Functional and Structural Basis of Human Parainfluenza Virus Type 3 Neutralization with Human Monoclonal Antibodies

Overview

Journal Nat Microbiol

Specialties Microbiology
Parasitology

Date 2024 Jun 10

PMID 38858594

Authors

Naveenchandra Suryadevara

Ana Rita Otrelo-Cardoso

Nurgun Kose

Yao-Xiong Hu

Elad Binshtein

Rachael M Wolters

Alexander L Greninger

Laura S Handal

Robert H Carnahan

Anne Moscona

Theodore S Jardetzky

James E Crowe Jr

Affiliations

Soon will be listed here.

Abstract

Human parainfluenza virus type 3 (hPIV3) is a respiratory pathogen that can cause severe disease in older people and infants. Currently, vaccines against hPIV3 are in clinical trials but none have been approved yet. The haemagglutinin-neuraminidase (HN) and fusion (F) surface glycoproteins of hPIV3 are major antigenic determinants. Here we describe naturally occurring potently neutralizing human antibodies directed against both surface glycoproteins of hPIV3. We isolated seven neutralizing HN-reactive antibodies and a pre-fusion conformation F-reactive antibody from human memory B cells. One HN-binding monoclonal antibody (mAb), designated PIV3-23, exhibited functional attributes including haemagglutination and neuraminidase inhibition. We also delineated the structural basis of neutralization for two HN and one F mAbs. MAbs that neutralized hPIV3 in vitro protected against infection and disease in vivo in a cotton rat model of hPIV3 infection, suggesting correlates of protection for hPIV3 and the potential clinical utility of these mAbs.

Citing Articles

Molecular Evolution of the () Genes in Human Parainfluenza Virus Type 2.

Shirai T, Mizukoshi F, Kimura R, Matsuoka R, Sada M, Shirato K Microorganisms. 2025; 13(2).

PMID: 40005765 PMC: 11857903. DOI: 10.3390/microorganisms13020399.

Phylogenomic Analyses of the Hemagglutinin-Neuraminidase () Gene in Human Parainfluenza Virus Type 4 Isolates in Japan.

Otani K, Kimura R, Nagasawa N, Hayashi Y, Ohmiya S, Watanabe O Microorganisms. 2025; 13(2).

PMID: 40005750 PMC: 11857914. DOI: 10.3390/microorganisms13020384.

Molecular Evolutionary Analyses of the Fusion Genes in Human Parainfluenza Virus Type 4.

Mizukoshi F, Kimura H, Sugimoto S, Kimura R, Nagasawa N, Hayashi Y Microorganisms. 2024; 12(8).

PMID: 39203475 PMC: 11356533. DOI: 10.3390/microorganisms12081633.

References

Chanock R, PARROTT R, Cook K, Andrews B, Bell J, REICHELDERFER T . Newly recognized myxoviruses from children with respiratory disease. N Engl J Med. 1958; 258(5):207-13. DOI: 10.1056/NEJM195801302580502. View

Shah D, Shah P, Azzi J, Chemaly R . Parainfluenza virus infections in hematopoietic cell transplant recipients and hematologic malignancy patients: A systematic review. Cancer Lett. 2015; 370(2):358-64. PMC: 4684719. DOI: 10.1016/j.canlet.2015.11.014. View

Fontana L, Strasfeld L . Respiratory Virus Infections of the Stem Cell Transplant Recipient and the Hematologic Malignancy Patient. Infect Dis Clin North Am. 2019; 33(2):523-544. PMC: 7126949. DOI: 10.1016/j.idc.2019.02.004. View

Moscona A, Peluso R . Fusion properties of cells persistently infected with human parainfluenza virus type 3: participation of hemagglutinin-neuraminidase in membrane fusion. J Virol. 1991; 65(6):2773-7. PMC: 240891. DOI: 10.1128/JVI.65.6.2773-2777.1991. View

Porotto M, Salah Z, Gui L, DeVito I, Jurgens E, Lu H . Regulation of paramyxovirus fusion activation: the hemagglutinin-neuraminidase protein stabilizes the fusion protein in a pretriggered state. J Virol. 2012; 86(23):12838-48. PMC: 3497673. DOI: 10.1128/JVI.01965-12. View

Farzan S, Palermo L, Yokoyama C, Orefice G, Fornabaio M, Sarkar A . Premature activation of the paramyxovirus fusion protein before target cell attachment with corruption of the viral fusion machinery. J Biol Chem. 2011; 286(44):37945-37954. PMC: 3207398. DOI: 10.1074/jbc.M111.256248. View

