The genetic basis of pneumococcal and staphylococcal infections: inborn errors of human TLR and IL-1R immunity

Boisson, Bertrand

doi:10.1007/s00439-020-02111-z

Cited by 14 publications

(19 citation statements)

References 103 publications

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“…As an example, studies of the considerable genetic diversity of PIDs underlying invasive pneumococcal disease revealed a common immunological mechanism. The opsonization of pneumococci by antibodies (Abs) or complement as well as their destruction by splenic macrophages constitute the essential mechanism of antipneumococcal immunity (62,67).…”

Section: The Pathogenesis Of Infectious Diseases Inferred From Primary Immunodeficienciesmentioning

confidence: 99%

“…The study of invasive pneumococcal disease provided a second example of a relatively common infection that turned out to be monogenic in some cases. Pneumococcus (Streptococcus pneumoniae) is a bacterium that infects almost all humans but causes life-threatening, invasive disease only rarely (67). Known genetic etiologies include disorders of the phagocytosis of opsonized bacteria by splenic macrophages (62,67).…”

Section: Invasive Pyogenic Bacterial Diseasementioning

confidence: 99%

“…Pneumococcus (Streptococcus pneumoniae) is a bacterium that infects almost all humans but causes life-threatening, invasive disease only rarely (67). Known genetic etiologies include disorders of the phagocytosis of opsonized bacteria by splenic macrophages (62,67). Patients with such defects are prone to multiple infections (PIDs), with the exception of those with isolated congenital asplenia, half of whom carry mutations causing haploinsufficiency at the RPSA locus (146,147).…”

Section: Invasive Pyogenic Bacterial Diseasementioning

confidence: 99%

“…Patients with MyD88 or IRAK-4 deficiencies do not respond to Toll-like receptor (TLR) agonists (except TLR3), IL-1, IL-18, IL-33, or related cytokines. Remarkably, they suffer from invasive bacterial disease caused by pneumococcus and/or, more rarely, Staphylococcus aureus (67).…”

Section: Invasive Pyogenic Bacterial Diseasementioning

confidence: 99%

“…Another example is provided by the genetic heterogeneity of invasive pneumococcal disease, which is high among both PIDs and monogenic infections. However, children with isolated pneumococcal disease or isolated congenital asplenia display a high level of genetic homogeneity (67,146,147). For patients with MSMD or invasive pneumococcal disease, however, the genetic heterogeneity does not mask an equally high level of physiological homogeneity.…”

Section: Genetic Heterogeneity and Physiological Homogeneitymentioning

confidence: 99%

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Lethal Infectious Diseases as Inborn Errors of Immunity: Toward a Synthesis of the Germ and Genetic Theories

Casanova

Abel

2021

Annu. Rev. Pathol. Mech. Dis.

104

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It was first demonstrated in the late 19th century that human deaths from fever were typically due to infections. As the germ theory gained ground, it replaced the old, unproven theory that deaths from fever reflected a weak personal or even familial constitution. A new enigma emerged at the turn of the 20th century, when it became apparent that only a small proportion of infected individuals die from primary infections with almost any given microbe. Classical genetics studies gradually revealed that severe infectious diseases could be driven by human genetic predisposition. This idea gained ground with the support of molecular genetics, in three successive, overlapping steps. First, many rare inborn errors of immunity were shown, from 1985 onward, to underlie multiple, recurrent infections with Mendelian inheritance. Second, a handful of rare and familial infections also segregating as Mendelian traits but striking humans resistant to other infections were deciphered molecularly from 1996 onward. Third, a growing number of rare or common sporadic infections were shown to result from monogenic, but not Mendelian, inborn errors from 2007 onward. A synthesis of the hitherto mutually exclusive germ and genetic theories is now in view. This article has been accepted for publication on April 14, 2020. Changes may still occur before final publication. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 16 is January 24, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Section: The Pathogenesis Of Infectious Diseases Inferred From Primary Immunodeficienciesmentioning

confidence: 99%

Section: Invasive Pyogenic Bacterial Diseasementioning

confidence: 99%

Section: Invasive Pyogenic Bacterial Diseasementioning

confidence: 99%

Section: Invasive Pyogenic Bacterial Diseasementioning

confidence: 99%

Section: Genetic Heterogeneity and Physiological Homogeneitymentioning

confidence: 99%

See 3 more Smart Citations

Lethal Infectious Diseases as Inborn Errors of Immunity: Toward a Synthesis of the Germ and Genetic Theories

Casanova

Abel

2021

Annu. Rev. Pathol. Mech. Dis.

