Murid herpesvirus 4 (MuHV-4) is a B cell-tropic gammaherpesvirus that can be studied in vivo. Despite viral evasion, type I interferons (IFN-I) limit its spread. After MuHV-4 inoculation into footpads, IFN-I protect lymph node subcapsular sinus macrophages (SSM) against productive infection; after peritoneal inoculation, they protect splenic marginal zone macrophages, and they limit MuHV-4 replication in the lungs. While invasive infections can be used to test specific aspects of host colonization, it is also important to understand natural infection. MuHV-4 taken up spontaneously by alert mice enters them via olfactory neurons. We determined how IFN-I act in this context. Blocking IFN-I signaling did not increase neuronal infection but allowed the virus to spread to the adjacent respiratory epithelium. In lymph nodes, a complete IFN-I signaling block increased MuHV-4 lytic infection in SSM and increased the number of dendritic cells (DC) expressing viral green fluorescent protein (GFP) independently of lytic infection. A CD11c⁺ cell-directed signaling block increased infection of DC only. However, this was sufficient to increase downstream infection, consistent with DC providing the main viral route to B cells. The capacity of IFN-I to limit DC infection indicated that viral IFN-I evasion was only partly effective. Therefore, DC are a possible target for IFN-I-based interventions to reduce host colonization.

IMPORTANCE Human gammaherpesviruses infect B cells and cause B cell cancers. Interventions to block virus binding to B cells have not stopped their infection. Therefore, we must identify other control points that are relevant to natural infection. Human infections are difficult to analyze. However, gammaherpesviruses colonize all mammals. A related gammaherpesvirus of mice reaches B cells not directly but via infected dendritic cells. We show that type I interferons, an important general antiviral defense, limit gammaherpesvirus B cell infection by acting on dendritic cells. Therefore, dendritic cell infection is a potential point of interferon-based therapeutic intervention.

Murid疱疹病毒4（MuHV-4）是一种B细胞嗜性γ疱疹病毒，可以在体内进行研究。尽管有病毒逃逸，但I型干扰素（IFN-I）限制了其扩散。在将MuHV-4接种到脚垫中后，IFN-I保护淋巴结包膜下窦巨噬细胞（SSM）免受生产性感染。腹膜接种后，它们可保护脾脏边缘区巨噬细胞，并限制MuHV-4在肺中的复制。虽然侵入性感染可用于测试宿主定植的特定方面，但了解自然感染也很重要。机敏的小鼠自发摄取的MuHV-4通过嗅觉神经元进入它们。我们确定了IFN-1在这种情况下的作用。阻断IFN-I信号传导不会增加神经元感染，但会使病毒传播到相邻的呼吸道上皮。在淋巴结中 完整的IFN-1信号传导阻滞增加了SSM中的MuHV-4裂解感染，并增加了表达病毒绿色荧光蛋白（GFP）的树突状细胞（DC）的数量，而与裂解感染无关。CD11c⁺细胞定向信号传导阻滞仅增加DC的感染。但是，这足以增加下游感染，这与DC提供通往B细胞的主要病毒途径一致。IFN-1限制DC感染的能力表明，病毒IFN-1逃避仅部分有效。因此，DC是基于IFN-I的干预以减少宿主定植的可能靶标。

重要信息人类γ疱疹病毒感染B细胞并引起B细胞癌症。阻止病毒与B细胞结合的干预措施尚未停止其感染。因此，我们必须确定与自然感染有关的其他控制点。人类感染难以分析。但是，γ疱疹病毒在所有哺乳动物中均定居。小鼠的一种相关的γ疱疹病毒不是直接而是通过感染的树突状细胞到达B细胞。我们显示，I型干扰素是一种重要的一般抗病毒防御剂，通过作用于树突状细胞来限制γ疱疹病毒B细胞的感染。因此，树突状细胞感染是基于干扰素的治疗干预的潜在点。