫组比较, pCI neoGAG联合白细胞介素 12基因免疫组小鼠血清的 IFN γ升高,有显著性差异(P<0.01);pCI neoGAG联合白细胞介素 12基因免疫组小鼠的脾淋巴细胞增殖实验刺激指数(SI)以及特异性 CTL活性均高于 pCI neoGAG免疫组,有显著性差异(P<0.01)。因此,白细胞介素 12基因基因联合HIV 1核酸疫苗免疫小鼠,可能增强特异性Th1细胞和CTL反应,白细胞介素 12基因对体液免疫有抑制作用。     

IL-12基因对HIV-1核酸疫苗诱导的免疫应答的影响

研究白细胞介素-12(IL 12)基因对HIV-1核酸疫苗诱导免疫应答的影响,以探求治疗性HIV-1核酸疫苗的新策略.将pCI-neoGAG联合白细胞介素-12基因或者pCI-neoGAG单独免疫Balb/c小鼠,通过ELISA检测免疫小鼠的特异性抗体和IFN-γ,通过MTT实验检测免疫小鼠脾淋巴细胞增殖实验,通过乳酸脱氢酶(LDH)实验检测小鼠特异性细胞毒性T淋巴细胞(CTL)反应.与pCI-neoGAG免疫组比较,pCI-neoGAG联合白细胞介素-12基因免疫组小鼠血清的抗HIV-1p24抗体滴度降低,有显著性差异(P＜0.01);而与pCI-neoGAG免疫组比较,pCI-neoGAG联合白细胞介素-12基因免疫组小鼠血清的IFN-γ升高,有显著性差异(P＜0.01);pCI-neoGAG联合白细胞介素-12基因免疫组小鼠的脾淋巴细胞增殖实验刺激指数(SI)以及特异性CTL活性均高于pCI-neoGAG免疫组,有显著性差异(P＜0.01).因此,白细胞介素-12基因基因联合HIV-1核酸疫苗免疫小鼠,可能增强特异性Th1细胞和CTL反应,白细胞介素-12基因对体液免疫有抑制作用.     

SDF-1基因对HIV-1核酸疫苗诱导的免疫应答

研究SDF-1基因对HIV-1核酸疫苗诱导免疫应答的影响,以探求治疗性HIV-1核酸疫苗的新策略。将pCIneoGAG联合SDF1基因或者pCIneoGAG单独免疫Balb/c小鼠,采用ELISA检测免疫小鼠的特异性抗体和IFNγ水平,用MTT比色法检测免疫小鼠脾淋巴细胞的增殖,用乳酸脱氢酶(LDH)试验检测小鼠特异性细胞毒性T淋巴细胞(CTL)的应答。研究结果提示:与pCIneoGAG免疫组比较,pCIneoGAG联合SDF-1基因免疫组小鼠血清的抗HIV-1p24抗体滴度降低,有显著性差异(p<0.01);而与pCIneoGAG免疫组比较,pCIneoGAG联合SDF-1基因免疫组小鼠血清的IFNγ升高,差异显著(p<0.01);pCIneoGAG联合SDF-1基因免疫组小鼠的脾淋巴细胞增殖实验刺激指数(SI)以及特异性CTL活性均高于pCIneoGAG免疫组,有显著性差异(p<0.01)。因此,SDF-1基因联合HIV-1核酸疫苗免疫小鼠,可能增强特异性Th1细胞和CTL反应,SDF-1基因对体液免疫有抑制作用。SDF-1基因对于治疗性HIV-1核酸疫苗是具有较好应用前景的免疫佐剂。     

IL-18 DNA免疫对HIV-1核酸疫苗诱导的免疫应答的影响

为了研究白细胞介素-18(IL-18)基因对人免疫缺陷病毒(HIV-1)核酸疫苗诱导免疫应答的影响,将人IL-18基因插入到真核表达载体pVAX1中,构建了真核表达载体pVAX1-IL-18;将pCI-neoGAG联合pVAX1-IL-18或者pCI-neoGAG单独免疫Balb/c小鼠,检测免疫小鼠的特异性抗体和IFN-γ,同时观察免疫小鼠脾淋巴细胞增殖和小鼠特异性细胞毒性T淋巴细胞(CTL)反应.酶切及测序结果表明成功地构建了人IL-18基因真核表达载体;与pCI-neoGAG免疫组比较,pCI-neoGAG联合pVAX1-IL-18免疫组小鼠血清的抗HIV-1p24抗体滴度降低(P<0.01);而与pCI-neoGAG免疫组比较,pCI-neoGAG联合pVAX1-IL-18免疫组小鼠血清的IFN-γ升高(P<0.01);pCI-neoGAG联合pVAX1-IL-18免疫组小鼠的脾淋巴细胞增殖实验刺激指数(SI)以及特异性CTL活性均高于pCI-neoGAG免疫组(P<0.01).IL-18基因联合HIV-1核酸疫苗免疫小鼠,可能增强特异性Th1细胞和CTL反应,白细胞介素-18基因对体液免疫有抑制作用.     

