Pivotal and sex-specific role of RNA helicase DDX3X in innate antimicrobial immune response

30/11/2018

To establish an immune response, cells need to sense microbial molecules of pathogens, signal this information to the nucleus and initiate transcription of pro-inflammatory cytokines and chemokines. In previous studies the researchers identified DDX3X as a regulator of type I interferon (IFN-I)-induced transcription after infection with viruses or Listeria monocytogenes (Lm). The organismal context however, remained elusive. Researchers from MFPL, IMBA, CEMM and the University of Veterinary Medicine showed in a collaborative effort that the DEAD box RNA helicase DDX3X is an essential mediator of innate antimicrobial immunity in vivo.

Consequences for Innate immunity

Mice lacking DDX3X in hematopoietic stem cells have reduced number of lymphocytes and NK cells indicating a role in hematopoiesis, which concomitantly impacts the innate immune system. In DDX3X-deficient fibroblasts infected with VSV (vesicular stomatitis virus), transcription of IFNs was lower and the viral load accordingly higher than in control cells. Surprisingly, viral clearance was only marginally affected in vivo.

In contrast, infection with Lm showed strong impact on innate immunity. DDX3X-deficient macrophages show impaired inflammatory cytokine production and are unable to control Lm growth. Mice lacking DDX3X in the hematopoietic system produce reduced amounts of serum IL-12 and IFNγ. DDX3X loss alters the cytokine cocktail needed for cell recruitment and functional activation of innate immune cells.

Sex specific Role of DDX3X

In both, mice and humans, DDX3X has a homolog called DDX3Y encoded on the Y-Chromosome. The presence of DDX3Y allows male mice, but not female mice, to survive the loss of DDX3X in hematopoietic cells. However, in spite of a ~90% homology of DDX3X and DDX3Y in mice, they are only partially redundant. During infection with Lm DDX3Y is not sufficient to fully compensate for DDX3X loss. Male mice lacking DDX3X in their hematopoietic stem cells exhibited increased susceptibility to Lm infection. In macrophages a sex-dependent impairment of cytokine synthesis was observed. Thus, DDX3X may contribute to sex differences in immunity to pathogens and inflammatory disease.

The RNA helicase DDX3X is an essential mediator of innate antimicrobial immunity. Szappanos D, Tschismarov R, Perlot T, Westermayer S, Fischer K, Platanitis E, Kallinger F, Novatchkova M, Lassnig C, Müller M, Sexl V, Bennett KL, Foong-Sobis M, Penninger JM, Decker T. PLoS Pathog. 2018 Nov 26