From rare disorders of immunity to common determinants of infection: Following the mechanistic thread

Cell, Год журнала: 2022, Номер 185(17), С. 3086 - 3103

Опубликована: Авг. 1, 2022

The immense interindividual clinical variability during any infection is a long-standing enigma. Inborn errors of IFN-γ and IFN-α/β immunity underlying rare infections with weakly virulent mycobacteria seasonal influenza virus have inspired studies two common infections: tuberculosis COVID-19. A TYK2 genotype impairing production accounts for about 1% cases, autoantibodies neutralizing account 15% critical COVID-19 cases. discovery inborn mechanisms drove the identification monogenic or autoimmune determinants related infections. This “rare-to-common” genetic mechanistic approach to infectious diseases may be heuristic value.

Язык: Английский

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Recessive inborn errors of type I IFN immunity in children with COVID-19 pneumonia

The Journal of Experimental Medicine, Год журнала: 2022, Номер 219(8)

Опубликована: Июнь 16, 2022

Recessive or dominant inborn errors of type I interferon (IFN) immunity can underlie critical COVID-19 pneumonia in unvaccinated adults. The risk children, which is much lower than adults, remains unexplained. In an international cohort 112 children (<16 yr old) hospitalized for pneumonia, we report 12 (10.7%) aged 1.5–13 with (7 children), severe (3), and moderate (2) 4 the 15 known clinically recessive biochemically complete IFN immunity: X-linked TLR7 deficiency children) autosomal IFNAR1 (1), STAT2 TYK2 (3) deficiencies. Fibroblasts deficient IFNAR1, STAT2, are highly vulnerable to SARS-CoV-2. These deficiencies were not found 1,224 adults benign SARS-CoV-2 infection without (P = 1.2 × 10−11) overlapping age, sex, consanguinity, ethnicity characteristics. may ∼10% hospitalizations children.

Язык: Английский

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Autoantibodies against type I IFNs in patients with critical influenza pneumonia

The Journal of Experimental Medicine, Год журнала: 2022, Номер 219(11)

Опубликована: Сен. 16, 2022

Autoantibodies neutralizing type I interferons (IFNs) can underlie critical COVID-19 pneumonia and yellow fever vaccine disease. We report here on 13 patients harboring autoantibodies IFN-α2 alone (five patients) or with IFN-ω (eight from a cohort of 279 (4.7%) aged 6–73 yr influenza pneumonia. Nine four had antibodies high low concentrations, respectively, IFN-α2, six two IFN-ω. The patients’ increased A virus replication in both A549 cells reconstituted human airway epithelia. prevalence these was significantly higher than that the general population for <70 age (5.7 vs. 1.1%, P = 2.2 × 10−5), but not >70 (3.1 4.4%, 0.68). risk highest concentrations (OR 11.7, 1.3 especially those old 139.9, 3.1 10−10). also identified 10 additional patient cohorts. IFNs account ∼5% cases life-threatening old.

Язык: Английский

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Unlocking life-threatening COVID-19 through two types of inborn errors of type I IFNs

Journal of Clinical Investigation, Год журнала: 2023, Номер 133(3)

Опубликована: Янв. 31, 2023

Since 2003, rare inborn errors of human type I IFN immunity have been discovered, each underlying a few severe viral illnesses. Autoantibodies neutralizing IFNs due to autoimmune regulator (AIRE)-driven T cell tolerance were discovered in 2006, but not initially linked any disease. These two lines clinical investigation converged 2020, with the discovery that inherited and/or deficiencies accounted for approximately 15%-20% cases critical COVID-19 pneumonia unvaccinated individuals. Thus, insufficient at onset SARS-CoV-2 infection may be general determinant life-threatening COVID-19. findings illustrate unpredictable, considerable, contribution study genetic diseases basic biology and public health.

Язык: Английский

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Human life within a narrow range: The lethal ups and downs of type I interferons

Science Immunology, Год журнала: 2024, Номер 9(97)

Опубликована: Июль 5, 2024

The past 20 years have seen the definition of human monogenic disorders and their autoimmune phenocopies underlying either defective or enhanced type I interferon (IFN) activity. These delineate impact IFNs in natural conditions demonstrate that only a narrow window IFN activity is beneficial. Insufficient predisposes humans to life-threatening viral diseases (albeit unexpectedly few) with central role immunity respiratory cerebral infection. Excessive IFN, perhaps counterintuitively, appears underlie greater number autoinflammatory and/or known as interferonopathies, whose study has revealed multiple molecular programs involved induction signaling. observations suggest manipulation within physiological range may be clinically relevant for prevention treatment inflammatory diseases.