IL—18DNA免疫对HIV—1核酸疫苗诱导的免疫应答的影响

为了研究白细胞介素-18(IL-18)基因对人免疫缺陷病毒(HIV-1)核酸疫苗诱导免疫应答的影响,将人IL-18基因插入到真核表达载体pVAX1中,构建了真核表达载体pVAX1-IL-18;将pCI-neoGAG联合pVAX1-IL-18或者pCI-neoGAG单独免疫Balb/c小鼠,检测免疫小鼠的特异性抗体和IFN-γ,同时观察免疫小鼠脾淋巴细胞增殖和小鼠特异性细胞毒性T淋巴细胞(CTL)反应。酶切及测序结果表明成功地构建了人IL-18基因真核表达载体;与pCI-neoGAG免疫组比较,pCI-neoGAG联合pVAX1-IL-18免疫组小鼠血清的抗HIV-1p24抗体滴度降低(P<0.01);而与pCI-neoGAG免疫组比较,pCI-neoGAG联合pVAX1-IL-18免疫组小鼠血清的IFN-γ升高(P<0.01);pCI-neoGAG联合pVAX1-IL-18免疫组小鼠的脾淋巴细胞增殖实验刺激指数(SI)以及特异性CTL活性均高于pCI-neoGAG免疫组(P<0.01)。IL-18基因联合HIV-1核酸疫苗免疫小鼠,可能增强特异性Th1细胞和CTL反应,白细胞介素-18基因对体液免疫有抑制作用。     

Activation of Plant Innate Immunity by Extracellular High Mobility Group Box 3 and Its Inhibition by Salicylic Acid

Damage-associated molecular pattern molecules (DAMPs) signal the presence of tissue damage to induce immune responses in plants and animals. Here, we report that High Mobility Group Box 3 (HMGB3) is a novel plant DAMP. Extracellular HMGB3, through receptor-like kinases BAK1 and BKK1, induced hallmark innate immune responses, including i) MAPK activation, ii) defense-related gene expression, iii) callose deposition, and iv) enhanced resistance to Botrytis cinerea. Infection by necrotrophic B. cinerea released HMGB3 into the extracellular space (apoplast). Silencing HMGBs enhanced susceptibility to B. cinerea, while HMGB3 injection into apoplast restored resistance. Like its human counterpart, HMGB3 binds salicylic acid (SA), which results in inhibition of its DAMP activity. An SA-binding site mutant of HMGB3 retained its DAMP activity, which was no longer inhibited by SA, consistent with its reduced SA-binding activity. These results provide cross-kingdom evidence that HMGB proteins function as DAMPs and that SA is their conserved inhibitor.     

Immune Responses to Varicella-Zoster Virus Glycoprotein E Formulated with Poly(Lactic-co-Glycolic Acid) Nanoparticles and Nucleic Acid Adjuvants in Mice

Virologica Sinica - The subunit herpes zoster vaccine Shingrix is superior to attenuated vaccine&;nbsp;Zostavax in both safety and efficacy, yet its unlyophilizable liposome delivery system and...     

Group B Streptococcus Engages an Inhibitory Siglec through Sialic Acid Mimicry to Blunt Innate Immune and Inflammatory Responses In Vivo

Group B Streptococcus (GBS) is a common agent of bacterial sepsis and meningitis in newborns. The GBS surface capsule contains sialic acids (Sia) that engage Sia-binding immunoglobulin-like lectins (Siglecs) on leukocytes. Here we use mice lacking Siglec-E, an inhibitory Siglec of myelomonocytic cells, to study the significance of GBS Siglec engagement during in vivo infection. We found GBS bound to Siglec-E in a Sia-specific fashion to blunt NF-κB and MAPK activation. As a consequence, Siglec-E-deficient macrophages had enhanced pro-inflammatory cytokine secretion, phagocytosis and bactericidal activity against the pathogen. Following pulmonary or low-dose intravenous GBS challenge, Siglec-E KO mice produced more pro-inflammatory cytokines and exhibited reduced GBS invasion of the central nervous system. In contrast, upon high dose lethal challenges, cytokine storm in Siglec-E KO mice was associated with accelerated mortality. We conclude that GBS Sia mimicry influences host innate immune and inflammatory responses in vivo through engagement of an inhibitory Siglec, with the ultimate outcome of the host response varying depending upon the site, stage and magnitude of infection.