Inborn Errors of Nucleic Acid Sensing and Type I Interferon Signaling Determine Viral Susceptibility in Humans DOI
Leslie Naesens, Steven Callens, Tessa Kerre

и другие.

European Journal of Immunology, Год журнала: 2025, Номер 55(5)

Опубликована: Май 1, 2025

The innate immune system relies on nucleic acid (NA) sensors to detect viral infections and trigger type I interferon (IFN-I) responses, which are crucial for antiviral defense. NA pattern recognition receptors RNA or DNA within various cellular compartments, initiating signaling pathways. However, inherited deficiencies in these sensing mechanisms can result increased susceptibility severe infections. This review explores key genetic mutations affecting IFN-I pathways that predispose individuals life-threatening diseases, including herpesviruses, respiratory viruses, enteroviruses, arboviruses, vaccine-strain disseminated diseases. identification of monogenic defects afflicted by infections, along with the observed incomplete penetrance mutations, highlight intricate interplay host's intrinsic, innate, adaptive response invading pathogens. These insights into molecular basis immunity not only underscore clinical challenges associated but also offers opportunity personalized treatment strategies, screening, tailored vaccination protocols, targeted therapies.

Язык: Английский

Human inherited complete STAT2 deficiency underlies inflammatory viral diseases DOI Creative Commons
Giorgia Bucciol, Leen Moens, Masato Ogishi

и другие.

Journal of Clinical Investigation, Год журнала: 2023, Номер 133(12)

Опубликована: Март 28, 2023

STAT2 is a transcription factor activated by type I and III interferons. We report 23 patients with loss of function variants causing autosomal recessive (AR), complete deficiency. Both cells transfected mutant alleles the patients' display impaired expression interferon stimulated genes control in-vitro viral infections. Clinical manifestations from early childhood onward include severe adverse reaction to live attenuated vaccines (LAV, 12/17 patients) infections (10/23 patients), particularly critical influenza pneumonia (6 COVID-19 (1 patient), herpes simplex encephalitis patient). The various types hyperinflammation, often triggered infection or after LAV administration, which probably attests unresolved in absence STAT2-dependent IFN immunity (7 patients). Transcriptomic analysis reveals that circulating monocytes, neutrophils, CD8 memory T contribute this inflammation. Eight died (35%, 2 months-7 years): one HSV-1 encephalitis, fulminant hepatitis, six heart failure during febrile illness no identified etiology. 15 remain alive (5-40 years). AR deficiency underlies diseases, half surviving into teenage years adulthood.

Язык: Английский

Процитировано

25
Tuberculosis in otherwise healthy adults with inherited TNF deficiency DOI Creative Commons
Andrés A. Arias, Anna‐Lena Neehus, Masato Ogishi

и другие.

Nature, Год журнала: 2024, Номер 633(8029), С. 417 - 425

Опубликована: Авг. 28, 2024

Severe defects in human IFNγ immunity predispose individuals to both Bacillus Calmette-Guérin disease and tuberculosis, whereas milder only tuberculosis

Язык: Английский

Процитировано

11
Zika virus NS5 protein inhibits type I interferon signaling via CRL3 E3 ubiquitin ligase-mediated degradation of STAT2 DOI Creative Commons
Wenlin Ren, Chong-Lei Fu, Yu Zhang

и другие.

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(34)

Опубликована: Авг. 15, 2024

The ZIKA virus (ZIKV) evades the host immune response by degrading STAT2 through its NS5 protein, thereby inhibiting type I interferon (IFN)-mediated antiviral immunity. However, molecular mechanism underlying this process has remained elusive. In study, we performed a genome-wide CRISPR/Cas9 screen, revealing that ZSWIM8 as substrate receptor of Cullin3-RING E3 ligase is required for NS5-mediated degradation. Genetic depletion and CUL3 substantially impeded Biochemical analysis illuminated enhances interaction between ZSWIM8–CUL3 complex, facilitating ubiquitination. Moreover, knockout endowed A549 Huh7 cells with partial resistance to ZIKV infection protected from cytopathic effects induced ZIKV, which was attributed restoration levels activation IFN signaling. Subsequent studies in physiologically relevant model, utilizing human neural progenitor cells, demonstrated reduced infection, resulting enhanced signaling sustained STAT2. Our findings shed light on role NS5, serving scaffold reprograms complex orchestrate proteasome-dependent degradation, evasion study provides unique insights into ZIKV–host interactions holds promise development antivirals prophylactic vaccines.

Язык: Английский

Процитировано

10
Human type I IFN deficiency does not impair B cell response to SARS-CoV-2 mRNA vaccination DOI Creative Commons
Aurélien Sokal, Paul Bastard, Pascal Chappert

и другие.

The Journal of Experimental Medicine, Год журнала: 2022, Номер 220(1)

Опубликована: Ноя. 7, 2022

Inborn and acquired deficits of type I interferon (IFN) immunity predispose to life-threatening COVID-19 pneumonia. We longitudinally profiled the B cell response mRNA vaccination in SARS-CoV-2 naive patients with inherited TLR7, IRF7, or IFNAR1 deficiency, as well young autoantibodies neutralizing IFNs due autoimmune polyendocrine syndrome type-1 (APS-1) older individuals age-associated IFNs. The receptor-binding domain spike protein (RBD)–specific memory all was quantitatively qualitatively similar healthy donors. Sustained germinal center responses led accumulation somatic hypermutations immunoglobulin heavy chain genes. amplitude duration of, viral neutralization by, RBD-specific IgG serological were also largely unaffected by deficiencies up 7 mo after patients. These results suggest that induction IFN is not required for efficient generation a humoral against vaccines.

