Arenaviruses such as Lassa virus (LASV) cause hemorrhagic fever. Terminal shock is associated with a systemic cytokine storm, but the mechanisms are ill defined. Here we used HLA-A2-expressing mice infected with a monkey-pathogenic strain of lymphocytic choriomeningitis virus (LCMV-WE), a close relative of LASV, to investigate the pathophysiology of arenavirus hemorrhagic fever (AHF). AHF manifested as pleural effusions, edematous skin swelling, and serum albumin loss, culminating in hypovolemic shock. A characteristic cytokine storm included numerous pro-inflammatory cytokines and nitric oxide (NO) metabolites. Edema formation and terminal shock were abrogated in mice lacking inducible nitric oxide synthase (iNOS), although the cytokine storm persisted. iNOS was upregulated in the liver in a T cell- and interferon-γ (IFN-γ)-dependent fashion. Accordingly, blockade of IFN-γ or depletion of T cells repressed hepatic iNOS and prevented disease despite unchecked high-level viremia. We identify the IFN-γ-iNOS axis as an essential and potentially druggable molecular pathway to AHF-induced shock.

诸如拉沙病毒（LASV）的小球状病毒会引起出血热。终末休克与全身性细胞因子风暴有关，但机制尚不明确。在这里，我们使用感染了猴性致病性淋巴细胞性脉络膜脑膜炎病毒（LCMV-WE）（LASV的近亲）的HLA-A2表达小鼠来研究类风疹病毒出血热（AHF）的病理生理。AHF表现为胸腔积液，水肿性皮肤肿胀和血清白蛋白丢失，最终导致低血容量性休克。典型的细胞因子风暴包括多种促炎性细胞因子和一氧化氮（NO）代谢产物。尽管细胞因子风暴持续存在，但缺乏诱导型一氧化氮合酶（iNOS）的小鼠可消除水肿和末梢休克。肝脏中的iNOS以T细胞和干扰素-γ（IFN-γ）依赖性方式上调。因此，尽管未经检查的高水平病毒血症，但阻断IFN-γ或T细胞的消耗仍能抑制肝iNOS并预防疾病。我们将IFN-γ-iNOS轴确定为AHF诱发休克的必要且潜在可药物治疗的分子途径。