Endogenous Retroviruses Provide Protection Against Vaginal HSV-2 Disease.
Endogenous Retroviruses Provide Protection Against Vaginal HSV-2 Disease.
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DOI：
10.3389/fimmu.2021.758721
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发表时间：
2021
影响因子：
7.3
通讯作者：
Tokuyama M
中科院分区：
文献类型：
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作者：
Jayewickreme R;Mao T;Philbrick W;Kong Y;Treger RS;Lu P;Rakib T;Dong H;Dang-Lawson M;Guild WA;Lau TJ;Iwasaki A;Tokuyama M
内源性逆转录病毒(ERV)是起源于逆转录病毒的基因组序列，存在于大多数真核基因组中。ERV既有有益的功能，也有有害的功能，但ERV是否有助于抗病毒免疫尚不清楚。在这里，我们使用单纯疱疹病毒2型(HSV-2)感染作为模型，发现与野生型C57BL/6小鼠相比，具有高系统感染性ERV水平的Toll样受体7(TLR7-/-)缺陷小鼠可免受阴道内HSV-2感染和疾病的影响。我们在TLR7-/-背景(Emv2-/-TLR7-/-)上删除了内源性生态小鼠白血病病毒(Emv2)基因，发现Emv2-/-TLR7-/-小鼠失去了对HSV-2感染的保护作用。在HSV-2感染之前，阴道内应用来自TLR7-/-小鼠的纯化ERV可以延缓野生型和高度易感的干扰素-α受体缺陷(Ifnar1-/-)小鼠的疾病。然而，阴道内ERV治疗不能保护Emv2-/-TLR7-/-小鼠免受HSV-2疾病的影响，提示外源性ERV治疗介导的保护机制可能不同于TLR7-/-小鼠结构性和系统性表达的ERV。我们没有在TLR7-/-小鼠的阴道组织中观察到增强型干扰素信号，而是发现与细胞外基质组织相关的基因丰富。综上所述，我们的结果表明，ERV的结构性和/或系统性表达可以保护小鼠免受HSV-2阴道感染并延缓疾病的发生。
Endogenous retroviruses (ERVs) are genomic sequences that originated from retroviruses and are present in most eukaryotic genomes. Both beneficial and detrimental functions are attributed to ERVs, but whether ERVs contribute to antiviral immunity is not well understood. Here, we used herpes simplex virus type 2 (HSV-2) infection as a model and found that Toll-like receptor 7 (Tlr7 -/-) deficient mice that have high systemic levels of infectious ERVs are protected from intravaginal HSV-2 infection and disease, compared to wildtype C57BL/6 mice. We deleted the endogenous ecotropic murine leukemia virus (Emv2) locus on the Tlr7 -/- background (Emv2 -/- Tlr7 -/-) and found that Emv2 -/- Tlr7 -/- mice lose protection against HSV-2 infection. Intravaginal application of purified ERVs from Tlr7-/- mice prior to HSV-2 infection delays disease in both wildtype and highly susceptible interferon-alpha receptor-deficient (Ifnar1- /-) mice. However, intravaginal ERV treatment did not protect Emv2-/-Tlr7-/- mice from HSV-2 disease, suggesting that the protective mechanism mediated by exogenous ERV treatment may differ from that of constitutively and systemically expressed ERVs in Tlr7-/- mice. We did not observe enhanced type I interferon (IFN-I) signaling in the vaginal tissues from Tlr7-/- mice, and instead found enrichment in genes associated with extracellular matrix organization. Together, our results revealed that constitutive and/or systemic expression of ERVs protect mice against vaginal HSV-2 infection and delay disease.