Induction of Antiviral Immune Response through Recognition of the Repeating Subunit Pattern of Viral Capsids Is Toll-Like Receptor 2 Dependent

ABSTRACT Although viruses and viral capsids induce rapid immune responses, little is known about viral pathogen-associated molecular patterns (PAMPs) that are exhibited on their surface. Here, we demonstrate that the repeating protein subunit pattern common to most virus capsids is a molecular patte...

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Autores principales:	Kelly M. Shepardson, Benjamin Schwarz, Kyle Larson, Rachelle V. Morton, John Avera, Kimberly McCoy, Alayna Caffrey, Ann Harmsen, Trevor Douglas, Agnieszka Rynda-Apple
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	pattern recognition bacterial superinfection innate immunity Toll-like receptors virology virus-host interactions Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/bf3aeed89b554e81bd3b7e859806801e
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spelling	oai:doaj.org-article:bf3aeed89b554e81bd3b7e859806801e2021-11-15T15:51:55ZInduction of Antiviral Immune Response through Recognition of the Repeating Subunit Pattern of Viral Capsids Is Toll-Like Receptor 2 Dependent10.1128/mBio.01356-172150-7511https://doaj.org/article/bf3aeed89b554e81bd3b7e859806801e2017-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01356-17https://doaj.org/toc/2150-7511ABSTRACT Although viruses and viral capsids induce rapid immune responses, little is known about viral pathogen-associated molecular patterns (PAMPs) that are exhibited on their surface. Here, we demonstrate that the repeating protein subunit pattern common to most virus capsids is a molecular pattern that induces a Toll-like-receptor-2 (TLR2)-dependent antiviral immune response. This early antiviral immune response regulates the clearance of subsequent bacterial superinfections, which are a primary cause of morbidities associated with influenza virus infections. Utilizing this altered susceptibility to subsequent bacterial challenge as an outcome, we determined that multiple unrelated, empty, and replication-deficient capsids initiated early TLR2-dependent immune responses, similar to intact influenza virus or murine pneumovirus. These TLR2-mediated responses driven by the capsid were not dependent upon the capsid’s shape, size, origin, or amino acid sequence. However, they were dependent upon the multisubunit arrangement of the capsid proteins, because unlike intact capsids, individual capsid subunits did not enhance bacterial clearance. Further, we demonstrated that even a linear microfilament protein built from repeating protein subunits (F-actin), but not its monomer (G-actin), induced similar kinetics of subsequent bacterial clearance as did virus capsid. However, although capsids and F-actin induced similar bacterial clearance, in macrophages they required distinct TLR2 heterodimers for this response (TLR2/6 or TLR2/1, respectively) and different phagocyte populations were involved in the execution of these responses in vivo. Our results demonstrate that TLR2 responds to invading viral particles that are composed of repeating protein subunits, indicating that this common architecture of virus capsids is a previously unrecognized molecular pattern. IMPORTANCE Rapid and precise pathogen identification is critical for the initiation of pathogen-specific immune responses and pathogen clearance. Bacteria and fungi express common molecular patterns on their exteriors that are recognized by cell surface-expressed host pattern recognition receptors (PRRs) prior to infection. In contrast, viral molecular patterns are primarily nucleic acids, which are recognized after virus internalization. We found that an initial antiviral immune response is induced by the repeating subunit pattern of virus exteriors (capsids), and thus, induction of this response is independent of viral infection. This early response to viral capsids required the cell surface-expressed PRR TLR2 and allowed for improved clearance of subsequent bacterial infection that commonly complicates respiratory viral infections. Since the repeating protein subunit pattern is conserved across viral capsids, this suggests that it is not easy for a virus to change without altering fitness. Targeting this vulnerability could lead to development of a universal antiviral vaccine.Kelly M. ShepardsonBenjamin SchwarzKyle LarsonRachelle V. MortonJohn AveraKimberly McCoyAlayna CaffreyAnn HarmsenTrevor DouglasAgnieszka Rynda-AppleAmerican Society for Microbiologyarticlepattern recognitionbacterial superinfectioninnate immunityToll-like receptorsvirologyvirus-host interactionsMicrobiologyQR1-502ENmBio, Vol 8, Iss 6 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	pattern recognition bacterial superinfection innate immunity Toll-like receptors virology virus-host interactions Microbiology QR1-502
