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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.
MyD88 was first described as a “macrophage differentiation marker” for which mRNA accumulated in murine M1 myeloleukemic cells upon activation with IL-6 [1, 2]. Human MYD88 maps to chromosome 3p22-p21.3 and contains five exons . The full-length cDNA for human MYD88 encodes 296 amino acids forming a 33 kDa protein . Murine Myd88 maps to chromosome 9q119. It also has five exons and the full-length cDNA encodes 296 amino acids forming a 33 kDa protein. The MyD88 protein includes an N-terminal “death domain” (DD) and a C-terminal Toll-interleukin receptor (TIR)-domain, similar to the intracellular domains of Toll-like receptors (TLRs) and members of the interleukin-1 receptor (IL-1R) superfamily, collectively referred to as TIR receptors [2–6]. Human IRAK4 maps to chromosome 12q12 and contains 13 exons. The full-length cDNA for human IRAK-4 encodes 460 amino acids, forming a 52 kDa protein. The murine Irak4 gene maps to chromosome 15q94 and also contains 13 exons. The corresponding full-length cDNA encodes 459 amino acids, forming a 52 kDa protein. The IRAK-4 protein contains an N-terminal DD and a central kinase domain (KD) .
MyD88 and IRAK-4 are essential for signaling via all TLRs with the exception of TLR3 and, to some extent, TLR4, and for signaling via most IL-1Rs, including IL-1R1, IL-18R and IL-33R (ST2) [8–17]. Following its activation, MyD88 binds to the IL-1Rs and TLRs via its TIR domain, forming an oligomer; it then recruits IRAK-4 to the receptor via its DD [5, 18–21], mediating the activation of various transcription factors, including IRF5 and IRF7, AP-1 and NF-κB, depending in part on the cell type and the cell surface receptor stimulated  (see figure 1). Thus, TIR-MyD88-IRAK-4-mediated signaling appears to be important for the innate recognition of pathogens and the ignition of inflammation, and, as such, is indispensable for the induction of protective immunity.
However, most demonstrations of the importance of TIR-MyD88-IRAK-4-dependent pathways for protective immunity have been based on studies of experimental infections in mice in which protective immunity against a broad range of infectious agents has been shown; however, the essential nature of the role of TIR signaling in such broad-ranging immunity has been called into question by both clinical genetic and evolutionary genetic studies [23–28]. In particular, the identification of human IRAK-4 and MyD88 deficiencies as immunological and clinical phenocopies has provided considerable insights [29, 30]. Detailed immunological and clinical descriptions of a large cohort of patients with these deficiencies have led to a reassessment of the importance of the TIR-MyD88-IRAK-4-dependent pathway for general protective immunity in humans under natural conditions .
Myd88-deficient mice are known to be susceptible to experimental infections with 45 pathogens: 27 bacteria [32–77], eight viruses [78–91], seven protozoa [92–107], and four fungi [108–113]. Enhanced pathogen growth in Myd88-deficient mice has been observed for:
IRAK-4-deficient mice showed enhanced pathogen growth when challenged with Staphylococcus aureus i.p. .
As greater pathogen growth in vivo is not always correlated with lower levels of survival, we consider here the published mortality data for experimental infections of MyD88-deficient mice. Mortality due to experimental infections was greater in MyD88-deficient mice than in wild-type mice for 33 pathogens:
IRAK-4-deficient mice displayed lower levels of survival than wild-type mice following i.p. challenge with Staphylococcus aureus .
The initial description of human IRAK-4 deficiency was based on three patients  and that of human MyD88 deficiency was based on nine patients . These patients all carried either homozygous or compound heterozygous mutations of the IRAK4 or MYD88 gene that lead to nonfunctional proteins [29, 30]. Given these small numbers of patients, only brief preliminary conclusions could be made concerning the infectious phenotype associated with the absence of MyD88-IRAK-4-dependent signaling. The cumulative evidence from the large number of case reports since published and from the comprehensive description of a cohort of 76 patients (52 with IRAK-4 deficiency and 24 with MyD88 deficiency) allow firmer conclusions about the infectious phenotype in the absence of MyD88-IRAK-4-dependent signaling to be drawn [31, 114–129]. There are also an additional five patients with IRAK-4 deficiency and two patients with MyD88 deficiency for whom no data have yet been published. The infectious phenotype of MyD88- and IRAK-4-deficient patients is dominated by invasive pyogenic infections. The most frequent of such infections are meningitis, sepsis, arthritis and osteomyelitis, and the principal bacteria isolated in cases of invasive infection are Streptococcus pneumoniae, Staphylococcus aureus and Pseudmomonas aeruginosa (for a list of all the pathogens isolated from Myd88- and IRAK-4-deficient patients, see Table 3). These patients also typically suffer from deep tissue infections of the upper respiratory tract, such as severe tonsillitis due to Pseudomonas aeruginosa in particular, and superficial skin infections, mostly caused by Staphylococcus aureus. We cannot rule out the possibility that the predominance of Gram-positive bacteria in patients with MyD88 and IRAK-4 deficiencies results at least in part from a patient recruitment bias. No patients with these deficiencies have yet been identified on the Indian subcontinent, in South America or in China. Patients with MyD88- or IRAK-4-deficiencies in these areas of the world might perhaps present a higher frequency of infections with Gram-negative bacteria, as suggested by case reports of invasive infection with Shigella spp. during endemic diarrhea outbreaks [119, 127]. However, by contrast to this uncertainty concerning positive associations about the infectious phenotype, we can highlight much more emphatically the negative associations drawn concerning the roles of MyD88 and IRAK-4 in host anti-pathogen defense. Most, if not all, of the 76 patients identified to date have been exposed to mycobacteria, viruses, Toxoplasma, Pneumocystis and other fungi, but none of these pathogens caused invasive infection. This strongly suggests that MyD88 and IRAK-4 are dispensable in humans for defense against these pathogens, contrary to expectations based on the results obtained in the mouse model .
