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

Annual Review of Pathology Mechanisms of Disease, Journal Year: 2020, Volume and Issue: 16(1), P. 23 - 50

Published: April 14, 2020

It was first demonstrated in the late nineteenth century that human deaths from fever were typically due to infections. As germ theory gained ground, it replaced old, unproven reflected a weak personal or even familial constitution. A new enigma emerged at turn of twentieth century, when became apparent only small proportion infected individuals die primary infections with almost any given microbe. Classical genetics studies gradually revealed severe infectious diseases could be driven by genetic predisposition. This idea ground support molecular genetics, three successive, overlapping steps. First, many rare inborn errors immunity shown, 1985 onward, underlie multiple, recurrent Mendelian inheritance. Second, handful and infections, also segregating as traits but striking humans resistant other deciphered molecularly beginning 1996. Third, 2007 growing number common sporadicinfections shown result monogenic, not Mendelian, errors. synthesis hitherto mutually exclusive theories is now view.

Language: Английский

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An ancient viral epidemic involving host coronavirus interacting genes more than 20,000 years ago in East Asia

Current Biology, Journal Year: 2021, Volume and Issue: 31(16), P. 3504 - 3514.e9

Published: June 24, 2021

The current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has emphasized the vulnerability of human populations to novel viral pressures, despite vast array epidemiological and biomedical tools now available. Notably, modern genomes contain evolutionary information tracing back tens thousands years, which may help identify viruses that have impacted our ancestors-pointing future potential. Here, we apply analyses genomic datasets recover selection events involving genes interact with coronaviruses, including SARS-CoV-2, likely started more than 20,000 years ago. These adaptive were limited population ancestral East Asian populations. Multiple lines functional evidence support an ancient selective pressure, Asia is geographical origin several epidemics. An arms race coronavirus, or a different virus happened use similar interactions as coronaviruses hosts, thus taken place in By learning about foes, study highlights promise better predict pandemics future. Importantly, adaptation epidemics specific does not necessarily imply any difference genetic susceptibility between populations, points toward overwhelming impact socioeconomic factors case disease 2019 (COVID-19).

Language: Английский

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Human ancient DNA analyses reveal the high burden of tuberculosis in Europeans over the last 2,000 years

The American Journal of Human Genetics, Journal Year: 2021, Volume and Issue: 108(3), P. 517 - 524

Published: March 1, 2021

Tuberculosis (TB), usually caused by Mycobacterium tuberculosis bacteria, is the first cause of death from an infectious disease at worldwide scale, yet mode and tempo TB pressure on humans remain unknown. The recent discovery that homozygotes for P1104A polymorphism TYK2 are higher risk to develop clinical forms provided evidence a common, monogenic predisposition TB, offering unique opportunity inform human co-evolution with deadly pathogen. Here, we investigate history exposure determining evolutionary trajectory variant in Europe, where considered be deadliest documented disease. Leveraging large dataset 1,013 ancient genomes using approximate Bayesian computation approach, find originated common ancestors West Eurasians ∼30,000 years ago. Furthermore, show that, following large-scale population movements Anatolian Neolithic farmers Eurasian steppe herders into has markedly fluctuated frequency over last 10,000 European history, dramatic decrease after Bronze Age. Our analyses indicate such drop attributable strong negative selection starting ∼2,000 ago, relative fitness reduction 20%, among highest genome. Together, our results provide genetic imposed heavy burden health two millennia.

Language: Английский

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Clinical implications of host genetic variation and susceptibility to severe or critical COVID-19

Genome Medicine, Journal Year: 2022, Volume and Issue: 14(1)

Published: Aug. 19, 2022

Since the start of coronavirus disease 2019 (COVID-19) pandemic, important insights have been gained into virus biology and host factors that modulate human immune response against severe acute respiratory syndrome 2 (SARS-CoV-2). COVID-19 displays a highly variable clinical picture ranges from asymptomatic to lethal pneumonia. Apart well-established general risk such as advanced age, male sex chronic comorbidities, differences in genetics shown influence individual predisposition develop manifestations COVID-19. These range common susceptibility loci rare genetic variants with strongly predisposing effects, or proven pathogenic lead known novel inborn errors immunity (IEI), which constitute growing group heterogeneous Mendelian disorders increased infectious disease, auto-inflammation, auto-immunity, allergy malignancies. The current findings point towards convergence impact interferon signalling pathways patients critical Monogenic IFN-I an expected prevalence between 1 5% young, previously healthy individuals (<60 years age) identification these IEI X-linked TLR7 deficiency indicates possibility for targeted screening personalized management. This review aims provide overview our understanding predispose focuses on genes their potential implications.

