RESUMEN
The humoral arm of innate immunity includes diverse molecules with antibody-like functions, some of which serve as disease severity biomarkers in coronavirus disease 2019 (COVID-19). The present study was designed to conduct a systematic investigation of the interaction of human humoral fluid-phase pattern recognition molecules (PRMs) with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Of 12 PRMs tested, the long pentraxin 3 (PTX3) and mannose-binding lectin (MBL) bound the viral nucleocapsid and spike proteins, respectively. MBL bound trimeric spike protein, including that of variants of concern (VoC), in a glycan-dependent manner and inhibited SARS-CoV-2 in three in vitro models. Moreover, after binding to spike protein, MBL activated the lectin pathway of complement activation. Based on retention of glycosylation sites and modeling, MBL was predicted to recognize the Omicron VoC. Genetic polymorphisms at the MBL2 locus were associated with disease severity. These results suggest that selected humoral fluid-phase PRMs can play an important role in resistance to, and pathogenesis of, COVID-19, a finding with translational implications.
Asunto(s)
COVID-19/inmunología , Inmunidad Humoral , Receptores de Reconocimiento de Patrones/inmunología , SARS-CoV-2/inmunología , Animales , Proteína C-Reactiva/inmunología , Proteína C-Reactiva/metabolismo , COVID-19/metabolismo , COVID-19/virología , Estudios de Casos y Controles , Chlorocebus aethiops , Activación de Complemento , Proteínas de la Nucleocápside de Coronavirus/genética , Proteínas de la Nucleocápside de Coronavirus/inmunología , Proteínas de la Nucleocápside de Coronavirus/metabolismo , Femenino , Glicosilación , Células HEK293 , Interacciones Huésped-Patógeno , Humanos , Masculino , Lectina de Unión a Manosa/genética , Lectina de Unión a Manosa/inmunología , Lectina de Unión a Manosa/metabolismo , Fosfoproteínas/genética , Fosfoproteínas/inmunología , Fosfoproteínas/metabolismo , Polimorfismo Genético , Unión Proteica , Receptores de Reconocimiento de Patrones/genética , Receptores de Reconocimiento de Patrones/metabolismo , SARS-CoV-2/genética , SARS-CoV-2/metabolismo , SARS-CoV-2/patogenicidad , Componente Amiloide P Sérico/inmunología , Componente Amiloide P Sérico/metabolismo , Transducción de Señal , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/inmunología , Glicoproteína de la Espiga del Coronavirus/metabolismo , Células VeroRESUMEN
A male sex bias has emerged in the COVID-19 pandemic, fitting to the sex-biased pattern in other viral infections. Males are 2.84 times more often admitted to the ICU and mortality is 1.39 times higher as a result of COVID-19. Various factors play a role in this, and novel studies suggest that the gene-dose of Toll-Like Receptor (TLR) 7 could contribute to the sex-skewed severity. TLR7 is one of the crucial pattern recognition receptors for SARS-CoV-2 ssRNA and the gene-dose effect is caused by X chromosome inactivation (XCI) escape. Female immune cells with TLR7 XCI escape have biallelic TLR7 expression and produce more type 1 interferon (IFN) upon TLR7 stimulation. In COVID-19, TLR7 in plasmacytoid dendritic cells is one of the pattern recognition receptors responsible for IFN production and a delayed IFN response has been associated with immunopathogenesis and mortality. Here, we provide a hypothesis that females may be protected to some extend against severe COVID-19, due to the biallelic TLR7 expression, allowing them to mount a stronger and more protective IFN response early after infection. Studies exploring COVID-19 treatment via the TLR7-mediated IFN pathway should consider this sex difference. Various factors such as age, sex hormones and escape modulation remain to be investigated concerning the TLR7 gene-dose effect.
Asunto(s)
COVID-19/mortalidad , Dosificación de Gen/genética , Interferón Tipo I/biosíntesis , Receptor Toll-Like 7/genética , Receptor Toll-Like 7/metabolismo , COVID-19/patología , Cromosomas Humanos X/genética , Cuidados Críticos/estadística & datos numéricos , Células Dendríticas/inmunología , Femenino , Humanos , Interferón Tipo I/inmunología , Masculino , ARN Viral/genética , Receptores de Reconocimiento de Patrones/genética , Receptores de Reconocimiento de Patrones/metabolismo , Factores de Riesgo , SARS-CoV-2/inmunología , Factores Sexuales , Transducción de Señal/inmunología , Inactivación del Cromosoma X/genética , Tratamiento Farmacológico de COVID-19RESUMEN
BACKGROUND: Older aged adults and those with pre-existing conditions are at highest risk for severe COVID-19 associated outcomes. METHODS: Using a large dataset of genome-wide RNA-seq profiles derived from human dermal fibroblasts (GSE113957) we investigated whether age affects the expression of pattern recognition receptor (PRR) genes and ACE2, the receptor for SARS-CoV-2. RESULTS: Extremes of age are associated with increased expression of selected PRR genes, ACE2 and four genes that encode proteins that have been shown to interact with SAR2-CoV-2 proteins. CONCLUSIONS: Assessment of PRR expression might provide a strategy for stratifying the risk of severe COVID-19 disease at both the individual and population levels.