SARS-CoV-2 Accessory Protein ORF8 Targets the Dimeric IgA Receptor pIgR.

SARS-CoV-2 is a highly pathogenic respiratory virus that successfully initiates and establishes its infection at the respiratory mucosa. However, little is known about how SARS-CoV-2 antagonizes the host's mucosal immunity. Recent findings have shown a marked reduction in the expression of the polymeric Ig receptor (pIgR) in COVID-19 patients. This receptor maintains mucosal homeostasis by transporting the dimeric IgA (dIgA) and pentameric IgM (pIgM) across mucosal epithelial cells to neutralize the invading respiratory pathogens. By studying the interaction between pIgR and SARS-CoV-2 proteins, we discovered that the viral accessory protein Open Reading Frame 8 (ORF8) potently downregulates pIgR expression and that this downregulation activity of ORF8 correlates with its ability to interact with pIgR. Importantly, the ORF8-mediated downregulation of pIgR diminishes the binding of dIgA or pIgM, and the ORF8 proteins of the variants of concern of SARS-CoV-2 preserve the function of downregulating pIgR, indicating the importance of this conserved activity of ORF8 in SARS-CoV-2 pathogenesis. We further observed that the secreted ORF8 binds to cell surface pIgR, but that this interaction does not trigger the cellular internalization of ORF8, which requires the binding of dIgA to pIgR. These findings suggest the role of ORF8 in SARS-CoV-2 mucosal immune evasion.

SARS-CoV-2 ORF8: A Rapidly Evolving Immune and Viral Modulator in COVID-19.

The COVID-19 pandemic has resulted in upwards of 6.8 million deaths over the past three years, and the frequent emergence of variants continues to strain global health. Although vaccines have greatly helped mitigate disease severity, SARS-CoV-2 is likely to remain endemic, making it critical to understand its viral mechanisms contributing to pathogenesis and discover new antiviral therapeutics. To efficiently infect, this virus uses a diverse set of strategies to evade host immunity, accounting for its high pathogenicity and rapid spread throughout the COVID-19 pandemic. Behind some of these critical host evasion strategies is the accessory protein Open Reading Frame 8 (ORF8), which has gained recognition in SARS-CoV-2 pathogenesis due to its hypervariability, secretory property, and unique structure. This review discusses the current knowledge on SARS-CoV-2 ORF8 and proposes actualized functional models describing its pivotal roles in both viral replication and immune evasion. A better understanding of ORF8's interactions with host and viral factors is expected to reveal essential pathogenic strategies utilized by SARS-CoV-2 and inspire the development of novel therapeutics to improve COVID-19 disease outcomes.

SARS-CoV-2 Accessory Protein ORF8 Decreases Antibody-Dependent Cellular Cytotoxicity.

Viruses use many different strategies to evade host immune responses. In the case of SARS-CoV-2, its Spike mutates rapidly to escape from neutralizing antibodies. In addition to this strategy, ORF8, a small accessory protein encoded by SARS-CoV-2, helps immune evasion by reducing the susceptibility of SARS-CoV-2-infected cells to the cytotoxic CD8+ T cell response. Interestingly, among all accessory proteins, ORF8 is rapidly evolving and a deletion in this protein has been linked to milder disease. Here, we studied the effect of ORF8 on peripheral blood mononuclear cells (PBMC). Specifically, we found that ORF8 can bind monocytes as well as NK cells. Strikingly, ORF8 binds CD16a (FcγRIIIA) with nanomolar affinity and decreases the overall level of CD16 at the surface of monocytes and, to a lesser extent, NK cells. This decrease significantly reduces the capacity of PBMCs and particularly monocytes to mediate antibody-dependent cellular cytotoxicity (ADCC). Overall, our data identifies a new immune-evasion activity used by SARS-CoV-2 to escape humoral responses.

Homens idosos residentes na zona rural: aspectos relacionados à qualidade de vida / Elderly men living in rural areas: quality of life-related aspects / Hombres mayores que viven en la zona rural: aspectos relacionados con la calidad de vida

Objetivo: verificar os fatores socioeconômicos e de saúde associados à qualidade de vida (QV) de homens idosos rurais. Método: estudo descritivo, quantitativo com inquérito domiciliar e analítico realizado com 449 homens idosos da zona rural. Os dados foram coletados no período de junho de 2010 a março de 2011, em Uberaba-MG. Utilizaram-se os questionários: estruturado, Índex de Katz, Escala de Lawton e Brody, World Health Organization Quality of Life ­ BREF e World Health Organization Quality of Life Assessment for Older Adults. Realizou-se análise descritiva e regressão linear múltipla (p<0,05). Resultados: os menores escores nos domínios e facetas de QV apresentam diferentes preditores socioeconômicos e de saúde, a saber: as incapacidades funcionais; o uso de equipamentos de apoio; a insatisfação com o lazer; a renda inferior a um salário mínimo, e; a ausência de companheira. Conclusão: devem ser priorizadas ações que minimizem o impacto à QV relacionada aos fatores socioeconômicos e incapacidades.

