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DDX41 Recognizes RNA/DNA Retroviral Reverse Transcripts and Is Critical for In Vivo Control of Murine Leukemia Virus Infection.
- Source :
-
MBio [mBio] 2018 Jun 05; Vol. 9 (3). Date of Electronic Publication: 2018 Jun 05. - Publication Year :
- 2018
-
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.<br /> (Copyright © 2018 Stavrou et al.)
- Subjects :
- Animals
DEAD-box RNA Helicases genetics
DNA, Viral chemistry
DNA, Viral genetics
Dendritic Cells enzymology
Dendritic Cells virology
Host-Pathogen Interactions
Humans
Leukemia Virus, Murine physiology
Macrophages enzymology
Macrophages virology
Male
Mice
Mice, Inbred C57BL
Nucleotidyltransferases genetics
Nucleotidyltransferases metabolism
RNA, Viral chemistry
RNA, Viral genetics
Retroviridae Infections genetics
DEAD-box RNA Helicases metabolism
DNA, Viral metabolism
Leukemia Virus, Murine genetics
RNA, Viral metabolism
Retroviridae Infections enzymology
Retroviridae Infections virology
Subjects
Details
- Language :
- English
- ISSN :
- 2150-7511
- Volume :
- 9
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- MBio
- Publication Type :
- Academic Journal
- Accession number :
- 29871919
- Full Text :
- https://doi.org/10.1128/mBio.00923-18