Abstract
ABSTRACTHost 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.
Highlights
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 showed that depletion of DEAD-box helicase 41 (DDX41), IFI203, or cyclic GMP-AMP synthase (cGAS) diminished the IFN- response with and without three prime repair exonuclease 1 (TREX1); that all three molecules bound murine leukemia virus (MLV) reverse-transcribed DNA; and that IFI203 and DDX41 bound to each other and stimulator of IFN genes (STING) but not to cGAS [9]
To determine if DDX41/IFI203 and cGAS acted synergistically to generate an anti-MLV response, we tested the effects of DDX41, IFI203, and STING depletion in bone marrow-derived macrophages (BMDMs) and dendritic cells (DCs) (BMDCs) isolated from cGas knockout (KO) mice that lacked APOBEC3; APOBEC3 depletion leads to increased reverse transcript levels and higher levels of IFN induction and greater assay sensitivity [4, 9]
Summary
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. Reverse transcription creates potential ligands for host sensors that recognize foreign nucleic acids Cellular recognition of these retroviral reverse transcripts activates the innate immune response. The TREX1-sensitive retroviral reverse transcripts are recognized by cellular DNA sensors such as cyclic GMP-AMP synthase (cGAS), DEAD-box helicase 41 (DDX41), and ALR family members such as IFN-induced 16 (IFI16) in humans and IFI203 in mice [9,10,11,12,13, 61]. DNA binding to DDX41 and the ALRs induces type I IFN production via the STING pathway [20] It is not understood how DDX41, which belongs to a family of DEAD-box helicase-containing genes commonly thought to bind RNA, participates in the recognition of nucleic acid. Familial and sporadic mutations in human DDX41 lead to acute myeloblastic leukemia and myelodysplastic syndromes (AML/MDS), suggesting that it functions as a tumor suppressor [21, 22]
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