Macrophage Depletion Reactivates Fecal Virus Shedding following Resolution of Acute Hepatitis A in Ifnar1-/- Mice.
Macrophage Depletion Reactivates Fecal Virus Shedding following Resolution of Acute Hepatitis A in Ifnar1-/- Mice.
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Ifnar1-/- 小鼠急性甲型肝炎消退后，巨噬细胞耗竭可重新激活粪便病毒排出。
DOI：
10.1128/jvi.01496-22
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发表时间：
2022
影响因子：
5.4
通讯作者：
Hirai-Yuki,Asuka
中科院分区：
文献类型：
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作者：
Shiota,Tomoyuki;Matsuda,Mami;Zheng,Xin;Nagata,Noriyo;Ishii,Koji;Suzuki,Ryosuke;Muramatsu,Masamichi;Takimoto,Kazuhiro;Hanaki,Ken-Ichi;Lemon,StanleyM;McGivern,DavidR;Hirai-Yuki,Asuka
尽管甲型肝炎病毒（HAV）仅与人类的急性肝炎有关，但在甲型肝炎的黑猩猩和小鼠模型中，在肝脏炎症消退和粪便病毒脱落停止后，HAV RNA在肝脏内持续存在数月。我们证实了感染difnar1−/−的小鼠的肝脏与血清和粪便中HAV RNA清除动力学的显著差异，并研究了血清丙氨酸转氨酶（ALT）水平正常化后肝脏中病毒RNA持续存在的性质。肝细胞中产生的病毒的粪便排出量在第14天至第126天的峰值之间下降了3000倍，而肝内HAV RNA在第154天仅下降了32倍。接种后3至4个月，在肝细胞内鉴定出病毒RNA，并与膜相关，带在1.07至1.14 g/cm3的异氰酸碘二醇梯度之间。含有甲肝病毒RNA的梯度组分在接种给小鼠时没有传染性，但含有中和性抗甲肝病毒抗体。在感染的这个后期消耗CD4+或CD8+T细胞对肝脏中的病毒RNA丰度没有影响，而在接种后110天至120天之间消耗巨噬细胞的氯钠脂体导致粪便病毒脱落的显著复发，血清中病毒RNA的重现，同时肝内因子γ、Tnfα、Ccl5和其他趋化因子转录物的减少。我们的数据表明，在ifnar1 - / -小鼠急性肝炎消退后，在存在中和抗体的情况下，复制能力强的HAV RNA在肝脏内持续存在数月，并且巨噬细胞在感染后期的病毒控制中发挥关键作用。在中和抗体出现后，hav RNA在受感染的黑猩猩和干扰素受体缺陷小鼠的肝脏中持续存在数月，病毒已从血液中清除，粪便病毒脱落已终止。在这里，我们发现这种病毒RNA位于肝细胞内，并且在肝脏炎症消退几个月后巨噬细胞的消耗恢复了粪便病毒脱落和循环病毒RNA。我们的研究确定了巨噬细胞在ifnar1 - / -小鼠急性甲型肝炎消退后的病毒控制中的重要作用，并且可能与人类甲型肝炎复发有关。
Although hepatitis A virus (HAV) is associated only with acute hepatitis in humans, HAV RNA persists within the liver for months following resolution of liver inflammation and cessation of fecal virus shedding in chimpanzees and murine models of hepatitis A. Here, we confirm striking differences in the kinetics of HAV RNA clearance from liver versus serum and feces in infectedIfnar1−/−mice and investigate the nature of viral RNA persisting in the liver following normalization of serum alanine aminotransferase (ALT) levels. Fecal shedding of virus produced in hepatocytes declined >3,000-fold between its peak at day 14 and day 126, whereas intrahepatic HAV RNA declined only 32-fold by day 154. Viral RNA was identified within hepatocytes 3 to 4 months after inoculation and was associated with membranes, banding between 1.07 and 1.14 g/cm3in isopycnic iodixanol gradients. Gradient fractions containing HAV RNA demonstrated no infectivity when inoculated into naive mice but contained neutralizing anti-HAV antibody. Depleting CD4+or CD8+T cells at this late point in infection had no effect on viral RNA abundance in the liver, whereas clodronate-liposome depletion of macrophages between days 110 and 120 postinoculation resulted in a striking recrudescence of fecal virus shedding and the reappearance of viral RNA in serum coupled with reductions in intra-hepaticIfnγ,Tnfα,Ccl5, and other chemokine transcripts. Our data suggest that replication-competent HAV RNA persists for months within the liver in the presence of neutralizing antibody following resolution of acute hepatitis inIfnar1−/−mice and that macrophages play a key role in viral control late in infection.IMPORTANCEHAV RNA persists in the liver of infected chimpanzees and interferon receptor-deficientIfnar1−/−mice for many months after neutralizing antibodies appear, virus has been cleared from the blood, and fecal virus shedding has terminated. Here, we show this viral RNA is located within hepatocytes and that the depletion of macrophages months after the resolution of hepatic inflammation restores fecal virus shedding and circulating viral RNA. Our study identifies an important role for macrophages in virus control following resolution of acute hepatitis A inIfnar1−/−mice and may have relevance to relapsing hepatitis A in humans.