Neuraminidase Activity Modulates Cellular Coinfection during Influenza A Virus Multicycle Growth

Guo, Zijian; He, Yuanyuan; Xu, Jian; Benegal, Ananya; Brody, Steven L.; Vahey, Michael D.

doi:10.1128/mbio.03591-22

Cited by 4 publications

(3 citation statements)

References 77 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…During virion release, NA liberates newly assembled virions from the sialic acids on the cell, preventing entrapment and aggregation and promoting virus spread ( Palese et al. 1974 , Palese and Compans 1976 , Guo et al. 2023 ).…”

Section: Introductionmentioning

confidence: 99%

Natural variation in neuraminidase activity influences the evolutionary potential of the seasonal H1N1 lineage hemagglutinin

Liu,

Reiser,

Tan

et al. 2024

Virus Evolution

View full text Add to dashboard Cite

The antigenic evolution of the influenza A virus hemagglutinin (HA) gene poses a major challenge for the development of vaccines capable of eliciting long-term protection. Prior efforts to understand the mechanisms that govern viral antigenic evolution mainly focus on HA in isolation, ignoring the fact that HA must act in concert with the viral neuraminidase (NA) during replication and spread. Numerous studies have demonstrated that the degree to which the receptor-binding avidity of HA and receptor-cleaving activity of NA are balanced with each other influences overall viral fitness. We recently showed that changes in NA activity can significantly alter the mutational fitness landscape of HA in the context of a lab-adapted virus strain. Here, we test whether natural variation in relative NA activity can influence the evolutionary potential of HA in the context of the seasonal H1N1 lineage (pdmH1N1) that has circulated in humans since the 2009 pandemic. We observed substantial variation in the relative activities of NA proteins encoded by a panel of H1N1 vaccine strains isolated between 2009 and 2019. We comprehensively assessed the effect of NA background on the HA mutational fitness landscape in the circulating pdmH1N1 lineage using deep mutational scanning and observed pronounced epistasis between NA and residues in or near the receptor-binding site of HA. To determine whether NA variation could influence the antigenic evolution of HA, we performed neutralizing antibody selection experiments using a panel of monoclonal antibodies targeting different HA epitopes. We found that the specific antibody escape profiles of HA were highly contingent upon NA background. Overall, our results indicate that natural variation in NA activity plays a significant role in governing the evolutionary potential of HA in the currently circulating pdmH1N1 lineage.

show abstract

Section: Introductionmentioning

confidence: 99%

Natural variation in neuraminidase activity influences the evolutionary potential of the seasonal H1N1 lineage hemagglutinin

Liu,

Reiser,

Tan

et al. 2024

Virus Evolution

View full text Add to dashboard Cite

show abstract

“…Supernatants from the HEK-293T cells were collected for affinity purification. Full details on antibody purification and enzymatic labeling are described elsewhere ( 57 ).…”

