McIndoo Eric R, Wood Ethan, Kuffel Gina, Zilliox Michael J, Radke Jay R
Research Section, Boise Veteran Affairs Medical Center and Idaho Veterans Research & Education Foundation, Boise, ID 83702, USA.
Department of Chemistry, Northwest Nazarene University, Nampa, ID 83686, USA.
Viruses. 2025 Jun 11;17(6):838. doi: 10.3390/v17060838.
Adenovirus is a frequent cause of mild, usually self-limited infections in infants and young children. Severe infections occur in immunocompromised patients but are rarely observed in healthy, immunocompetent adults. However, there have been outbreaks of infections with different adenoviral (Ad) types around the world that have resulted in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) in some of those infected. Ad14p1 is the predominant circulating strain of Ad14 worldwide that has caused ARDS. An explanation for the severity of illness caused by Ad14p1 infection in immunocompetent patients is unknown. Previously, we have shown that A549 cells infected with Ad14 repress macrophage pro-inflammatory responses, whereas cells infected with Ad14p1 fail to repress macrophages and instead can increase pro-inflammatory responses. Adenoviral infection has been shown to modulate host miRNA expression, and we hypothesized that differences in miRNA expression between Ad14- and Ad14p1-infected cells might explain the differential responses of macrophages to Ad14- and Ad14p1-infected cells. Analysis of host miRNA showed that 98 miRNAs are differentially expressed when infection reaches full cytopathic effect (CPE), the same point at which Ad14 and Ad14p1 CPE corpses induce differential inflammatory responses in macrophages. Only 10 of the miRNAs that were enriched in Ad14 CPE corpses were expressed at levels that are potentially biologically relevant. Pathway enrichment analysis showed that the differentially expressed miRNAs might explain the increased pathogenesis of Ad14p1 through strain-related loss of modulation of cytokine expression when compared with prototype Ad14. Overall, the data suggest a role for viral regulation of host miRNA expression in pathogenesis by regulating host inflammatory responses through the delivery of de-regulated miRNAs by viral CPE corpses to macrophages.
腺病毒是婴幼儿轻度感染的常见病因，这类感染通常具有自限性。严重感染见于免疫功能低下的患者，但在健康、免疫功能正常的成年人中很少见。然而，世界各地曾爆发过不同腺病毒（Ad）类型的感染，导致部分感染者出现急性肺损伤（ALI）和急性呼吸窘迫综合征（ARDS）。Ad14p1是全球范围内导致ARDS的Ad14主要流行毒株。免疫功能正常的患者感染Ad14p1后病情严重的原因尚不清楚。此前，我们发现感染Ad14的A549细胞可抑制巨噬细胞的促炎反应，而感染Ad14p1的细胞则无法抑制巨噬细胞，反而会增强促炎反应。腺病毒感染已被证明可调节宿主miRNA表达，我们推测Ad14和Ad14p1感染细胞之间miRNA表达的差异可能解释了巨噬细胞对Ad14和Ad14p1感染细胞的不同反应。对宿主miRNA的分析表明，当感染达到完全细胞病变效应（CPE）时，有98种miRNA表达存在差异，此时Ad14和Ad14p1的CPE尸体在巨噬细胞中诱导不同的炎症反应。在Ad14 CPE尸体中富集的miRNA中，只有10种的表达水平可能具有生物学相关性。通路富集分析表明，与原型Ad14相比，差异表达的miRNA可能通过与毒株相关的细胞因子表达调节丧失来解释Ad14p1发病机制的增加。总体而言，数据表明病毒对宿主miRNA表达的调节在发病机制中发挥作用，即通过病毒CPE尸体向巨噬细胞传递失调的miRNA来调节宿主炎症反应。