Язык: Английский

Процитировано

33
Into the Wild: A novel wild-derived inbred strain resource expands the genomic and phenotypic diversity of laboratory mouse models DOI Creative Commons
Beth L. Dumont, Daniel M. Gatti, Mallory A. Ballinger

и другие.

PLoS Genetics, Год журнала: 2024, Номер 20(4), С. e1011228 - e1011228

Опубликована: Апрель 10, 2024

The laboratory mouse has served as the premier animal model system for both basic and preclinical investigations over a century. However, mice capture only subset of genetic variation found in wild populations, ultimately limiting potential classical inbred strains to uncover phenotype-associated variants pathways. Wild populations are reservoirs diversity that could facilitate discovery new functional disease-associated alleles, but scarcity commercially available, well-characterized limits their broader adoption biomedical research. To overcome this barrier, we have recently developed, sequenced, phenotyped set 11 derived from wild-caught Mus musculus domesticus. Each these "Nachman strains" immortalizes unique haplotype sampled one five environmentally distinct locations across North South America. Whole genome sequence analysis reveals each strain carries between 4.73-6.54 million single nucleotide differences relative GRCm39 reference, with 42.5% Nachman genomes absent current panels. We on customized pipeline assess scope disease-relevant neurobehavioral, biochemical, physiological, metabolic, morphological trait variation. exhibit significant inter-strain >90% 1119 surveyed traits expand range phenotypic captured These novel wild-derived resources empower discoveries

Язык: Английский

Процитировано

8
Human determinants of age-dependent patterns of death from infection DOI Creative Commons
Laurent Abel, Jean‐Laurent Casanova

Immunity, Год журнала: 2024, Номер 57(7), С. 1457 - 1465

Опубликована: Июль 1, 2024

Regardless of microbial virulence (i.e., the global infection-fatality ratio), age generally drives prevalence death from infection in unvaccinated humans. Four mortality patterns are recognized: common U- and L-shaped curves endemic infections unique W- J-shaped pandemic infections. We suggest that these result different sets human genetic immunological determinants. In this model, it is interplay between (1) monogenic genotypes affecting immunity to primary preferentially manifest early life related or their phenocopies, including auto-antibodies, which later (2) occurrence persistence adaptive, acquired cross-reactive infections, shapes age-dependent pattern deaths infection.

Язык: Английский

Процитировано

7
Human TMEFF1 is a restriction factor for herpes simplex virus in the brain DOI Creative Commons
Yi‐Hao Chan, Zhiyong Liu, Paul Bastard

и другие.

Nature, Год журнала: 2024, Номер 632(8024), С. 390 - 400

Опубликована: Июль 24, 2024

Most cases of herpes simplex virus 1 (HSV-1) encephalitis (HSE) remain unexplained

Язык: Английский

Процитировано

7
Genetic defects of brain immunity in childhood herpes simplex encephalitis DOI
Shen‐Ying Zhang, Jean‐Laurent Casanova

Nature, Год журнала: 2024, Номер 635(8039), С. 563 - 573

Опубликована: Ноя. 20, 2024

Язык: Английский

Процитировано

6
Reconciling Mouse and Human Immunology at the Altar of Genetics DOI Creative Commons
Philippe Gros, Jean‐Laurent Casanova

Annual Review of Immunology, Год журнала: 2022, Номер 41(1), С. 39 - 71

Опубликована: Дек. 16, 2022

Immunity to infection has been extensively studied in humans and mice bearing naturally occurring or experimentally introduced germline mutations. Mouse studies are sometimes neglected by human immunologists, on the basis that not infections experimental natural. Conversely, mouse of uncontrolled conditions study small numbers patients. However, both sides would agree infectious phenotypes patients with inborn errors immunity often differ from those corresponding mutant mice. Why is that? We argue this important question best addressed revisiting reinterpreting findings a genetic perspective. Greater caution required for reverse-genetics than forward-genetics studies, but analysis sufficiently strong define likely stand test time. Genetically robust can provide invaluable complementary insights into mechanisms common specific these two species.

Язык: Английский

Процитировано

22
Inborn Errors of Immunity Predisposing to Herpes Simplex Virus Infections of the Central Nervous System DOI Creative Commons
Morten Kelder Skouboe, Marvin Werner, Trine H. Mogensen

и другие.

Pathogens, Год журнала: 2023, Номер 12(2), С. 310 - 310

Опубликована: Фев. 13, 2023

Herpesvirus infections can lead to a number of severe clinical manifestations, particularly when involving the central nervous system (CNS), causing encephalitis and meningitis. However, understanding host factors conferring increased susceptibility these diseases their complications remains incomplete. Previous studies have uncovered defects in innate Toll-like receptor 3 pathway production type I interferon (IFN-I) children adults that predispose them herpes simplex encephalitis. More recently, there is accumulating evidence for an important role IFN-independent cell-autonomous intrinsic mechanisms, including small nucleolar RNAs, RNA lariat metabolism, autophagy, restricting herpesvirus replication protection against CNS infection. The present review first describes manifestations HSV infection with focus on neurological then summarizes host–pathogen interactions immune pathways responsible sensing herpesviruses triggering antiviral responses immunity. Next, we current landscape inborn errors immunity underlying genetic disturbances cellular confer CNS. Ultimately, discuss some outstanding unanswered questions relating together perspectives future directions research pathogenesis humans.

Язык: Английский

Процитировано

12