Язык: Английский

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Human immunity

Опубликована: Фев. 26, 2025

Due to the burden of infectious diseases, human life expectancy at birth remained about 20–25 years until end 19th century, implying that host defense—which operates individual level, and only poorly that—is barely sufficient population level. Microbes preceded us by three billion evolve much more rapidly. Moreover, protective immunity has been selected evolutionary cost allergy, autoinflammation, autoimmunity. It is therefore no exaggeration predict almost all humans carry inborn errors immunity, with insufficient or excessive responses some environmental triggers, otherwise. Thanks remarkable power its concepts recent progress in methods, genetics finally made it possible investigate mechanisms molecular cellular levels. Human provide countless opportunities analyze derailments natural conditions, an unprecedented scale, are thus a unique asset from both biological medical perspectives. Hence, Journal Immunity.

Язык: Английский

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Respiratory viral infections in otherwise healthy humans with inherited IRF7 deficiency

The Journal of Experimental Medicine, Год журнала: 2022, Номер 219(7)

Опубликована: Июнь 7, 2022

Autosomal recessive IRF7 deficiency was previously reported in three patients with single critical influenza or COVID-19 pneumonia episodes. The patients' fibroblasts and plasmacytoid dendritic cells produced no detectable type I III IFNs, except IFN-β. Having discovered four new patients, we describe the genetic, immunological, clinical features of seven IRF7-deficient from six families five ancestries. Five were homozygous two compound heterozygous for variants. Patients typically had one episode pulmonary viral disease. Age at onset surprisingly broad, 6 mo to 50 yr (mean age 29 yr). respiratory viruses implicated included SARS-CoV-2, virus, syncytial adenovirus. Serological analyses indicated previous infections many common viruses. Cellular revealed strong antiviral immunity expanded populations influenza- SARS-CoV-2-specific memory CD4+ CD8+ T cells. individuals are prone tract but otherwise healthy, potentially due residual IFN-β compensatory adaptive immunity.

Язык: Английский

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Interfering with Interferons: A Critical Mechanism for Critical COVID-19 Pneumonia

Annual Review of Immunology, Год журнала: 2023, Номер 41(1), С. 561 - 585

Опубликована: Апрель 26, 2023

Infection with SARS-CoV-2 results in clinical outcomes ranging from silent or benign infection most individuals to critical pneumonia and death a few. Genetic studies patients have established that cases can result inborn errors of TLR3- TLR7-dependent type I interferon immunity, preexisting autoantibodies neutralizing primarily IFN-α and/or IFN-ω. These findings are consistent virological showing multiple proteins interfere pathways induction of, response to, interferons. They also congruent cellular mouse models found interferons limit replication vitro vivo, while their absence diminution unleashes viral growth. Collectively, these point insufficient during the first days as general mechanism underlying COVID-19 pneumonia, implications for treatment directions future research.

Язык: Английский

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Bacterial-induced or passively administered interferon gamma conditions the lung for early control of SARS-CoV-2

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Дек. 12, 2023

Type-1 and type-3 interferons (IFNs) are important for control of viral replication; however, less is known about the role Type-2 IFN (IFNγ) in anti-viral immunity. We previously observed that lung infection with Mycobacterium bovis BCG achieved though intravenous (iv) administration provides strong protection against SARS-CoV-2 mice yet drives low levels type-1 IFNs but robust IFNγ. Here we examine ongoing IFNγ responses to pre-established bacterial on disease outcomes two murine models. report required iv induced reduction pulmonary loads, an outcome dependent receptor expression by non-hematopoietic cells. Importantly, show prompts epithelial cells upregulate IFN-stimulated genes reported activity IFNγ-dependent manner, suggesting a possible mechanism protection. Finally, confirm properties demonstrating recombinant cytokine itself challenge when administered intranasally. Together, our data response within protective infection, concurrent or recent infections drive may limit pathogenesis supporting prophylactic uses COVID-19 management.

Язык: Английский

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Human inherited complete STAT2 deficiency underlies inflammatory viral diseases

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

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