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1.
Commun Biol ; 5(1): 439, 2022 05 11.
Article in English | MEDLINE | ID: covidwho-1839575

ABSTRACT

SARS-CoV-2 variants shaped the second year of the COVID-19 pandemic and the discourse around effective control measures. Evaluating the threat posed by a new variant is essential for adapting response efforts when community transmission is detected. In this study, we compare the dynamics of two variants, Alpha and Iota, by integrating genomic surveillance data to estimate the effective reproduction number (Rt) of the variants. We use Connecticut, United States, in which Alpha and Iota co-circulated in 2021. We find that the Rt of these variants were up to 50% larger than that of other variants. We then use phylogeography to show that while both variants were introduced into Connecticut at comparable frequencies, clades that resulted from introductions of Alpha were larger than those resulting from Iota introductions. By monitoring the dynamics of individual variants throughout our study period, we demonstrate the importance of routine surveillance in the response to COVID-19.


Subject(s)
COVID-19 , SARS-CoV-2 , COVID-19/epidemiology , Genomics , Humans , Pandemics , SARS-CoV-2/genetics , United States/epidemiology
2.
Cell Rep Med ; 3(4): 100583, 2022 04 19.
Article in English | MEDLINE | ID: covidwho-1735052

ABSTRACT

The SARS-CoV-2 Delta variant rose to dominance in mid-2021, likely propelled by an estimated 40%-80% increased transmissibility over Alpha. To investigate if this ostensible difference in transmissibility is uniform across populations, we partner with public health programs from all six states in New England in the United States. We compare logistic growth rates during each variant's respective emergence period, finding that Delta emerged 1.37-2.63 times faster than Alpha (range across states). We compute variant-specific effective reproductive numbers, estimating that Delta is 63%-167% more transmissible than Alpha (range across states). Finally, we estimate that Delta infections generate on average 6.2 (95% CI 3.1-10.9) times more viral RNA copies per milliliter than Alpha infections during their respective emergence. Overall, our evidence suggests that Delta's enhanced transmissibility can be attributed to its innate ability to increase infectiousness, but its epidemiological dynamics may vary depending on underlying population attributes and sequencing data availability.


Subject(s)
COVID-19 , SARS-CoV-2 , COVID-19/epidemiology , Humans , New England/epidemiology , Public Health , SARS-CoV-2/genetics
3.
Sci Immunol ; 6(62)2021 08 19.
Article in English | MEDLINE | ID: covidwho-1434876

ABSTRACT

Autosomal inborn errors of type I IFN immunity and autoantibodies against these cytokines underlie at least 10% of critical COVID-19 pneumonia cases. We report very rare, biochemically deleterious X-linked TLR7 variants in 16 unrelated male individuals aged 7 to 71 years (mean: 36.7 years) from a cohort of 1,202 male patients aged 0.5 to 99 years (mean: 52.9 years) with unexplained critical COVID-19 pneumonia. None of the 331 asymptomatically or mildly infected male individuals aged 1.3 to 102 years (mean: 38.7 years) tested carry such TLR7 variants (p = 3.5 × 10-5). The phenotypes of five hemizygous relatives of index cases infected with SARS-CoV-2 include asymptomatic or mild infection (n=2, 5 and 38 years), or moderate (n=1, 5 years), severe (n=1, 27 years), or critical (n=1, 29 years) pneumonia. Two boys (aged 7 and 12 years) from a cohort of 262 male patients with severe COVID-19 pneumonia (mean: 51.0 years) are hemizygous for a deleterious TLR7 variant. The cumulative allele frequency for deleterious TLR7 variants in the male general population is < 6.5x10-4 We also show that blood B cell lines and myeloid cell subsets from the patients do not respond to TLR7 stimulation, a phenotype rescued by wild-type TLR7 The patients' blood plasmacytoid dendritic cells (pDCs) produce low levels of type I IFNs in response to SARS-CoV-2. Overall, X-linked recessive TLR7 deficiency is a highly penetrant genetic etiology of critical COVID-19 pneumonia, in about 1.8% of male patients below the age of 60 years. Human TLR7 and pDCs are essential for protective type I IFN immunity against SARS-CoV-2 in the respiratory tract.


Subject(s)
COVID-19/complications , Genetic Diseases, X-Linked/complications , Immune System Diseases/complications , Toll-Like Receptor 7/deficiency , Adolescent , Adult , Aged , Aged, 80 and over , Alleles , Child , Child, Preschool , Humans , Infant , Male , Middle Aged , Pedigree , Penetrance , Toll-Like Receptor 7/genetics , Young Adult
4.
Sci Immunol ; 6(62)2021 08 19.
Article in English | MEDLINE | ID: covidwho-1367380