At the time of writing, 24 patients with MyD88 deficiency have been identified (22 published , 2 unpublished (von Bernuth, unpublished)). Nine of these patients have died since identification: five in infancy and four in early childhood. The youngest of these nine patients died at one month of age and the oldest died at four years of age. The 15 surviving patients are currently four, seven, 11, 14 and 20 years old. Fifty-two patients with IRAK-4 deficiency have been identified . Twenty-one of these patients have died since identification: 10 in infancy and 11 in early childhood. The youngest of these 19 patients was two months old, and the oldest was seven years old, at the time of death; the latter being patient P23 from the large cohort published in 2010  who recently died of S. pneumoniae meningitis (unpublished observation). The 31 surviving patients are currently two (two patients), three (one patient), four (one patient), five (two patients), six (two patients), seven (three patients), nine (one patient), 12 (one patient), 13 (two patients), 14 (two patients), 15 (two patients), 16 (two patients), 17 (two patients), 18 (one patient), 20 (one patient), 21 (one patient), 22 (one patient), 30 (one patient), 33 (two patients) and 38 (one patient) years old . Thus, it can clearly be seen that human MyD88- and IRAK-4-deficiencies are life-threatening. MyD88 and IRAK-4 are indispensable for survival in infancy and early childhood and, before the advent of vaccines and antibiotics, most if not all children with these defects would have died in the first few years of life. However, several individuals with MyD88 deficiency or its immunological phenocopy, IRAK-4-deficiency, who were given antibiotic prophylaxis and even sometimes IgG substitution following the genetic identification of the disease, have survived into adolescence and adulthood. Many of these patients have since stopped taking regular antibiotic prophylaxis, but have not yet developed invasive pyogenic infections. MyD88-IRAK-4-dependent signaling, therefore, appears to be dispensable for survival after adolescence.
The notion that TLR- and IL-1R-mediated innate immune recognition is indispensable for survival and protective defense against many pathogens — based largely on findings in mouse models of experimental infections — should be reconsidered in light of the naturally occurring infections in humans with MyD88- or IRAK-4-deficiency. By contrast to the broad susceptibility of MyD88-deficient mice to 46 different bacteria, viruses, protozoa and fungi (i.e. to almost nearly all the microbes tested), patients with MyD88- or IRAK-4-deficiencies are susceptible to invasive and non-invasive infections with only a few Gram-positive and Gram-negative bacteria. Moreover, MyD88-IRAK-4-mediated TLR and IL-1R immunity is undoubtedly vital in infancy and early childhood, but gradually becomes dispensable, from adolescence onwards. Overall, MyD88-dependent TLR and IL-1R immunity is vital in both mice and humans, but its role in the course of naturally occurring infections in humans seems to be much more restricted than initially inferred from experimental infections in mice, as humans lacking functional MyD88 or IRAK-4 proteins are susceptible to a narrow range of pathogens, and only in infancy and early childhood. The different outcomes between experimental infections in mice and natural infections in humans may be due to species-specific differences, or more likely to differences in the modes of infection. In that regard, the study of naturally occurring infections in MyD88- and IRAK-4-deficient mice would be insightful, as suggested by preliminary studies . In any case, the studies of MyD88- and IRAK4-deficient humans neatly illustrate the value of dissecting inborn errors of immunity underlying pediatric infectious diseases for deciphering the redundant and non-redundant roles of host defense genes in natura [23–28]. Immunological redundancy is greater in the course of natural infections in outbred human populations than in the course of experimental infections in inbred mice. Genetic studies of this type will facilitate the burgeoning, long-awaited investigation of the contribution of immunity to health and disease in humans [131–133].
We thank all patients, their families and physicians for their trust and cooperation. We thank Pegah Ghandil, Cheng-Lung Ku, Maya Chrabieh, Jacqueline Feinberg and Laurent Abel, members of the laboratory for Human Genetics of Infectious Diseases, Paris and Anne-Hélène Lebrun, Michael Bauer and Karoline Strehl, members of Kinderklinik mit Schwerpunkt Pneumologie und Immunologie, Berlin for critically reading the manuscript. The Laboratory of Human Genetics of Infectious Diseases is supported by grants from The Rockefeller University Center for Clinical and Translational Science (5UL1RR024143-03) and The Rockefeller University. The Laboratory of Human Genetics of Infectious Diseases was supported by the March of Dimes, the Dana Foundation, the ANR, INSERM, and PHRC. HvB received funding from the University San Raffaele (Milan, Italy), the Legs Poix (Paris, France), the Deutsche Forschungsgemeinschaft (DFG VO 995/1-1, VO 995/1-2). HvB receives ongoing support by the Deutsche Forschungsgemeinschaft (DFG BE 3895/3-1) (Bonn, Germany), the Bundesministerium für Bildung und Forschung (PID-NET) (Berlin, Germany), the Sonnenfeldstiftung (Berlin) and intramural funding from the Medical Faculty, Charité, Berlin.