Human genetics of infectious diseases: between proof of principle and paradigm

Alcaïs, Alexandre; Abel, Laurent; Casanova, Jean‐Laurent

doi:10.1172/jci38111

Cited by 159 publications

(140 citation statements)

References 95 publications

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“…Admittedly, this proportion is larger than that in a comparable group of well-fed children. However, this hypothesis cannot account for the deaths from fever of Darwin's son and two daughters and Pasteur's three daughters, all of whom lived in upper-class clean environments with adequate nutrition and a good education (41). Understanding the deaths of these children and others living in similar conditions, which probably occured during a primary infection, can be seen as a holy grail in the field of infectious diseases.…”

Section: Acquired Immunodeficiencymentioning

confidence: 98%

“…From this perspective, how can we account for the deaths from infection of the children of Pasteur and Darwin? Had Darwin been aware of the work of Mendel, he might have suspected, by 1865, that the childhood deaths from fever in his own family could be autosomal recessive, because he had married his first cousin, Emma, and lost 3 of his 10 children to fever (41). Admittedly, he also might have been side-tracked by the observation that one of the three children that died had Down syndrome, which is associated with an immunodeficiency.…”

Section: Human Geneticistsmentioning

confidence: 99%

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Human genetic basis of interindividual variability in the course of infection

Casanova

2015

Proc. Natl. Acad. Sci. U.S.A.

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161

111

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The key problem in human infectious diseases was posed at the turn of the 20th century: their pathogenesis. For almost any given virus, bacterium, fungus, or parasite, life-threatening clinical disease develops in only a small minority of infected individuals. Solving this infection enigma is important clinically, for diagnosis, prognosis, prevention, and treatment. Some microbes will inevitably remain refractory to, or escape vaccination, or chemotherapy, or both. The solution also is important biologically, because the emergence and evolution of eukaryotes alongside more rapidly evolving prokaryotes, archaea, and viruses posed immunological challenges of an ecological and evolutionary nature. We need to study these challenges in natural, as opposed to experimental, conditions, and also at the molecular and cellular levels. According to the human genetic theory of infectious diseases, inborn variants underlie life-threatening infectious diseases. Here I review the history of the field of human genetics of infectious diseases from the turn of the 19th century to the second half of the 20th century. This paper thus sets the scene, providing the background information required to understand and appreciate the more recently described monogenic forms of resistance or predisposition to specific infections discussed in a second paper in this issue.

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Section: Acquired Immunodeficiencymentioning

confidence: 98%

Section: Human Geneticistsmentioning

confidence: 99%

Human genetic basis of interindividual variability in the course of infection

Casanova

2015

Proc. Natl. Acad. Sci. U.S.A.

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161

111

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“…Moreover, neutralization of IL-12 in a mouse model of typhoid fever abrogates host immunity to primary Salmonella infection (13). In addition, clinical reports have shown that patients immunocompromised as a consequence of HIV infection, chronic granulomatous disease, or functional genetic defects in the IL-12/ IL-23 (IL-12b, IL-12Rb1) and IFN-g (IFN-gR1, IFN-gR2, STAT1) pathways are predisposed to Mendelian susceptibility to mycobacterial disease and/or disseminated Salmonella infection (14)(15)(16)(17)(18)(19). The following highlights the importance of systemic immunity to control invasive S. enterica infections.…”

mentioning

confidence: 99%

Altered IFN-γ–Mediated Immunity and Transcriptional Expression Patterns in N-Ethyl-N-Nitrosourea–Induced STAT4 Mutants Confer Susceptibility to Acute Typhoid-like Disease