spellingShingle	pattern recognition bacterial superinfection innate immunity Toll-like receptors virology virus-host interactions Microbiology QR1-502 Kelly M. Shepardson Benjamin Schwarz Kyle Larson Rachelle V. Morton John Avera Kimberly McCoy Alayna Caffrey Ann Harmsen Trevor Douglas Agnieszka Rynda-Apple Induction of Antiviral Immune Response through Recognition of the Repeating Subunit Pattern of Viral Capsids Is Toll-Like Receptor 2 Dependent
description	ABSTRACT Although viruses and viral capsids induce rapid immune responses, little is known about viral pathogen-associated molecular patterns (PAMPs) that are exhibited on their surface. Here, we demonstrate that the repeating protein subunit pattern common to most virus capsids is a molecular pattern that induces a Toll-like-receptor-2 (TLR2)-dependent antiviral immune response. This early antiviral immune response regulates the clearance of subsequent bacterial superinfections, which are a primary cause of morbidities associated with influenza virus infections. Utilizing this altered susceptibility to subsequent bacterial challenge as an outcome, we determined that multiple unrelated, empty, and replication-deficient capsids initiated early TLR2-dependent immune responses, similar to intact influenza virus or murine pneumovirus. These TLR2-mediated responses driven by the capsid were not dependent upon the capsid’s shape, size, origin, or amino acid sequence. However, they were dependent upon the multisubunit arrangement of the capsid proteins, because unlike intact capsids, individual capsid subunits did not enhance bacterial clearance. Further, we demonstrated that even a linear microfilament protein built from repeating protein subunits (F-actin), but not its monomer (G-actin), induced similar kinetics of subsequent bacterial clearance as did virus capsid. However, although capsids and F-actin induced similar bacterial clearance, in macrophages they required distinct TLR2 heterodimers for this response (TLR2/6 or TLR2/1, respectively) and different phagocyte populations were involved in the execution of these responses in vivo. Our results demonstrate that TLR2 responds to invading viral particles that are composed of repeating protein subunits, indicating that this common architecture of virus capsids is a previously unrecognized molecular pattern. IMPORTANCE Rapid and precise pathogen identification is critical for the initiation of pathogen-specific immune responses and pathogen clearance. Bacteria and fungi express common molecular patterns on their exteriors that are recognized by cell surface-expressed host pattern recognition receptors (PRRs) prior to infection. In contrast, viral molecular patterns are primarily nucleic acids, which are recognized after virus internalization. We found that an initial antiviral immune response is induced by the repeating subunit pattern of virus exteriors (capsids), and thus, induction of this response is independent of viral infection. This early response to viral capsids required the cell surface-expressed PRR TLR2 and allowed for improved clearance of subsequent bacterial infection that commonly complicates respiratory viral infections. Since the repeating protein subunit pattern is conserved across viral capsids, this suggests that it is not easy for a virus to change without altering fitness. Targeting this vulnerability could lead to development of a universal antiviral vaccine.
format	article
author	Kelly M. Shepardson Benjamin Schwarz Kyle Larson Rachelle V. Morton John Avera Kimberly McCoy Alayna Caffrey Ann Harmsen Trevor Douglas Agnieszka Rynda-Apple
author_facet	Kelly M. Shepardson Benjamin Schwarz Kyle Larson Rachelle V. Morton John Avera Kimberly McCoy Alayna Caffrey Ann Harmsen Trevor Douglas Agnieszka Rynda-Apple
author_sort	Kelly M. Shepardson
title	Induction of Antiviral Immune Response through Recognition of the Repeating Subunit Pattern of Viral Capsids Is Toll-Like Receptor 2 Dependent
title_short	Induction of Antiviral Immune Response through Recognition of the Repeating Subunit Pattern of Viral Capsids Is Toll-Like Receptor 2 Dependent
title_full	Induction of Antiviral Immune Response through Recognition of the Repeating Subunit Pattern of Viral Capsids Is Toll-Like Receptor 2 Dependent
title_fullStr	Induction of Antiviral Immune Response through Recognition of the Repeating Subunit Pattern of Viral Capsids Is Toll-Like Receptor 2 Dependent
title_full_unstemmed	Induction of Antiviral Immune Response through Recognition of the Repeating Subunit Pattern of Viral Capsids Is Toll-Like Receptor 2 Dependent
title_sort	induction of antiviral immune response through recognition of the repeating subunit pattern of viral capsids is toll-like receptor 2 dependent
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/bf3aeed89b554e81bd3b7e859806801e
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Induction of Antiviral Immune Response through Recognition of the Repeating Subunit Pattern of Viral Capsids Is Toll-Like Receptor 2 Dependent

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