Objective: to ascertain the socioeconomic and health-related factors associated with quality of life (QOL) of elderly men in rural areas. Method: quantitative, descriptive study based on an analytical home survey of 449 elderly rural men. Data were collected between June 2010 and March 2011 in Uberaba, Minas Gerais, using the following questionnaires: structured, Katz Index, Lawton and Brody Scale, World Health Organization Quality of Life (BREF) and World Health Organization Quality of Life Assessment for Older Adults. Descriptive analysis and multiple linear regression were performed (p<0.05). Results: the lowest QOL domains and facet scores show different socioeconomic and health predictors, viz.: functional disabilities; use of support equipment; dissatisfaction with leisure; income of less than one minimum wage; and lack of a companion. Conclusion: priority should be given to measures to minimize impact on QOL related to socioeconomic factors and disabilities.

Objetivo: evaluar la calidad relacionada con la salud socio-económico y de vida (QOL) de los hombres mayores. Método: estudio analítico de 449 ancianos del campo. Los datos fueron recolectados en el período junio 2010 hasta marzo 2011 en Uberaba-MG. Resultados: se utilizaron cuestionarios: estructura, índice de Katz, Lawton y Brody escala, Calidad Mundial de la Salud Organización de la Vida - BREF y la Organización Mundial de la Salud de Calidad de la Evaluación de la Vida de los Adultos Mayores. Se realizó un análisis descriptivo y de regresión lineal múltiple (p<0,05). Resultados: las puntuaciones más bajas de dominios y facetas QV tienen diferentes predictores socioeconómicos y de salud, a saber: la incapacidad funcional; el uso de equipos de apoyo; la insatisfacción con el ocio; menos de un salario mínimo, y; ningún compañero. Conclusión: deben ser priorizadas acciones que minimicen el impacto en la QOL relacionada con factores socioeconómicos y la discapacidad.

Perfil sociodemográfico, capacidade funcional e qualidade de vida de homens idosos residentes na zona rural / Perfil sociodemográfico, capacidad funcional y calidad de vida de hombres ancianos residentes en zonas rurales / The sociodemographic profile, functional capacity and quality of life of older men living in the rural area

Objetivou-se com este trabalho descrever as características sociodemográficas, a capacidade funcional e a qualidade de vida (QV) dos homens idosos residentes na zona rural. Trata-se de inquérito domiciliar, transversal, observacional e descritivo. Foram entrevistados 449 homens idosos no domicílio com instrumento estruturado. Os dados foram submetidos à análise descritiva. O maior percentual tinha entre 60├70 anos, morava com companheira em casa própria, possuía de 4├8 anos de estudo, renda de um salário mínimo, não apresentava incapacidades funcionais para realizar as atividades básicas e instrumentais da vida diária, assistia à TV e ouvia rádio como passatempo, estavam satisfeito com o lazer e era sedentário. O maior escore de QV foi no domínio relações sociais e na faceta morte e morrer, e os menores foram para o meio ambiente e participação social. Melhorias de infraestrutura, acesso aos serviços de saúde e ampliação da possibilidade de atividades sociais podem contribuir para melhoria da QV dos homens idosos.

The objective was to describe the sociodemographic characteristics, functional capacity and quality of life (QL) of older men living in the rural area. This is a cross-sectional, observational and descriptive household survey. Home interviews were performed with 449 older men, using a structured instrument. The data were submitted to descriptive analysis. Most men were aged between 60 to70 years and lived with a partner in their own home; they had 4 to 8 years of education; an income of one minimum salary; and did not show any functional incapacities in performing basic and instrumental activities of daily living...

Se objetivó describir características sociodemográficas, capacidad funcional y calidad de vida (QV) de hombres ancianos residentes en zona rural. Encuesta domiciliaria, transversal, observacional, descriptiva. Fueron entrevistados 449 hombres ancianos en domicilio con instrumento estructurado. Datos sometidos a análisis descriptivo. El porcentaje mayor tenía entre 60 y 70 años, vivían con compañera en casa propia, poseía 4 a 8 años de escolarización, renta equivalente a un salario mínimo, no presentaban incapacidades funcionales para actividades básicas e instrumentales del cotidiano, veían televisión y oían radio como pasatiempo, estaban satisfechos con el ocio y eran sedentarios. El mayor puntaje de QV se encontró en el dominio relaciones sociales y en la faceta muerte y morir; y los menores correspondieron a medio ambiente y participación social. Mejoras estructurales, acceso a servicios de salud y ampliación de posibilidades de actividades sociales pueden contribuir a la mejora de la QV de los hombres ancianos.