Disparate macrophage responses are linked to infection outcome of Hantan virus in humans or rodents

Hongwei Ma, Yongheng Yang, Tiejian Nie, Rong Yan, Yue Si, Jing Wei, Mengyun Li, He Liu, Wei Ye, Hui Zhang, Linfeng Cheng, Liang Zhang, Xin Lv, Limin Luo, Zhikai Xu (), Xijing Zhang (), Yingfeng Lei () and Fanglin Zhang ()
Additional contact information
Hongwei Ma: Air Force Medical University (the Fourth Military Medical University)
Yongheng Yang: Air Force Medical University (the Fourth Military Medical University)
Tiejian Nie: Air Force Medical University (the Fourth Military Medical University)
Rong Yan: Air Force Medical University (the Fourth Military Medical University)
Yue Si: Air Force Medical University (the Fourth Military Medical University)
Jing Wei: Air Force Medical University (the Fourth Military Medical University)
Mengyun Li: Air Force Medical University (the Fourth Military Medical University)
He Liu: Air Force Medical University (the Fourth Military Medical University)
Wei Ye: Air Force Medical University (the Fourth Military Medical University)
Hui Zhang: Air Force Medical University (the Fourth Military Medical University)
Linfeng Cheng: Air Force Medical University (the Fourth Military Medical University)
Liang Zhang: Air Force Medical University (the Fourth Military Medical University)
Xin Lv: Air Force Medical University (the Fourth Military Medical University)
Limin Luo: Air Force Hospital of Southern Theatre Command
Zhikai Xu: Air Force Medical University (the Fourth Military Medical University)
Xijing Zhang: Air Force Medical University (the Fourth Military Medical University)
Yingfeng Lei: Air Force Medical University (the Fourth Military Medical University)
Fanglin Zhang: Air Force Medical University (the Fourth Military Medical University)

Nature Communications, 2024, vol. 15, issue 1, 1-25

Abstract: Abstract Hantaan virus (HTNV) is asymptomatically carried by rodents, yet causes lethal hemorrhagic fever with renal syndrome in humans, the underlying mechanisms of which remain to be elucidated. Here, we show that differential macrophage responses may determine disparate infection outcomes. In mice, late-phase inactivation of inflammatory macrophage prevents cytokine storm syndrome that usually occurs in HTNV-infected patients. This is attained by elaborate crosstalk between Notch and NF-κB pathways. Mechanistically, Notch receptors activated by HTNV enhance NF-κB signaling by recruiting IKKβ and p65, promoting inflammatory macrophage polarization in both species. However, in mice rather than humans, Notch-mediated inflammation is timely restrained by a series of murine-specific long noncoding RNAs transcribed by the Notch pathway in a negative feedback manner. Among them, the lnc-ip65 detaches p65 from the Notch receptor and inhibits p65 phosphorylation, rewiring macrophages from the pro-inflammation to the pro-resolution phenotype. Genetic ablation of lnc-ip65 leads to destructive HTNV infection in mice. Thus, our findings reveal an immune-braking function of murine noncoding RNAs, offering a special therapeutic strategy for HTNV infection.

Date: 2024
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DOI: 10.1038/s41467-024-44687-4

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