Selected Publications

• Pichlmair Andreas, Schulz Oliver, Tan Choon-Ping, Rehwinkel Jan, Kato Hiroki, Takeuchi Osamu, Akira Shizuo, Way Michael, Schiavo Giampietro, and Reis e Sousa Caetano (2009) Activation of MDA5 requires higher-order RNA structures generated during virus infection. J Virol, 83(20):10761-9.

• Rehwinkel Jan (2010) Exposing viruses: RNA patterns sensed by RIG-I-like receptors. J Clin Immunol, 30(4):491-5.

• Rehwinkel Jan and Reis e Sousa Caetano (2010) RIGorous detection: exposing virus through RNA sensing. Science, 327(5963):284-6.

• Rehwinkel Jan, Tan Choon P, Goubau Delphine, Schulz Oliver, Pichlmair Andreas, Bier Katja, Robb Nicole, Vreede Frank, Barclay Wendy, Fodor Ervin, and Reis e Sousa Caetano (2010) RIG-I detects viral genomic RNA during negative-strand RNA virus infection. Cell, 140(3):397-408.

• Schulz Oliver, Pichlmair Andreas, Rehwinkel Jan, Rogers Neil C, Scheuner Donalyn, Kato Hiroki, Takeuchi Osamu, Akira Shizuo, Kaufman Randal J, and Reis e Sousa Caetano (2010) Protein kinase R contributes to immunity against specific viruses by regulating interferon mRNA integrity. Cell Host Microbe, 7(5):354-61.

Jan Rehwinkel

The innate immune response is critical for successful host defence against virus infection. Cell-intrinsic mechanisms detect virus presence and signal for the induction of innate response genes such a type I interferons (IFNs). Nucleic acids are often a molecular signature of virus infection and are recognised by innate receptors such as toll-like receptors and RIG-I-like receptors (Figure 1). In addition to their protective role in infectious disease, some of these receptors have also been implicated in inflammatory conditions.

Our research dissects the molecular biology of activation and regulation of nucleic acid sensors. Previously, we identified the RNA recognized by RIG-I in cells infected with negative strand RNA viruses such as influenza A virus as progeny viral RNA genomes (Figure 2). Interestingly, these genomes bear a triphosphate moiety on the 5’-end that is essential for RIG-I activation and IFN induction. Such 5’-PPP-groups are absent from cellular RNA in the cytoplasm, providing an explanation for the specific triggering of RIG-I in virus-infected cells. Currently, we are developing three complementary projects focused on i) the analysis of the mechanisms of activation of the RNA binding receptors RIG-I and MDA5 in infected cells, ii) the analysis of mechanisms regulating the expression of cytosolic nucleic acid binding receptors and iii) the characterization of genetic disorders which result in the triggering of intracellular DNA and RNA sensors and induction of type I IFN.  This work at the intersection of molecular biology and immunology will provide important insights into activation of the innate immune system by nucleic acids. Our findings will have major implications for virus infection, inflammatory and autoimmune diseases and the development of vaccine adjuvants.

Our laboratory will be established within the MRC Human Immunology Unit at the Weatherall Institute of Molecular Medicine in February 2012.

 Figure 1 Innate nucleic acid receptors.

DNA and RNA receptors that signal to transcription of innate response genes are shown. TLR3, -7/8, and -9 localise to the endosomal compartment and are triggered by double stranded RNA, single stranded RNA and DNA, respectively. RIG-I, MDA5 and LGP2 constitute the RLR family and recognise RNA in the cytoplasm. DNA sensors in the cytoplasm include DAI, IFI16, RNA polymerase III – RIG-I, LRRFIP1, Ku70, DHX9, DHX36 and DDX41. LRR, leucine rich repeat domain; TIR, Toll/IL-1 receptor domain; CARD, caspase activation and recruitment domain; Helicase, DExD/H-box RNA helicase domain; RD/CTD, repressive domain (also known as C-terminal domain); Pyrin, Pyrin domain; Zalpha/beta, DNA binding domains.

Figure 2 RIG-I recognizes the 5’-PPP-bearing influenza A virus RNA genome.

A schematic representation of the flu life cycle is shown. Flu has a segmented genome consisting of eight negative sense RNA molecules carrying 5’-PPP groups. Virus particles enter cells via endocytosis, followed by uncoating and nuclear replication of the viral genome (vRNA). This involves a positive sense anti-genome intermediate (cRNA). The viral genome is also transcribed in the nucleus into capped viral messenger RNAs (mRNAs) that are exported to the cytoplasm and translated. Viral proteins and replicated viral genomes assemble progeny virus particles that bud from the cell surface. IFN induction during flu infection is mediated by RIG-I recognition of progeny viral genomes and signalling via the mitochondrial adaptor protein MAVS. CARD, caspase activation and recruitment domain; Helicase, DExD/H-box RNA helicase domain; RD/CTD, repressive domain, also known as C-terminal domain; TM, transmembrane domain.