DDX41 Recognizes RNA/DNA Retroviral Reverse Transcripts and Is Critical for <italic toggle="yes">In Vivo</italic> Control of Murine Leukemia Virus Infection

ABSTRACT Host recognition of viral nucleic acids generated during infection leads to the activation of innate immune responses essential for early control of virus. Retrovirus reverse transcription creates numerous potential ligands for cytosolic host sensors that recognize foreign nucleic acids, in...

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Autores principales:	Spyridon Stavrou, Alexya N. Aguilera, Kristin Blouch, Susan R. Ross
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	AML/MDS DEAD-box helicase antiviral interferon response cGAS cytosolic sensing Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/2aea56d3644c4e3a806aa62489105a5c
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spelling	oai:doaj.org-article:2aea56d3644c4e3a806aa62489105a5c2021-11-15T16:00:26ZDDX41 Recognizes RNA/DNA Retroviral Reverse Transcripts and Is Critical for <italic toggle="yes">In Vivo</italic> Control of Murine Leukemia Virus Infection10.1128/mBio.00923-182150-7511https://doaj.org/article/2aea56d3644c4e3a806aa62489105a5c2018-07-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00923-18https://doaj.org/toc/2150-7511ABSTRACT Host recognition of viral nucleic acids generated during infection leads to the activation of innate immune responses essential for early control of virus. Retrovirus reverse transcription creates numerous potential ligands for cytosolic host sensors that recognize foreign nucleic acids, including single-stranded RNA (ssRNA), RNA/DNA hybrids, and double-stranded DNA (dsDNA). We and others recently showed that the sensors cyclic GMP-AMP synthase (cGAS), DEAD-box helicase 41 (DDX41), and members of the Aim2-like receptor (ALR) family participate in the recognition of retroviral reverse transcripts. However, why multiple sensors might be required and their relative importance in in vivo control of retroviral infection are not known. Here, we show that DDX41 primarily senses the DNA/RNA hybrid generated at the first step of reverse transcription, while cGAS recognizes dsDNA generated at the next step. We also show that both DDX41 and cGAS are needed for the antiretroviral innate immune response to murine leukemia virus (MLV) and HIV in primary mouse macrophages and dendritic cells (DCs). Using mice with cell type-specific knockout of the Ddx41 gene, we show that DDX41 sensing in DCs but not macrophages was critical for controlling in vivo MLV infection. This suggests that DCs are essential in vivo targets for infection, as well as for initiating the antiviral response. Our work demonstrates that the innate immune response to retrovirus infection depends on multiple host nucleic acid sensors that recognize different reverse transcription intermediates. IMPORTANCE Viruses are detected by many different host sensors of nucleic acid, which in turn trigger innate immune responses, such as type I interferon (IFN) production, required to control infection. We show here that at least two sensors are needed to initiate a highly effective innate immune response to retroviruses—DDX41, which preferentially senses the RNA/DNA hybrid generated at the first step of retrovirus replication, and cGAS, which recognizes double-stranded DNA generated at the second step. Importantly, we demonstrate using mice lacking DDX41 or cGAS that both sensors are needed for the full antiviral response needed to control in vivo MLV infection. These findings underscore the need for multiple host factors to counteract retroviral infection.Spyridon StavrouAlexya N. AguileraKristin BlouchSusan R. RossAmerican Society for MicrobiologyarticleAML/MDSDEAD-box helicaseantiviral interferon responsecGAScytosolic sensingMicrobiologyQR1-502ENmBio, Vol 9, Iss 3 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	AML/MDS DEAD-box helicase antiviral interferon response cGAS cytosolic sensing Microbiology QR1-502
