Intrinsische Immunerkennung retroviraler Infektionen in SAMHD1 Knockout-Mäusen
Immunologie
Zusammenfassung der Projektergebnisse
The hereditary autoimmune disease Aicardi-Goutières syndrome (AGS) is characterized by spontaneous type I interferon (IFN) production and can be caused by defects of SAMHD1. SAMHD1 is dNTP triphosphohydrolase that regulates the intracellular dNTP content in a cell-cycle depend fashion. SAMHD1 is a retroviral restriction factor in myeloid cells and resting T cells. In addition, it has been shown that HIV-1 infection triggers an immune response in DCs and macrophages in the absence of SAMHD1. Previously, we were able to establish a SAMHD1 knockout mouse model and found that SAMHD1 inhibits HIV reporter virus infection in vivo and that mice lacking SMAHD1 display an endogenous IFN signature reminiscent of human AGS patients. Within this study we were able to characterizing the innate immune sensing of retroviral infection and comparing it to the endogenous immune response in the absence of SAMHD1. We analyzed the endogenous and HIV-1-induced immune responses in the absence of SAMHD1 and identified an IFN dependent block to HIV infection in human and murine cells in vitro and in vivo. This block seems to be dependent on the DNA sensor cGAS, since the infection of cGAS/SAMHD1 double KO mice /cells mirrors the phenotype of SAMHD1/IFNAR cells and highlights the importance of cGAS as a sensor for HIV infection. Using transcriptome analysis, we were able to identify enhanced ISG transcript levels in uninfected cells lacking SAMHD1, many of which were further upregulated upon infection, suggesting that the trigger and sensor in autoimmune reaction and HIV-induced immunity in the absence of SAMHD1 are similar. In addition, we helped to identify guanosine-containing Y-form DNA, which is also present in HIV during reverse transcription, as a novel trigger of a cGAS-mediated immune response. Furthermore, we were able to characterize the SAMHD1-mediated block to LINE-1 retroelements in great detail. Since an enhanced replication of endogenous retroelements in the absence of SAMHD1 is discussed as a potential trigger of AGS, our insights might explain how the autoimmune reaction is triggered and suggests that a very important and newly identified function of SAMHD1 might lie in the protection of the host genome from internal damage.
Projektbezogene Publikationen (Auswahl)
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Phosphorylation of murine SAMHD1 regulates its antiretroviral activity. Retrovirology 2015 Dec 15
Wittmann S, Behrendt R, Eissmann K, Volkmann B, Thomas D, Ebert T, Cribier A, Benkirane M, Hornung V, Bouzas NF, Gramberg T
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Sequence‐specific activation of the DNA sensor cGAS by Y‐form DNA structures as found in primary HIV‐1 cDNA. Nature Immunology. 2015 Oct;16(10):1025‐33
Herzner AM, Hagmann CA, Goldeck M, Wolter S, Kübler K, Wittmann S, Gramberg T, Andreeva L, Hopfner KP, Mertens C, Zillinger T, Jin T, Xiao TS, Bartok E, Coch C, AckermannD, Hornung V, Ludwig J, Barchet W, Hartmann G, Schlee M
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PML/TRIM19 restricts HIV infection in a cell typedependent manner, Viruses 2016, 8(1), 2
Kahle T, Volkmann B, Eissmann K, Herrmann A, Schmitt S, Wittmann S, Merkel L, Reuter N, Stamminger T, Gramberg T
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Then SAMHD1‐mediated block of LINE‐1 retroelements is regulated by phosphorylation, Mobile DNA 2018 9:11
Herrmann A, Wittmann S, Shepard CN, Thomas D, Ferreiros N, Kim B, Gramberg T
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IFI16 Targets the Transcription Factor Sp1 to Suppress HIV‐1 Transcription and Latency Reactivation, Cell Host & Microbe 2019 May 31
Hotter D., Bosso M., Jønsson K.L., Krapp C., Stürzel C.M., Das A., Littwitz‐Salomon E., Berkhout B., Russ A., Wittmann S., Gramberg T., Zheng Y., Martins L.J., Planelles V., Jakobsen M.R., Hahn B.H., Dittmer U., Sauter D., Kirchhoff F.