Language: Английский

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Diversity in immunogenomics: the value and the challenge

Nature Methods, Journal Year: 2021, Volume and Issue: 18(6), P. 588 - 591

Published: May 17, 2021

Language: Английский

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A global effort to dissect the human genetic basis of resistance to SARS-CoV-2 infection

Nature Immunology, Journal Year: 2021, Volume and Issue: 23(2), P. 159 - 164

Published: Oct. 18, 2021

SARS-CoV-2 infections display tremendous interindividual variability, ranging from asymptomatic to life-threatening disease. Inborn errors of, and autoantibodies directed against, type I interferons (IFNs) account for about 20% of critical COVID-19 cases among SARS-CoV-2-infected individuals. By contrast, the genetic immunological determinants resistance infection per se remain unknown. Following discovery that autosomal recessive deficiency in DARC chemokine receptor confers Plasmodium vivax, deficiencies 5 (CCR5) enzyme FUT2 were shown underlie HIV-1 noroviruses, respectively. Along same lines, we propose a strategy identifying, recruiting, genetically analyzing individuals who are naturally resistant infection.

Language: Английский

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A loss-of-function IFNAR1 allele in Polynesia underlies severe viral diseases in homozygotes

The Journal of Experimental Medicine, Journal Year: 2022, Volume and Issue: 219(6)

Published: April 20, 2022

Globally, autosomal recessive IFNAR1 deficiency is a rare inborn error of immunity underlying susceptibility to live attenuated vaccine and wild-type viruses. We report seven children from five unrelated kindreds western Polynesian ancestry who suffered severe viral diseases. All the patients are homozygous for same nonsense variant (p.Glu386*). This allele encodes truncated protein that absent cell surface loss-of-function. The fibroblasts do not respond type I IFNs (IFN-α2, IFN-ω, or IFN-β). Remarkably, this has minor frequency &gt;1% in Samoa also observed Cook, Society, Marquesas, Austral islands, as well Fiji, whereas it extremely other populations tested, including those Pacific region. Inherited should be considered individuals with illnesses.

Language: Английский

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The evolutionary and functional significance of germline immunoglobulin gene variation

Trends in Immunology, Journal Year: 2022, Volume and Issue: 44(1), P. 7 - 21

Published: Dec. 2, 2022

The recombination between immunoglobulin (IG) gene segments determines an individual's naïve antibody repertoire and, consequently, (auto)antigen recognition. Emerging evidence suggests that mammalian IG germline variation impacts humoral immune responses associated with vaccination, infection, and autoimmunity – from the molecular level of epitope specificity, up to profound changes in architecture repertoires. These links variants immunophenotype raise question on evolutionary causes consequences diversity within loci. We discuss why extreme loci remains a mystery, resolving this is important for design more effective vaccines therapeutics, how recent multiple lines inquiry may help us do so.

Language: Английский

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Dissecting human population variation in single-cell responses to SARS-CoV-2

Nature, Journal Year: 2023, Volume and Issue: 621(7977), P. 120 - 128

Published: Aug. 9, 2023

Humans display substantial interindividual clinical variability after SARS-CoV-2 infection1-3, the genetic and immunological basis of which has begun to be deciphered4. However, extent drivers population differences in immune responses remain unclear. Here we report single-cell RNA-sequencing data for peripheral blood mononuclear cells-from 222 healthy donors diverse ancestries-that were stimulated with or influenza A virus. We show that induces weaker, but more heterogeneous, interferon-stimulated gene activity compared virus, a unique pro-inflammatory signature myeloid cells. Transcriptional viruses marked differences, primarily driven by changes cell abundance including increased lymphoid differentiation associated latent cytomegalovirus infection. Expression quantitative trait loci mediation analyses reveal broad effect composition on disparities responses, variants exerting strong specific loci. Furthermore, natural selection particularly response East Asians, document cellular molecular mechanisms Neanderthal introgression altered functions, such as cells viruses. Finally, colocalization transcriptome-wide association an overlap between COVID-19 severity, providing insights into factors contributing current risk.

Language: Английский

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Mapping interindividual dynamics of innate immune response at single-cell resolution

Nature Genetics, Journal Year: 2023, Volume and Issue: 55(6), P. 1066 - 1075

Published: June 1, 2023

Common genetic variants across individuals modulate the cellular response to pathogens and are implicated in diverse immune pathologies, yet how they dynamically alter upon infection is not well understood. Here, we triggered antiviral responses human fibroblasts from 68 healthy donors, profiled tens of thousands cells using single-cell RNA-sequencing. We developed GASPACHO (GAuSsian Processes for Association mapping leveraging Cell HeterOgeneity), a statistical approach designed identify nonlinear dynamic effects transcriptional trajectories cells. This identified 1,275 expression quantitative trait loci (local false discovery rate 10%) that manifested during responses, many which were colocalized with susceptibility by genome-wide association studies infectious autoimmune diseases, including OAS1 splicing locus COVID-19 locus. In summary, our analytical provides unique framework delineation shape wide spectrum at resolution.

Language: Английский

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