104

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The human genetic determinism of life-threatening infectious diseases: genetic heterogeneity and physiological homogeneity?

Casanova

Abel

2020

Hum Genet

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Multicellular eukaryotes emerged late in evolution from an ocean of viruses, bacteria, archaea, and unicellular eukaryotes. These macroorganisms are exposed to and infected by a tremendous diversity of microorganisms. Those that are large enough can even be infected by multicellular fungi and parasites. Each interaction is unique, if only because it operates between two unique living organisms, in an infinite diversity of circumstances. This is neatly illustrated by the extraordinarily high level of interindividual clinical variability in human infections, even for a given pathogen, ranging from a total absence of clinical manifestations to death. We discuss here the idea that the determinism of human life-threatening infectious diseases can be governed by single-gene inborn errors of immunity, which are rarely Mendelian and frequently display incomplete penetrance. We briefly review the evidence in support of this notion obtained over the last two decades, referring to a number of focused and thorough reviews published by eminent colleagues in this issue of Human Genetics. It seems that almost any life-threatening infectious disease can be driven by at least one, and, perhaps, a great many diverse monogenic inborn errors, which may nonetheless be immunologically related. While the proportions of monogenic cases remain unknown, a picture in which genetic heterogeneity is combined with physiological homogeneity is emerging from these studies. A preliminary sketch of the human genetic architecture of severe infectious diseases is perhaps in sight.

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Inherited IRAK-4 Deficiency in Acute Human Herpesvirus-6 Encephalitis

et al. 2022

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Human herpesvirus-6 (HHV-6) infection can rarely cause life-threatening conditions, such as encephalitis, in otherwise healthy children, with unclear pathogenesis. We studied a child who presented with acute HHV-6 encephalitis at the age of 10 months and who was homozygous for a novel missense mutation in IRAK4 , encoding interleukin-1 receptor-associated kinase 4, identified by whole-exome sequencing. We tested the damaging impact of this mutation in silico by molecular dynamics simulations and in vitro by biochemical and functional experiments utilizing cell lines and patient’s cells. We found that the mutation is severely hypomorphic, impairing both the expression and function of IRAK-4. Patient’s leukocytes had barely detectable levels of IRAK-4 and diminished anti-viral immune responses to various stimuli inducing different Toll-like receptors and cytosolic nucleic acid sensors. Overall, these findings suggest that acute HHV-6 encephalitis can result from inborn errors of immunity to virus. This study represents the first report of isolated acute HHV-6 infection causing encephalitis in an inherited primary immunodeficiency, notably autosomal recessive (AR) partial IRAK-4 deficiency, and the first report of AR IRAK-4 deficiency presenting with a severe viral disease, notably HHV-6 encephalitis upon an acute infection, thereby expanding the clinical spectrum of IRAK-4 deficiency. Supplementary Information The online version contains supplementary material available at 10.1007/s10875-022-01369-4.

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The genetic basis of pneumococcal and staphylococcal infections: inborn errors of human TLR and IL-1R immunity

Cited by 14 publications

References 103 publications

Lethal Infectious Diseases as Inborn Errors of Immunity: Toward a Synthesis of the Germ and Genetic Theories

Lethal Infectious Diseases as Inborn Errors of Immunity: Toward a Synthesis of the Germ and Genetic Theories

The human genetic determinism of life-threatening infectious diseases: genetic heterogeneity and physiological homogeneity?

Inherited IRAK-4 Deficiency in Acute Human Herpesvirus-6 Encephalitis

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