Table 1_Cytokine secretion patterns distinguish herpes simplex virus type 2 meningitis from herpes simplex virus type 2 genital herpes.xlsx

The aim of this study was to identify immune factors that distinguish patients with herpes simplex virus type 2 (HSV-2) meningitis from patients with HSV-2 genital herpes by analyzing demographic data, in vitro production of cytokines and other immune factors secreted by patient peripheral blood mononuclear cells (PBMC), and existing antibody responses. PBMC and plasma were collected from patients previously diagnosed with HSV-2 meningitis (n=49) and HSV-2 genital herpes (n=38). PBMC were cultured in the presence or absence of HSV-2 and followed by multiplex analyses of culture supernatants for a panel of immune factors including Th1 and inflammatory cytokines, interferons, and chemokines. Plasma was analyzed for type-specific HSV antibodies and HSV-2 DNA. The multivariate method OPLS-DA was used to identify immune response patterns that differentiate the two patient groups. The multivariate analysis showed that the immune profile differed significantly between the two different HSV-2 disease manifestations. Meningitis patients were distinguished by the spontaneous production of several anti-viral immune factors by PBMC including type I and type III IFNs. PBMC from HSV-2 meningitis patients also secreted significantly higher levels of IFN-γ in response to HSV-2 compared to PBMC from HSV-2 genital herpes patients. Blocking the type I IFN receptor reduced the production of HSV-2-induced IFN-γ by PBMC suggesting that enhanced production of type I IFNs could promote IFN-γ recall responses. The levels of HSV-2 type-specific antibodies did not differ between the patient groups. In conclusion, we show that HSV-2 meningitis leads to a more profound activation of both innate and acquired PBMC immune responses, compared to that of HSV-2 genital herpes. Whether these differences are the cause, or the consequence, of the different disease manifestations remains to be determined.

本研究旨在通过分析人口统计学数据、患者外周血单个核细胞（peripheral blood mononuclear cells, PBMC）的体外细胞因子及其他免疫因子分泌水平，以及现有抗体应答特征，鉴别区分单纯疱疹病毒2型（herpes simplex virus type 2, HSV-2）脑膜炎患者与HSV-2生殖器疱疹患者的免疫相关特征。本研究共纳入此前确诊为HSV-2脑膜炎的患者（n=49）与HSV-2生殖器疱疹患者（n=38），采集其外周血单个核细胞与血浆样本。将采集到的外周血单个核细胞分别置于添加与不添加HSV-2的培养体系中培养，随后对培养上清液进行多重检测，分析包括Th1型细胞因子、炎性细胞因子、干扰素及趋化因子在内的一系列免疫因子水平，同时对血浆样本开展型特异性HSV抗体与HSV-2 DNA检测。本研究采用正交偏最小二乘判别分析（orthogonal projections to latent structures discriminant analysis, OPLS-DA）这一多变量分析方法，以筛选可区分两类患者群体的免疫应答模式。多变量分析结果显示，两种不同HSV-2疾病表型的免疫谱存在显著差异。脑膜炎患者的特征性免疫表现为其外周血单个核细胞可自发分泌多种抗病毒免疫因子，包括I型与III型干扰素（type I and type III IFNs）。相较于HSV-2生殖器疱疹患者的外周血单个核细胞，HSV-2脑膜炎患者的外周血单个核细胞在受HSV-2刺激后分泌的γ干扰素（IFN-γ）水平显著更高。阻断I型干扰素受体可降低外周血单个核细胞中HSV-2诱导的IFN-γ生成，提示I型干扰素的生成增强可促进IFN-γ的回忆应答。两类患者群体的HSV-2型特异性抗体水平无显著差异。综上，本研究证实相较于HSV-2生殖器疱疹，HSV-2脑膜炎可更显著地激活外周血单个核细胞的先天免疫与适应性免疫应答，上述差异究竟是不同疾病表型的成因还是结果，仍有待进一步明确。