Eva

Yuki

Dauphinee

et al. 2014

The Journal of Immunology

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Salmonella enterica is a ubiquitous Gram-negative intracellular bacterium that continues to pose a global challenge to human health. The etiology of Salmonella pathogenesis is complex and controlled by pathogen, environmental, and host genetic factors. In fact, patients immunodeficient in genes in the IL-12, IL-23/IFN-γ pathway are predisposed to invasive nontyphoidal Salmonella infection. Using a forward genomics approach by N-ethyl-N-nitrosourea (ENU) germline mutagenesis in mice, we identified the Ity14 (Immunity to Typhimurium locus 14) pedigree exhibiting increased susceptibility following in vivo Salmonella challenge. A DNA-binding domain mutation (p.G418_E445) in Stat4 (Signal Transducer and Activator of Transcription Factor 4) was the causative mutation. STAT4 signals downstream of IL-12 to mediate transcriptional regulation of inflammatory immune responses. In mutant Ity14 mice, the increased splenic and hepatic bacterial load resulted from an intrinsic defect in innate cell function, IFN-γ–mediated immunity, and disorganized granuloma formation. We further show that NK and NKT cells play an important role in mediating control of Salmonella in Stat4Ity14/Ity14 mice. Stat4Ity14/Ity14 mice had increased expression of genes involved in cell–cell interactions and communication, as well as increased CD11b expression on a subset of splenic myeloid dendritic cells, resulting in compromised recruitment of inflammatory cells to the spleen during Salmonella infection. Stat4Ity14/Ity14 presented upregulated compensatory mechanisms, although inefficient and ultimately Stat4Ity14/Ity14 mice develop fatal bacteremia. The following study further elucidates the pathophysiological impact of STAT4 during Salmonella infection.

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“…In addition to inherent and environmental factors, host genetic variations play an important role in susceptibility and outcomes of virtually all infectious diseases (1,(6)(7)(8)(9)(31)(32)(33)(34)(35)(36)(37)(38). We were specifically interested in determining the role of HLA-II allelic variations in GAS sepsis, because these highly polymorphic HLA-II molecules play a pivotal role in SAg presentation to T cells.…”

mentioning

confidence: 99%

Individual Genetic Variations Directly Effect Polarization of Cytokine Responses to Superantigens Associated with Streptococcal Sepsis: Implications for Customized Patient Care

Nooh

Nookala

Kansal

et al. 2011

The Journal of Immunology

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Host immunogenetic variations strongly influence the severity of group A streptococcus sepsis by modulating responses to streptococcal superantigens (Strep-SAgs). Although HLA-II–DR15/DQ6 alleles strongly protect against severe sepsis, HLA-II–DR14/DR7/DQ5 alleles significantly increase the risk for toxic shock syndrome. We found that, regardless of individual variations in TCR-Vβ repertoires, the presentation of Strep-SAgs by the protective HLA-II–DR15/DQ6 alleles significantly attenuated proliferative responses to Strep-SAgs, whereas their presentation by the high-risk alleles augmented it. Importantly, HLA-II variations differentially polarized cytokine responses to Strep-SAgs: the presentation of Strep-SAgs by HLA-II–DR15/DQ6 alleles elicited significantly higher ratios of anti-inflammatory cytokines (e.g., IL-10) to proinflammatory cytokines (e.g., IFN-γ) than did their presentation by the high-risk HLA-II alleles. Adding exogenous rIL-10 significantly attenuated responses to Strep-SAgs presented by the high-risk HLA-II alleles but did not completely block the response; instead, it reduced it to a level comparable to that seen when these superantigens were presented by the protective HLA-II alleles. Furthermore, adding neutralizing anti–IL-10 Abs augmented Strep-SAg responses in the presence of protective HLA-II alleles to the same level as (but no higher than) that seen when the superantigens were presented by the high-risk alleles. Our findings provide a molecular basis for the role of HLA-II allelic variations in modulating streptococcal sepsis outcomes and suggest the presence of an internal control mechanism that maintains superantigen responses within a defined range, which helps to eradicate the infection while attenuating pathological inflammatory responses that can inflict more harm than the infection itself.

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Human genetics of infectious diseases: between proof of principle and paradigm

Cited by 159 publications

References 95 publications

Human genetic basis of interindividual variability in the course of infection

Human genetic basis of interindividual variability in the course of infection

Altered IFN-γ–Mediated Immunity and Transcriptional Expression Patterns in N-Ethyl-N-Nitrosourea–Induced STAT4 Mutants Confer Susceptibility to Acute Typhoid-like Disease

Individual Genetic Variations Directly Effect Polarization of Cytokine Responses to Superantigens Associated with Streptococcal Sepsis: Implications for Customized Patient Care

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