spellingShingle	AML/MDS DEAD-box helicase antiviral interferon response cGAS cytosolic sensing Microbiology QR1-502 Spyridon Stavrou Alexya N. Aguilera Kristin Blouch Susan R. Ross DDX41 Recognizes RNA/DNA Retroviral Reverse Transcripts and Is Critical for <italic toggle="yes">In Vivo</italic> Control of Murine Leukemia Virus Infection
description	ABSTRACT Host recognition of viral nucleic acids generated during infection leads to the activation of innate immune responses essential for early control of virus. Retrovirus reverse transcription creates numerous potential ligands for cytosolic host sensors that recognize foreign nucleic acids, including single-stranded RNA (ssRNA), RNA/DNA hybrids, and double-stranded DNA (dsDNA). We and others recently showed that the sensors cyclic GMP-AMP synthase (cGAS), DEAD-box helicase 41 (DDX41), and members of the Aim2-like receptor (ALR) family participate in the recognition of retroviral reverse transcripts. However, why multiple sensors might be required and their relative importance in in vivo control of retroviral infection are not known. Here, we show that DDX41 primarily senses the DNA/RNA hybrid generated at the first step of reverse transcription, while cGAS recognizes dsDNA generated at the next step. We also show that both DDX41 and cGAS are needed for the antiretroviral innate immune response to murine leukemia virus (MLV) and HIV in primary mouse macrophages and dendritic cells (DCs). Using mice with cell type-specific knockout of the Ddx41 gene, we show that DDX41 sensing in DCs but not macrophages was critical for controlling in vivo MLV infection. This suggests that DCs are essential in vivo targets for infection, as well as for initiating the antiviral response. Our work demonstrates that the innate immune response to retrovirus infection depends on multiple host nucleic acid sensors that recognize different reverse transcription intermediates. IMPORTANCE Viruses are detected by many different host sensors of nucleic acid, which in turn trigger innate immune responses, such as type I interferon (IFN) production, required to control infection. We show here that at least two sensors are needed to initiate a highly effective innate immune response to retroviruses—DDX41, which preferentially senses the RNA/DNA hybrid generated at the first step of retrovirus replication, and cGAS, which recognizes double-stranded DNA generated at the second step. Importantly, we demonstrate using mice lacking DDX41 or cGAS that both sensors are needed for the full antiviral response needed to control in vivo MLV infection. These findings underscore the need for multiple host factors to counteract retroviral infection.
format	article
author	Spyridon Stavrou Alexya N. Aguilera Kristin Blouch Susan R. Ross
author_facet	Spyridon Stavrou Alexya N. Aguilera Kristin Blouch Susan R. Ross
author_sort	Spyridon Stavrou
title	DDX41 Recognizes RNA/DNA Retroviral Reverse Transcripts and Is Critical for <italic toggle="yes">In Vivo</italic> Control of Murine Leukemia Virus Infection
title_short	DDX41 Recognizes RNA/DNA Retroviral Reverse Transcripts and Is Critical for <italic toggle="yes">In Vivo</italic> Control of Murine Leukemia Virus Infection
title_full	DDX41 Recognizes RNA/DNA Retroviral Reverse Transcripts and Is Critical for <italic toggle="yes">In Vivo</italic> Control of Murine Leukemia Virus Infection
title_fullStr	DDX41 Recognizes RNA/DNA Retroviral Reverse Transcripts and Is Critical for <italic toggle="yes">In Vivo</italic> Control of Murine Leukemia Virus Infection
title_full_unstemmed	DDX41 Recognizes RNA/DNA Retroviral Reverse Transcripts and Is Critical for <italic toggle="yes">In Vivo</italic> Control of Murine Leukemia Virus Infection
title_sort	ddx41 recognizes rna/dna retroviral reverse transcripts and is critical for <italic toggle="yes">in vivo</italic> control of murine leukemia virus infection
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/2aea56d3644c4e3a806aa62489105a5c
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DDX41 Recognizes RNA/DNA Retroviral Reverse Transcripts and Is Critical for <italic toggle="yes">In Vivo</italic> Control of Murine Leukemia Virus Infection

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