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Structural monitoring of a transient intermediate in the hemagglutinin fusion machinery on influenza virions.

ABSTRACT: The influenza virus hemagglutinin (HA) fusion protein has long been viewed as a "spring-loaded" fusion machine whereby activation at low pH initiates a rapid and irreversible cascade of conformational changes that drives the membrane fusion reaction. This mechanism has shaped our understanding of how type 1 viral fusion proteins function as a whole. Experimental limitations have hindered efforts to expand our mechanistic and structural understanding of viral membrane fusion. Here, we used pulse-labeling hydrogen/deuterium exchange mass spectrometry and cryo-electron tomography to monitor and characterize the structural dynamics of HA during fusion activation on intact virions. Our data reveal how concurrent reorganizations at the HA1 receptor binding domain interface and HA2 fusion subunit produce a dynamic fusion intermediate ensemble in full-length HA. The soluble HA ectodomain transitions directly to the postfusion state with no observable intermediate.

SUBMITTER: Benhaim MA

PROVIDER: S-EPMC7190341 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Structural monitoring of a transient intermediate in the hemagglutinin fusion machinery on influenza virions.

Benhaim M A MA Mangala Prasad V V Garcia N K NK Guttman M M Lee K K KK

Science advances 20200429 18

The influenza virus hemagglutinin (HA) fusion protein has long been viewed as a "spring-loaded" fusion machine whereby activation at low pH initiates a rapid and irreversible cascade of conformational changes that drives the membrane fusion reaction. This mechanism has shaped our understanding of how type 1 viral fusion proteins function as a whole. Experimental limitations have hindered efforts to expand our mechanistic and structural understanding of viral membrane fusion. Here, we used pulse- ...[more]

PMID: 32494683

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Project description:The development of improved and universal anti-influenza vaccines would represent a major advance in the protection of human health. In order to facilitate the development of such vaccines, understanding how viral proteins can contribute to protection from disease is critical. Much of the previous work to address these questions relied on reductionist systems (i.e. vaccinating with individual proteins or VLPs that contain only a few viral proteins); thus we have an incomplete understanding of how immunity to different subsets of viral proteins contribute to protection. Here, we report the development of a platform in which a single viral protein can be deleted from an authentic viral particle that retains the remaining full complement of structural proteins and viral RNA. As a first study with this system, we chose to delete the major IAV antigen, the hemagglutinin protein, to evaluate how the other components of the viral particle contribute en masse to protection from influenza disease. Our results show that while anti-HA immunity plays a major role in protection from challenge with a vaccine-matched strain, the contributions from other structural proteins were the major drivers of protection against highly antigenically drifted, homosubtypic strains. This work highlights the importance of evaluating the inclusion of non-HA viral proteins in the development of broadly efficacious and long-lasting influenza vaccines.ImportanceInfluenza virus vaccines currently afford short-term protection from viruses that are closely related to the vaccine strains. There is currently much effort to develop improved, next-generation influenza vaccines that elicit broader and longer-lasting protection. While the hemagglutinin protein is the major viral antigen, in this work, we developed an approach with which to evaluate the contributions of the non-hemagglutinin proteins to vaccine mediated protection. Our results indicate that other structural proteins together may help to mediate broad antiviral protection and should be considered in the development of more universal influenza vaccines.

Dataset Information

Structural monitoring of a transient intermediate in the hemagglutinin fusion machinery on influenza virions.

Publications

Structural monitoring of a transient intermediate in the hemagglutinin fusion machinery on influenza virions.

Similar Datasets

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