Human Toll-like receptor-dependent induction of interferons in protective immunity to viruses.
Five of the 10 human Toll-like receptors (TLRs) (TLR3, TLR4, TLR7, TLR8, and TLR9), and four of the 12 mouse TLRs (TLR3, TLR4, TLR7, TLR9) can trigger interferon (IFN)-alpha, IFN-beta, and IFN-lambda, which are critical for antiviral immunity. Moreover, TLR3, TLR7, TLR8, and TLR9 differ from TLR4 in two particularly important ways for antiviral immunity: they can be activated by nucleic acid agonists mimicking compounds produced during the viral cycle, and they are typically present within the cell, along the endocytic pathway, where they sense viral products in the intraluminal space. Investigations in mice have demonstrated that the TLR7/9-IFN and TLR3-IFN pathways are different and critical for protective immunity to various experimental viral infections. Investigations in humans with interleukin-1 receptor-associated kinase-4 (IRAK-4) deficiency (unresponsive to TLR7, TLR8, and TLR9), UNC-93B deficiency (unresponsive to TLR3, TLR7, TLR8, and TLR9), and TLR3 deficiency have recently shed light on the role of these two pathways in antiviral immunity in natural conditions. UNC-93B- and TLR3-deficient patients appear to be specifically prone to herpes simplex virus 1 (HSV-1) encephalitis, although clinical penetrance is incomplete, whereas IRAK-4-deficient patients appear to be normally resistant to most viruses, including HSV-1. These experiments of nature suggest that the TLR7-, TLR8-, and TLR9-dependent induction of IFN-alpha, IFN-beta, and IFN-lambda is largely redundant in human antiviral immunity, whereas the TLR3-dependent induction of IFN-alpha, IFN-beta, and IFN-lambda is critical for primary immunity to HSV-1 in the central nervous system in children but redundant for immunity to most other viral infections.
Zhang
Shen-Ying
SY
Laboratory of Human Genetics of Infectious Diseases, Institut National de la Santé et de la Recherche Médicale, Paris, France, EU.
Jouanguy
Emmanuelle
E
Sancho-Shimizu
Vanessa
V
von Bernuth
Horst
H
Yang
Kun
K
Abel
Laurent
L
Picard
Capucine
C
Puel
Anne
A
Casanova
Jean-Laurent
JL
D000818:Animals; D006801:Humans; D007372:Interferons / Q000378:metabolism*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000172:deficiency / Q000235:genetics; D026901:Membrane Transport Proteins / Q000172:deficiency / Q000235:genetics; D051379:Mice; D051196:Toll-Like Receptor 3 / Q000172:deficiency / Q000235:genetics; D051193:Toll-Like Receptors / Q000235:genetics / Q000502:physiology*; D014777:Virus Diseases / Q000276:immunology*
D026901:Membrane Transport Proteins; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D051193:Toll-Like Receptors; C454130:UNC93B1 protein, human; D007372:Interferons; C507773:IRAK4 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases