PLoS ONE (Jan 2011)

STAT1 hyperphosphorylation and defective IL12R/IL23R signaling underlie defective immunity in autosomal dominant chronic mucocutaneous candidiasis.

  • Sanne P Smeekens,
  • Theo S Plantinga,
  • Frank L van de Veerdonk,
  • Bas Heinhuis,
  • Alexander Hoischen,
  • Leo A B Joosten,
  • Peter D Arkwright,
  • Andrew Gennery,
  • Bart Jan Kullberg,
  • Joris A Veltman,
  • Desa Lilic,
  • Jos W M van der Meer,
  • Mihai G Netea

DOI
https://doi.org/10.1371/journal.pone.0029248
Journal volume & issue
Vol. 6, no. 12
p. e29248

Abstract

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We recently reported the genetic cause of autosomal dominant chronic mucocutaneous candidiasis (AD-CMC) as a mutation in the STAT1 gene. In the present study we show that STAT1 Arg274Trp mutations in the coiled-coil (CC) domain is the genetic cause of AD-CMC in three families of patients. Cloning and transfection experiments demonstrate that mutated STAT1 inhibits IL12R/IL-23R signaling, with hyperphosphorylation of STAT1 as the likely underlying molecular mechanism. Inhibition of signaling through the receptors for IL-12 and IL-23 leads to strongly diminished Th1/Th17 responses and hence to increased susceptibility to fungal infections. The challenge for the future is to translate this knowledge into novel strategies for the treatment of this severe immunodeficiency.