Non-neutralizing SARS-CoV-2 N-terminal domain antibodies protect mice against severe disease using Fc-mediated effector functions.
Non-neutralizing SARS-CoV-2 N-terminal domain antibodies protect mice against severe disease using Fc-mediated effector functions.
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非中和性 SARS-CoV-2 N 末端结构域抗体利用 Fc 介导的效应功能保护小鼠免受严重疾病的侵害。
DOI：
10.1101/2023.07.25.550460
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Sa
中科院分区：
文献类型：
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作者：
Pierre,CamilleN;Adams,LilyE;Anasti,Kara;Goodman,Derrick;Stanfield-Oakley,Sherry;Powers,JohnM;Li,Dapeng;Rountree,Wes;Wang,Yunfei;Edwards,RobertJ;MunirAlam,S;Ferrari,Guido;Tomaras,GeorgiaD;Haynes,BartonF;Baric,RalphS;Sa
抗体具有中和和非中和效应器功能，可预防某些病原体引起的疾病。针对SARS-CoV-2刺突N末端结构域(NTD)的人抗体DH1052最近被证明是非中和的，但它能保护小鼠和食蟹猴免受严重疾病的侵袭。NTD非中和抗体介导的保护机制尚不清楚。在这里，我们证明了Fc效应功能介导了NTD非中和抗体(Non-NAB)对SARS-CoV-2MA10病毒攻击的保护作用。尽管非NAB预防性输注对肺部感染性病毒滴度的抑制作用不如NAB，但NAB组和非NAB组包括大体肺变色在内的疾病标志物相似。在NAB组中，Fc功能敲除替换取消了非NAB保护并增加了病毒滴度。与WT相比，Fc增强增强了非NAB保护，支持Fc功能与免受SARS-CoV-2感染的保护程度之间的正相关。对于抗体的治疗性给药，非NAB效应器功能有助于抑制病毒和减轻肺部变色，但为了最佳地预防疾病，需要存在中和。这项研究表明，非NABS可以利用Fc介导的机制来降低病毒载量，防止冠状病毒感染引起的肺损伤。
Antibodies perform both neutralizing and non-neutralizing effector functions that protect against certain pathogen-induced diseases. A human antibody directed at the SARS-CoV-2 Spike N-terminal domain (NTD), DH1052, was recently shown to be non-neutralizing, yet it protected mice and cynomolgus macaques from severe disease. The mechanisms of NTD non-neutralizing antibody-mediated protection are unknown. Here we show that Fc effector functions mediate NTD non-neutralizing antibody (non-nAb) protection against SARS-CoV-2 MA10 viral challenge in mice. Though non-nAb prophylactic infusion did not suppress infectious viral titers in the lung as potently as neutralizing antibody (nAb) infusion, disease markers including gross lung discoloration were similar in nAb and non-nAb groups. Fc functional knockout substitutions abolished non-nAb protection and increased viral titers in the nAb group. Fc enhancement increased non-nAb protection relative to WT, supporting a positive association between Fc functionality and degree of protection from SARS-CoV-2 infection. For therapeutic administration of antibodies, non-nAb effector functions contributed to virus suppression and lessening of lung discoloration, but the presence of neutralization was required for optimal protection from disease. This study demonstrates that non-nAbs can utilize Fc-mediated mechanisms to lower viral load and prevent lung damage due to coronavirus infection.