Bose S, Jardetzky T, Lamb R . Timing is everything: Fine-tuned molecular machines orchestrate paramyxovirus entry. Virology. 2015; 479-480:518-31. PMC: 4424121. DOI: 10.1016/j.virol.2015.02.037. View

Porotto M, Murrell M, Greengard O, Moscona A . Triggering of human parainfluenza virus 3 fusion protein (F) by the hemagglutinin-neuraminidase (HN) protein: an HN mutation diminishes the rate of F activation and fusion. J Virol. 2003; 77(6):3647-54. PMC: 149538. DOI: 10.1128/jvi.77.6.3647-3654.2003. View

Marcink T, Zipursky G, Cheng W, Stearns K, Stenglein S, Golub K . Subnanometer structure of an enveloped virus fusion complex on viral surface reveals new entry mechanisms. Sci Adv. 2023; 9(6):eade2727. PMC: 9917000. DOI: 10.1126/sciadv.ade2727. View

10.

Porotto M, Murrell M, Greengard O, Doctor L, Moscona A . Influence of the human parainfluenza virus 3 attachment protein's neuraminidase activity on its capacity to activate the fusion protein. J Virol. 2005; 79(4):2383-92. PMC: 546598. DOI: 10.1128/JVI.79.4.2383-2392.2005. View

11.

Huberman K, Peluso R, Moscona A . Hemagglutinin-neuraminidase of human parainfluenza 3: role of the neuraminidase in the viral life cycle. Virology. 1995; 214(1):294-300. DOI: 10.1006/viro.1995.9925. View

12.

Porotto M, Fornabaio M, Kellogg G, Moscona A . A second receptor binding site on human parainfluenza virus type 3 hemagglutinin-neuraminidase contributes to activation of the fusion mechanism. J Virol. 2007; 81(7):3216-28. PMC: 1866072. DOI: 10.1128/JVI.02617-06. View

13.

Xu R, Palmer S, Porotto M, Palermo L, Niewiesk S, Wilson I . Interaction between the hemagglutinin-neuraminidase and fusion glycoproteins of human parainfluenza virus type III regulates viral growth in vivo. mBio. 2013; 4(5):e00803-13. PMC: 3812707. DOI: 10.1128/mBio.00803-13. View

14.

Iketani S, Shean R, Ferren M, Makhsous N, Aquino D, des Georges A . Viral Entry Properties Required for Fitness in Humans Are Lost through Rapid Genomic Change during Viral Isolation. mBio. 2018; 9(4). PMC: 6030562. DOI: 10.1128/mBio.00898-18. View

15.

Porotto M, Palmer S, Palermo L, Moscona A . Mechanism of fusion triggering by human parainfluenza virus type III: communication between viral glycoproteins during entry. J Biol Chem. 2011; 287(1):778-793. PMC: 3249132. DOI: 10.1074/jbc.M111.298059. View

16.

Palmer S, Porotto M, Palermo L, Cunha L, Greengard O, Moscona A . Adaptation of human parainfluenza virus to airway epithelium reveals fusion properties required for growth in host tissue. mBio. 2012; 3(3). PMC: 3374391. DOI: 10.1128/mBio.00137-12. View

17.

Mishin V, Watanabe M, Taylor G, DeVincenzo J, Bose M, Portner A . N-linked glycan at residue 523 of human parainfluenza virus type 3 hemagglutinin-neuraminidase masks a second receptor-binding site. J Virol. 2010; 84(6):3094-100. PMC: 2826034. DOI: 10.1128/JVI.02331-09. View

18.

Lawrence M, Borg N, Streltsov V, Pilling P, Epa V, Varghese J . Structure of the haemagglutinin-neuraminidase from human parainfluenza virus type III. J Mol Biol. 2004; 335(5):1343-57. DOI: 10.1016/j.jmb.2003.11.032. View

19.

Streltsov V, Pilling P, Barrett S, McKimm-Breschkin J . Catalytic mechanism and novel receptor binding sites of human parainfluenza virus type 3 hemagglutinin-neuraminidase (hPIV3 HN). Antiviral Res. 2015; 123:216-23. DOI: 10.1016/j.antiviral.2015.08.014. View

20.

Dirr L, El-Deeb I, Chavas L, Guillon P, von Itzstein M . The impact of the butterfly effect on human parainfluenza virus haemagglutinin-neuraminidase inhibitor design. Sci Rep. 2017; 7(1):4507. PMC: 5495814. DOI: 10.1038/s41598-017-04656-y. View