Section: Methodsmentioning

confidence: 99%

Antibody inhibition of influenza A virus assembly and release

He,

Guo,

Subiaur

et al. 2024

J Virol

Self Cite

View full text Add to dashboard Cite

Antibodies are frontline defenders against influenza virus infection, providing protection through multiple complementary mechanisms. Although a subset of monoclonal antibodies (mAbs) has been shown to restrict replication at the level of virus assembly and release, it remains unclear how potent and pervasive this mechanism of protection is, due in part to the challenge of separating this effect from other aspects of antibody function. To address this question, we developed imaging-based assays to determine how effectively a broad range of mAbs against the IAV surface proteins can specifically restrict viral egress. We find that classically neutralizing antibodies against hemagglutinin are broadly multifunctional, inhibiting virus assembly and release at concentrations 1–20-fold higher than the concentrations at which they inhibit viral entry. These antibodies are also capable of altering the morphological features of shed virions, reducing the proportion of filamentous particles. We find that antibodies against neuraminidase and M2 also restrict viral egress and that inhibition by anti-neuraminidase mAbs is only partly attributable to a loss in enzymatic activity. In all cases, antigen crosslinking—either on the surface of the infected cell, between the viral and cell membrane, or both—plays a critical role in inhibition, and we are able to distinguish between these modes experimentally and through a structure-based computational model. Together, these results provide a framework for dissecting antibody multifunctionality that could help guide the development of improved therapeutic antibodies or vaccines and that can be extended to other viral families and antibody isotypes. IMPORTANCE Antibodies against influenza A virus provide multifaceted protection against infection. Although sensitive and quantitative assays are widely used to measure inhibition of viral attachment and entry, the ability of diverse antibodies to inhibit viral egress is less clear. We address this challenge by developing an imaging-based approach to measure antibody inhibition of virus release across a panel of monoclonal antibodies targeting the influenza A virus surface proteins. Using this approach, we find that inhibition of viral egress is common and can have similar potency to the ability of an antibody to inhibit viral entry. Insights into this understudied aspect of antibody function may help guide the development of improved countermeasures.

show abstract

“…These sialic acid receptors are common in the mucosal lumen, and NA plays an essential role in dissociating the virion from sialylated factors in the extracellular space or non-functional cell surface sialic acids to facilitate entry 22 . During virion release, NA liberates newly assembled virions from the sialic acids on the cell, preventing entrapment and aggregation, and promoting virus spread 23–25 . Thus, suboptimal HA-NA balance can affect the efficiency of both entry and release 22 .…”

Section: Introductionmentioning

confidence: 99%

Natural variation in neuraminidase activity influences the evolutionary potential of the seasonal H1N1 lineage hemagglutinin

Liu,

Reiser,

Tan

et al. 2024

Preprint

View full text Add to dashboard Cite

The antigenic evolution of the influenza A virus hemagglutinin (HA) gene poses a major challenge for the development of vaccines capable of eliciting long-term protection. Prior efforts to understand the mechanisms that govern viral antigenic evolution mainly focus on HA in isolation, ignoring the fact that HA must act in concert with the viral neuraminidase (NA) during replication and spread. Numerous studies have demonstrated that the degree to which the receptor binding avidity of HA and receptor cleaving activity of NA are balanced with each other influences overall viral fitness. We recently showed that changes in NA activity can significantly alter the mutational fitness landscape of HA in the context of a lab-adapted virus strain. Here, we test whether natural variation in relative NA activity can influence the evolutionary potential of HA in the context of the seasonal H1N1 lineage (pdmH1N1) that has circulated in humans since the 2009 pandemic. We observed substantial variation in the relative activities of NA proteins encoded by a panel of H1N1 vaccine strains isolated between 2009 and 2019. We comprehensively assessed the effect of NA background on the HA mutational fitness landscape in the circulating pdmH1N1 lineage using deep mutational scanning and observed pronounced epistasis between NA and residues in or near the receptor binding site of HA. To determine whether NA variation could influence the antigenic evolution of HA, we performed neutralizing antibody selection experiments using a panel of monoclonal antibodies targeting different HA epitopes. We found that the specific antibody escape profiles of HA were highly contingent upon NA background. Overall, our results indicate that natural variation in NA activity plays a significant role in governing the evolutionary potential of HA in the currently circulating pdmH1N1 lineage.

show abstract

Neuraminidase Activity Modulates Cellular Coinfection during Influenza A Virus Multicycle Growth

Abstract: Influenza virus populations are comprised of particles that are mostly noninfectious or only partly infectious. As a result, multiple virions are frequently needed for influenza to infect a new cell.

Cited by 4 publications

References 77 publications

Natural variation in neuraminidase activity influences the evolutionary potential of the seasonal H1N1 lineage hemagglutinin

Natural variation in neuraminidase activity influences the evolutionary potential of the seasonal H1N1 lineage hemagglutinin

Antibody inhibition of influenza A virus assembly and release

Natural variation in neuraminidase activity influences the evolutionary potential of the seasonal H1N1 lineage hemagglutinin

Contact Info

Product

Resources

About