ABSTRACT

Autosomal inborn errors of type I IFN immunity and autoantibodies against these cytokines underlie at least 10% of critical COVID-19 pneumonia cases. We report very rare, biochemically deleterious X-linked TLR7 variants in 16 unrelated male individuals aged 7 to 71 years (mean: 36.7 years) from a cohort of 1,202 male patients aged 0.5 to 99 years (mean: 52.9 years) with unexplained critical COVID-19 pneumonia. None of the 331 asymptomatically or mildly infected male individuals aged 1.3 to 102 years (mean: 38.7 years) tested carry such TLR7 variants (p = 3.5 × 10-5). The phenotypes of five hemizygous relatives of index cases infected with SARS-CoV-2 include asymptomatic or mild infection (n=2, 5 and 38 years), or moderate (n=1, 5 years), severe (n=1, 27 years), or critical (n=1, 29 years) pneumonia. Two boys (aged 7 and 12 years) from a cohort of 262 male patients with severe COVID-19 pneumonia (mean: 51.0 years) are hemizygous for a deleterious TLR7 variant. The cumulative allele frequency for deleterious TLR7 variants in the male general population is < 6.5x10-4 We also show that blood B cell lines and myeloid cell subsets from the patients do not respond to TLR7 stimulation, a phenotype rescued by wild-type TLR7 The patients' blood plasmacytoid dendritic cells (pDCs) produce low levels of type I IFNs in response to SARS-CoV-2. Overall, X-linked recessive TLR7 deficiency is a highly penetrant genetic etiology of critical COVID-19 pneumonia, in about 1.8% of male patients below the age of 60 years. Human TLR7 and pDCs are essential for protective type I IFN immunity against SARS-CoV-2 in the respiratory tract.


Subject(s)
COVID-19/complications , Genetic Diseases, X-Linked/complications , Immune System Diseases/complications , Toll-Like Receptor 7/deficiency , Adolescent , Adult , Aged , Aged, 80 and over , Alleles , Child , Child, Preschool , Humans , Infant , Male , Middle Aged , Pedigree , Penetrance , Toll-Like Receptor 7/genetics , Young Adult
5.
J Exp Med ; 218(3)2021 03 01.
Article in English | MEDLINE | ID: covidwho-1024074

ABSTRACT

Although COVID-19 is considered to be primarily a respiratory disease, SARS-CoV-2 affects multiple organ systems including the central nervous system (CNS). Yet, there is no consensus on the consequences of CNS infections. Here, we used three independent approaches to probe the capacity of SARS-CoV-2 to infect the brain. First, using human brain organoids, we observed clear evidence of infection with accompanying metabolic changes in infected and neighboring neurons. However, no evidence for type I interferon responses was detected. We demonstrate that neuronal infection can be prevented by blocking ACE2 with antibodies or by administering cerebrospinal fluid from a COVID-19 patient. Second, using mice overexpressing human ACE2, we demonstrate SARS-CoV-2 neuroinvasion in vivo. Finally, in autopsies from patients who died of COVID-19, we detect SARS-CoV-2 in cortical neurons and note pathological features associated with infection with minimal immune cell infiltrates. These results provide evidence for the neuroinvasive capacity of SARS-CoV-2 and an unexpected consequence of direct infection of neurons by SARS-CoV-2.


Subject(s)
Angiotensin-Converting Enzyme 2 , Antibodies, Blocking/chemistry , COVID-19 , Cerebral Cortex , Neurons , SARS-CoV-2/metabolism , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/metabolism , COVID-19/pathology , Cerebral Cortex/metabolism , Cerebral Cortex/pathology , Cerebral Cortex/virology , Disease Models, Animal , Female , Humans , Male , Mice , Middle Aged , Neurons/metabolism , Neurons/pathology , Neurons/virology , Organoids/metabolism , Organoids/pathology , Organoids/virology
6.
Science ; 370(6515)2020 10 23.
Article in English | MEDLINE | ID: covidwho-889832

ABSTRACT

Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-ω (IFN-ω) (13 patients), against the 13 types of IFN-α (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men.


Subject(s)
Autoantibodies/blood , Coronavirus Infections/immunology , Interferon Type I/immunology , Interferon alpha-2/immunology , Pneumonia, Viral/immunology , Adult , Aged , Aged, 80 and over , Antibodies, Neutralizing/blood , Asymptomatic Infections , Betacoronavirus , COVID-19 , Case-Control Studies , Critical Illness , Female , Humans , Immunoglobulin G/blood , Male , Middle Aged , Pandemics , SARS-CoV-2
7.
Science ; 370(6515)2020 10 23.
Article in English | MEDLINE | ID: covidwho-796722

ABSTRACT

Clinical outcome upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ranges from silent infection to lethal coronavirus disease 2019 (COVID-19). We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern Toll-like receptor 3 (TLR3)- and interferon regulatory factor 7 (IRF7)-dependent type I interferon (IFN) immunity to influenza virus in 659 patients with life-threatening COVID-19 pneumonia relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally defined LOF variants underlying autosomal-recessive or autosomal-dominant deficiencies in 23 patients (3.5%) 17 to 77 years of age. We show that human fibroblasts with mutations affecting this circuit are vulnerable to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection.


Subject(s)
Coronavirus Infections/genetics , Coronavirus Infections/immunology , Interferon Type I/immunology , Loss of Function Mutation , Pneumonia, Viral/genetics , Pneumonia, Viral/immunology , Adolescent , Adult , Aged , Aged, 80 and over , Alleles , Asymptomatic Infections , Betacoronavirus , COVID-19 , Child , Child, Preschool , Female , Genetic Loci , Genetic Predisposition to Disease , Humans , Infant , Interferon Regulatory Factor-7/deficiency , Interferon Regulatory Factor-7/genetics , Male , Middle Aged , Pandemics , Receptor, Interferon alpha-beta/deficiency , Receptor, Interferon alpha-beta/genetics , SARS-CoV-2 , Toll-Like Receptor 3/deficiency , Toll-Like Receptor 3/genetics , Young Adult
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