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Helen Connaris, doi: 10.1073/pnas.1404205111
Prevention of influenza by targeting host receptors using engineered proteins
Helen Connarisa,1,2,
Elena A. Govorkovab,1,
Yvonne Ligertwoodc,
Bernadette M. Dutiac,
Lei Yanga,
Sandra Taubera,
Margaret A. Taylora,
Nadiawati Aliasa,
Robert Hagana,
Anthony A. Nashc,
Robert G. Websterb,2, and
Garry L. Taylora,2
Author Affiliations
aBiomedical Sciences Research Complex, University of St Andrews, North Haugh, St Andrews, Fife KY16 9ST, United Kingdom;
bDepartment of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105; and
cCentre for Infectious Diseases, The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush EH25 9RG, United Kingdom
Contributed by Robert G. Webster, March 6, 2014 (sent for review November 21, 2013)
Abstract
Authors & Info
SI
Metrics
PDF
PDF + SI
Significance
We have developed a new class of host-targeted biologics to prevent influenza by engineering multivalent carbohydrate-binding modules that bind with high affinity to sialic acid, the critical component of the influenza virus cell surface receptor. Mouse studies reveal a remarkable efficacy: a single 1-μg dose of the lead biologic given 7 d before a lethal challenge with 2009 pandemic H1N1 influenza virus provides complete protection. This new approach has the potential to be a front-line defense against any current and future influenza virus, overcoming viral escape to vaccines and antivirals. In addition, the biologics may have broader application against other respiratory pathogens.
Abstract
There is a need for new approaches for the control of influenza given the burden caused by annual seasonal outbreaks, the emergence of viruses with pandemic potential, and the development of resistance to current antiviral drugs. We show that multivalent biologics, engineered using carbohydrate-binding modules specific for sialic acid, mask the cell-surface receptor recognized by the influenza virus and protect mice from a lethal challenge with 2009 pandemic H1N1 influenza virus. The most promising biologic protects mice when given as a single 1-μg intranasal dose 7 d in advance of viral challenge. There also is sufficient virus replication to establish an immune response, potentially protecting the animal from future exposure to the virus. Furthermore, the biologics appear to stimulate inflammatory mediators, and this stimulation may contribute to their protective ability. Our results suggest that this host-targeted approach could provide a front-line prophylactic that has the potential to protect against any current and future influenza virus and possibly against other respiratory pathogens that use sialic acid as a receptor.
Prevention of influenza by targeting host receptors using engineered proteins
Helen Connarisa,1,2,
Elena A. Govorkovab,1,
Yvonne Ligertwoodc,
Bernadette M. Dutiac,
Lei Yanga,
Sandra Taubera,
Margaret A. Taylora,
Nadiawati Aliasa,
Robert Hagana,
Anthony A. Nashc,
Robert G. Websterb,2, and
Garry L. Taylora,2
Author Affiliations
aBiomedical Sciences Research Complex, University of St Andrews, North Haugh, St Andrews, Fife KY16 9ST, United Kingdom;
bDepartment of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105; and
cCentre for Infectious Diseases, The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush EH25 9RG, United Kingdom
Contributed by Robert G. Webster, March 6, 2014 (sent for review November 21, 2013)
Abstract
Authors & Info
SI
Metrics
PDF + SI
Significance
We have developed a new class of host-targeted biologics to prevent influenza by engineering multivalent carbohydrate-binding modules that bind with high affinity to sialic acid, the critical component of the influenza virus cell surface receptor. Mouse studies reveal a remarkable efficacy: a single 1-μg dose of the lead biologic given 7 d before a lethal challenge with 2009 pandemic H1N1 influenza virus provides complete protection. This new approach has the potential to be a front-line defense against any current and future influenza virus, overcoming viral escape to vaccines and antivirals. In addition, the biologics may have broader application against other respiratory pathogens.
Abstract
There is a need for new approaches for the control of influenza given the burden caused by annual seasonal outbreaks, the emergence of viruses with pandemic potential, and the development of resistance to current antiviral drugs. We show that multivalent biologics, engineered using carbohydrate-binding modules specific for sialic acid, mask the cell-surface receptor recognized by the influenza virus and protect mice from a lethal challenge with 2009 pandemic H1N1 influenza virus. The most promising biologic protects mice when given as a single 1-μg intranasal dose 7 d in advance of viral challenge. There also is sufficient virus replication to establish an immune response, potentially protecting the animal from future exposure to the virus. Furthermore, the biologics appear to stimulate inflammatory mediators, and this stimulation may contribute to their protective ability. Our results suggest that this host-targeted approach could provide a front-line prophylactic that has the potential to protect against any current and future influenza virus and possibly against other respiratory pathogens that use sialic acid as a receptor.
