title: Experimental and natural infections in MyD88- and IRAK-4-deficient mice and humans.
abstract: Most Toll-like-receptors (TLRs) and interleukin-1 receptors (IL-1Rs) signal via myeloid differentiation primary response 88 (MyD88) and interleukin-1 receptor-associated kinase 4 (IRAK-4). The combined roles of these two receptor families in the course of experimental infections have been assessed in MyD88- and IRAK-4-deficient mice for almost fifteen years. These animals have been shown to be susceptible to 46 pathogens: 27 bacteria, eight viruses, seven parasites, and four fungi. Humans with inborn MyD88 or IRAK-4 deficiency were first identified in 2003. They suffer from naturally occurring life-threatening infections caused by a small number of bacterial species, although the incidence and severity of these infections decrease with age. Mouse TLR- and IL-1R-dependent immunity mediated by MyD88 and IRAK-4 seems to be vital to combat a wide array of experimentally administered pathogens at most ages. By contrast, human TLR- and IL-1R-dependent immunity mediated by MyD88 and IRAK-4 seems to be effective in the natural setting against only a few bacteria and is most important in infancy and early childhood. The roles of TLRs and IL-1Rs in protective immunity deduced from studies in mutant mice subjected to experimental infections should therefore be reconsidered in the light of findings for natural infections in humans carrying mutations as discussed in this review.
authors.affiliation: Pediatric Pneumology and Immunology, Charité Hospital - Humboldt University, Berlin, Germany. burkhard.ludewig@kssg.ch
authors.forename: Horst
authors.initials: H
authors.lastname: von Bernuth
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.forename: Anne
authors.initials: A
authors.lastname: Puel
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
mesh_terms: D000818:Animals; D001424:Bacterial Infections / Q000235:genetics / Q000276:immunology*; D004195:Disease Models, Animal; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics / Q000276:immunology*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology*; D000081207:Primary Immunodeficiency Diseases; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000276:immunology; D051193:Toll-Like Receptors / Q000235:genetics / Q000276:immunology
chemical_list: C507779:MYD88 protein, human; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D017472:Receptors, Interleukin-1; D051193:Toll-Like Receptors; C507773:IRAK4 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases; C507774:Irak4 protein, mouse