Nature communications · 2024
Cleavage-intermediate Lassa virus trimer elicits neutralizing responses, identifies neutralizing nanobodies, and reveals an apex-situated site-of-vulnerability.
СтатьяПоддержка NIH: внешняя программаResearch Support, N.I.H., IntramuralПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Gorman Jason, Cheung Crystal Sao-Fong, Duan Zhijian, Ou Li, Wang Maple, Chen Xuejun, Cheng Cheng, Biju Andrea, Sun Yaping, Wang Pengfei, Yang Yongping, Zhang Baoshan, Boyington Jeffrey C, Bylund Tatsiana, Charaf Sam, Chen Steven J, Du Haijuan, Henry Amy R, Liu Tracy, Sarfo Edward K, Schramm Chaim A, Shen Chen-Hsiang, Stephens Tyler, Teng I-Ting, Todd John-Paul, Tsybovsky Yaroslav, Verardi Raffaello, Wang Danyi, Wang Shuishu, Wang Zhantong, Zheng Cheng-Yan, Zhou Tongqing, Douek Daniel C, Mascola John R, Ho David D, Ho Mitchell, Kwong Peter D
Аннотация
Lassa virus (LASV) infection is expanding outside its traditionally endemic areas in West Africa, posing a pandemic biothreat. LASV-neutralizing antibodies, moreover, have proven difficult to elicit. To gain insight into LASV neutralization, here we develop a prefusion-stabilized LASV glycoprotein trimer (GPC), pan it against phage libraries comprising single-domain antibodies (nanobodies) from shark and camel, and identify one, D5, which neutralizes LASV. Cryo-EM analyses reveal D5 to recognize a cleavage-dependent site-of-vulnerability at the trimer apex. The recognized site appears specific to GPC intermediates, with protomers lacking full cleavage between GP1 and GP2 subunits. Guinea pig immunizations with the prefusion-stabilized cleavage-intermediate LASV GPC, first as trimer and then as a nanoparticle, induce neutralizing responses, targeting multiple epitopes including that of D5; we identify a neutralizing antibody (GP23) from the immunized guinea pigs. Collectively, our findings define a prefusion-stabilized GPC trimer, reveal an apex-situated site-of-vulnerability, and demonstrate elicitation of LASV-neutralizing responses by a cleavage-intermediate LASV trimer.