Maelfait team: Nucleic Acid Immunity lab

Research Field: Nucleic Acid Sensing in Infection and Inflammation

Team leader: Prof. Dr. Jonathan Maelfait

Tel: +32 9 33 13 710


Research topic

Our lab studies the interplay between viruses and the immune system. Our research contributes to the development of better antivirals and aims to understand the molecular basis of autoinflammatory diseases.

Viruses are obligate intracellular pathogens. In order to replicate they need to deliver their genomes, which are made of RNA or DNA, inside the host cell. Cells contain sensory proteins called nucleic acid receptors, which detect virally derived nucleic acids. Different types of nucleic acid receptors activate distinct antiviral defence mechanisms, which cooperate to clear the viral pathogen. Some receptors respond to infection by releasing antiviral molecules such as type I/III interferons, which prepare surrounding cells for the ensuing viral attack. Others, including the nucleic acid receptor ZBP1, instruct the infected cell to commit suicide thereby preventing viral dissemination. Our research focuses on the identification of the precise molecular mechanisms that activate nucleic acid receptors and how viruses fight back by blocking these processes.

In another aspect of our research we try to understand how nucleic acid receptors recognise viral nucleic acids and avoid contact with cellular RNA and DNA. Healthy uninfected cells are packed with RNA and DNA molecules, which make up our genetic material and contribute to normal cell function. Unwanted detection of these nucleic acids can result in the development of autoinflammatory diseases. We study the molecular processes that drive pathology through recognition of self-nucleic acids. In the future, this will enable us to selectively interfere with disease-causing mechanisms while leaving all other cellular processes untouched.

Areas of expertise

  • Nucleic acid sensors
  • Type I interferon signalling
  • Regulated cell death (apoptosis, necroptosis)
  • Z-DNA/Z-RNA binding proteins (ADAR1, ZBP1)

Technology transfer potential

  • Mouse models of autoinflammatory disease
  • Antiviral therapies

Selected publications

  1. de Reuver R, et al. ADAR1 prevents autoinflammation by suppressing spontaneous ZBP1 activation.
    Nature. 607(7920), 784-789. 2022.
  2. Verdonck S, et al. Viral manipulation of host cell necroptosis and pyroptosis.
    Trends Microbiol. 30(6), 593-605, 2022.
  3. de Reuver R, et al. ADAR1 interaction with Z-RNA promotes editing of endogenous double-stranded RNA and prevents MDA5-dependent immune activation.
    Cell Rep. 36(6), 109500, 2021.
  4. Devos M, et al. Sensing of endogenous nucleic acids by ZBP1 induces keratinocyte necroptosis and skin inflammation.
    J Exp Med. 217(7), e20191913, 2020.
  5. Maelfait J. et al. Sensing of viral and endogenous Z-RNA by ZBP1/DAI induces necroptosis.
    EMBO J. 36, 2529-2543, 2017.
Click to enlarge. Virus infection experiment showing that the Z-form nucleic acid binding Zα domains of ZBP1 are required for the antiviral activity of ZBP1. Infectious murine cytomegalovirus (MCMV) particles recovered 5 days post-infection from the spleens of wild type (+/+) or Zbp1 knock-in mice carrying one (+/Zα1α2) or two (Zα1α2/Zα1α2) Zα domain-mutant alleles of the nucleic acid receptor ZBP1. Wild type MCMV replicates normally in all genotypes, while a M45mutRHIM strain of MCMV, which is unable to escape the antiviral actions of ZBP1, only replicates in ZBP1 Zα domain-mutant mice (see Maelfait et al. EMBO Journal 2017)
Click to enlarge. Haematoxylin and eosin (H&E; top) and immunofluorescent (bottom) sections from mouse skin showing normal (left panels) and thickened/inflamed (right panels) epidermis. Skin inflammation results from the spontaneous detection of self-nucleic acids by ZBP1 due to loss of ADAR1 and RIPK1 function (see de Reuver, Verdonck et al. Nature 2022).

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