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, 8 viruses, 7 parasites, and 4 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.

Inherited human IRAK-1 deficiency selectively impairs TLR signaling in fibroblasts

“…In vivo studies have shown survival to be higher for Irak1 −/− , Irak2 −/− , and Irak4 −/− mice following LPS injection (Irak3 −/− mice were not tested) (11,38,39) and lower for Irak1 −/− and Irak4 −/− mice (the only two strains tested) following Staphylococcus aureus infection (11,40). Myd88 −/− mice and, by inference, Irak4 −/− mice are susceptible to many other pathogens not used for the inoculation of the other mutants (41). Overall, these studies suggest that the mouse IRAK-1, IRAK-2, and IRAK-4 proteins play activating roles in TLR and IL-1R responses and protective immunity to bacteria, albeit to different degrees, whereas IRAK-3 seems to have an inhibitory effect (34,42).…”

“…Human patients with autosomal-recessive complete IRAK-4 or MyD88 deficiency have a common clinical phenotype, characterized by extreme susceptibility to a small range of pyogenic bacterial infections, with normal resistance to other bacteria and most viruses, fungi, and parasites (41,43). IRAK-4-and MyD88-deficient patients present with meningitis, sepsis, arthritis, osteomyelitis, and deep inner-organ/tissue abscesses, mostly caused by gram-positive Streptococcus pneumoniae and S. aureus and, more rarely, by gram-negative Pseudomonas aeruginosa and Shigella sonnei .…”

“…They also display superficial skin infections, mostly caused by S. aureus. The first invasive infection occurs before the age of 2 y in 85% of patients and 92% of probands, and before the age of 6 mo in 42% of patients and probands (41,43,52,55,57,(59)(60)(61)(62)(63)(64). The frequency and severity of these infections decrease considerably from adolescence onward, even in the absence of preventive measures, suggesting that the MyD88/IRAK-4-dependent TIR pathway becomes redundant once acquired immunity is fully functional and can ensure protection (43).…”

Lack of IL-1 Receptor–Associated Kinase-4 Leads to Defective Th1 Cell Responses and Renders Mice Susceptible to Mycobacterial Infection

“…Nonetheless, the majority of studies relied on MyD88-deficient experimental systems (5,12). In humans, IRAK-4 deficiency is related to increased susceptibility to invasive pyogenic infections (13).…”

“…However, the clinical condition usually improves with age, such that IRAK-4 deficiency is life-threatening in infancy and early childhood but almost harmless in adulthood. This suggests that acquired immunity progressively compensates for the deficient innate immunity (12,14). Additionally, IRAK-4 polymorphism is associated with an increased risk for severe sepsis and cancer initiation, as well as tumor progression and therapy resistance (10,15).…”