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Cleavage-intermediate Lassa virus trimer elicits neutralizing responses, identifies neutralizing nanobodies, and reveals an apex-situated site-of-vulnerability.

ABSTRACT: 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.

SUBMITTER: Gorman J

PROVIDER: S-EPMC10767048 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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Cleavage-intermediate Lassa virus trimer elicits neutralizing responses, identifies neutralizing nanobodies, and reveals an apex-situated site-of-vulnerability.

Gorman Jason J Cheung Crystal Sao-Fong CS Duan Zhijian Z Ou Li L Wang Maple M Chen Xuejun X Cheng Cheng C Biju Andrea A Sun Yaping Y Wang Pengfei P Yang Yongping Y Zhang Baoshan B Boyington Jeffrey C JC Bylund Tatsiana T Charaf Sam S Chen Steven J SJ Du Haijuan H Henry Amy R AR Liu Tracy T Sarfo Edward K EK Schramm Chaim A CA Shen Chen-Hsiang CH Stephens Tyler T Teng I-Ting IT Todd John-Paul JP Tsybovsky Yaroslav Y Verardi Raffaello R Wang Danyi D Wang Shuishu S Wang Zhantong Z Zheng Cheng-Yan CY Zhou Tongqing T Douek Daniel C DC Mascola John R JR Ho David D DD Ho Mitchell M Kwong Peter D PD

Nature communications 20240104 1

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 ...[more]

PMID: 38177144

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Dataset Information

Cleavage-intermediate Lassa virus trimer elicits neutralizing responses, identifies neutralizing nanobodies, and reveals an apex-situated site-of-vulnerability.

Publications

Cleavage-intermediate Lassa virus trimer elicits neutralizing responses, identifies neutralizing nanobodies, and reveals an apex-situated site-of-vulnerability.

Similar Datasets

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