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Discrete viral E2 lysine residues and scavenger receptor MARCO are required for clearance of circulating alphaviruses

The magnitude and duration of vertebrate viremia is a critical determinant of arbovirus transmission, geographic spread, and disease severity. We find that multiple alphaviruses, including chikungunya (CHIKV), Ross River (RRV), and o’nyong ‘nyong (ONNV) viruses, are cleared from the circulation of m...

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Autores principales: Carpentier, Kathryn S, Davenport, Bennett J, Haist, Kelsey C, McCarthy, Mary K, May, Nicholas A, Robison, Alexis, Ruckert, Claudia, Ebel, Gregory D, Morrison, Thomas E
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839921/
https://www.ncbi.nlm.nih.gov/pubmed/31596239
http://dx.doi.org/10.7554/eLife.49163
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author Carpentier, Kathryn S
Davenport, Bennett J
Haist, Kelsey C
McCarthy, Mary K
May, Nicholas A
Robison, Alexis
Ruckert, Claudia
Ebel, Gregory D
Morrison, Thomas E
author_facet Carpentier, Kathryn S
Davenport, Bennett J
Haist, Kelsey C
McCarthy, Mary K
May, Nicholas A
Robison, Alexis
Ruckert, Claudia
Ebel, Gregory D
Morrison, Thomas E
author_sort Carpentier, Kathryn S
collection PubMed
description The magnitude and duration of vertebrate viremia is a critical determinant of arbovirus transmission, geographic spread, and disease severity. We find that multiple alphaviruses, including chikungunya (CHIKV), Ross River (RRV), and o’nyong ‘nyong (ONNV) viruses, are cleared from the circulation of mice by liver Kupffer cells, impeding viral dissemination. Clearance from the circulation was independent of natural antibodies or complement factor C3, and instead relied on scavenger receptor SR-A6 (MARCO). Remarkably, lysine to arginine substitutions at distinct residues within the E2 glycoproteins of CHIKV and ONNV (E2 K200R) as well as RRV (E2 K251R) allowed for escape from clearance and enhanced viremia and dissemination. Mutational analysis revealed that viral clearance from the circulation is strictly dependent on the presence of lysine at these positions. These findings reveal a previously unrecognized innate immune pathway that controls alphavirus viremia and dissemination in vertebrate hosts, ultimately influencing disease severity and likely transmission efficiency.
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spelling pubmed-68399212019-11-12 Discrete viral E2 lysine residues and scavenger receptor MARCO are required for clearance of circulating alphaviruses Carpentier, Kathryn S Davenport, Bennett J Haist, Kelsey C McCarthy, Mary K May, Nicholas A Robison, Alexis Ruckert, Claudia Ebel, Gregory D Morrison, Thomas E eLife Microbiology and Infectious Disease The magnitude and duration of vertebrate viremia is a critical determinant of arbovirus transmission, geographic spread, and disease severity. We find that multiple alphaviruses, including chikungunya (CHIKV), Ross River (RRV), and o’nyong ‘nyong (ONNV) viruses, are cleared from the circulation of mice by liver Kupffer cells, impeding viral dissemination. Clearance from the circulation was independent of natural antibodies or complement factor C3, and instead relied on scavenger receptor SR-A6 (MARCO). Remarkably, lysine to arginine substitutions at distinct residues within the E2 glycoproteins of CHIKV and ONNV (E2 K200R) as well as RRV (E2 K251R) allowed for escape from clearance and enhanced viremia and dissemination. Mutational analysis revealed that viral clearance from the circulation is strictly dependent on the presence of lysine at these positions. These findings reveal a previously unrecognized innate immune pathway that controls alphavirus viremia and dissemination in vertebrate hosts, ultimately influencing disease severity and likely transmission efficiency. eLife Sciences Publications, Ltd 2019-10-09 /pmc/articles/PMC6839921/ /pubmed/31596239 http://dx.doi.org/10.7554/eLife.49163 Text en © 2019, Carpentier et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Microbiology and Infectious Disease
Carpentier, Kathryn S
Davenport, Bennett J
Haist, Kelsey C
McCarthy, Mary K
May, Nicholas A
Robison, Alexis
Ruckert, Claudia
Ebel, Gregory D
Morrison, Thomas E
Discrete viral E2 lysine residues and scavenger receptor MARCO are required for clearance of circulating alphaviruses
title Discrete viral E2 lysine residues and scavenger receptor MARCO are required for clearance of circulating alphaviruses
title_full Discrete viral E2 lysine residues and scavenger receptor MARCO are required for clearance of circulating alphaviruses
title_fullStr Discrete viral E2 lysine residues and scavenger receptor MARCO are required for clearance of circulating alphaviruses
title_full_unstemmed Discrete viral E2 lysine residues and scavenger receptor MARCO are required for clearance of circulating alphaviruses
title_short Discrete viral E2 lysine residues and scavenger receptor MARCO are required for clearance of circulating alphaviruses
title_sort discrete viral e2 lysine residues and scavenger receptor marco are required for clearance of circulating alphaviruses
topic Microbiology and Infectious Disease
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839921/
https://www.ncbi.nlm.nih.gov/pubmed/31596239
http://dx.doi.org/10.7554/eLife.49163
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