Divergent androgenic modulation of SARS-CoV-2 infection cooperates with dysregulated immune response to dictate worse COVID-19 outcomes in men.

Autor: Duarte-Silva M; Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto - FCFRP/USP, Brazil; Departamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto - FMRP/USP, Brazil., Oliveira CNS; Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto - FCFRP/USP, Brazil; Departamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto - FMRP/USP, Brazil., Fuzo C; Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto - FCFRP/USP, Brazil., Silva-Neto PV; Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto - FCFRP/USP, Brazil; Instituto de Ciências Biológicas Amazonas, Universidade Federal do Amazonas - UFAM, Brazil., Toro DM; Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto - FCFRP/USP, Brazil; Instituto de Ciências Biológicas Amazonas, Universidade Federal do Amazonas - UFAM, Brazil., Pimentel VE; Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto - FCFRP/USP, Brazil; Departamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto - FMRP/USP, Brazil., Pérez MM; Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto - FCFRP/USP, Brazil., Fraga-Silva TFC; Departamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto - FMRP/USP, Brazil., Carvalho JCS; Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto - FCFRP/USP, Brazil; Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto - FFCLRP/USP, Brazil., Neto FMS; Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto - FCFRP/USP, Brazil., Júnior RBM; Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto - FCFRP/USP, Brazil; Departamento de Biologia Celular e Molecular e Bioagentes Patogênicos, Faculdade de Medicina de Ribeirão Preto - FMRP/USP, Brazil., Arruda E; Departamento de Biologia Celular e Molecular e Bioagentes Patogênicos, Faculdade de Medicina de Ribeirão Preto - FMRP/USP, Brazil., Vilar FC; Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto - FMRP/USP, Brazil., Degiovani AM; Hospital Santa Casa de Misericórdia de Ribeirão Preto, Brazil., Ostini FM; Hospital Santa Casa de Misericórdia de Ribeirão Preto, Brazil., Feitosa MR; Departamento de Cirurgia e Anatomia, Faculdade de Medicina de Ribeirão Preto - FMRP/USP, Brazil., Parra RS; Departamento de Cirurgia e Anatomia, Faculdade de Medicina de Ribeirão Preto - FMRP/USP, Brazil., Gaspar GG; Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto - FMRP/USP, Brazil., Rocha JJR; Departamento de Cirurgia e Anatomia, Faculdade de Medicina de Ribeirão Preto - FMRP/USP, Brazil., Feres O; Departamento de Cirurgia e Anatomia, Faculdade de Medicina de Ribeirão Preto - FMRP/USP, Brazil., Fernandes APM; Escola de Enfermagem de Ribeirão Preto, EERP/USP, Brazil., Maruyama SR; Departamento de Genética e Evolução, Centro de Ciências Biológicas e da Saúde, Universidade Federal de São Carlos - UFSCar, Brazil., Russo EMS; Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto - FCFRP/USP, Brazil., Bonato VLD; Departamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto - FMRP/USP, Brazil., Santos IKFM; Departamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto - FMRP/USP, Brazil., Sorgi CA; Departamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto - FMRP/USP, Brazil; Instituto de Ciências Biológicas Amazonas, Universidade Federal do Amazonas - UFAM, Brazil; Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto - FFCLRP/USP, Brazil., Dias-Baruffi M; Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto - FCFRP/USP, Brazil., Faccioli LH; Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto - FCFRP/USP, Brazil., Cardoso CRB; Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto - FCFRP/USP, Brazil. Electronic address: cristina@fcfrp.usp.br.
Jazyk: angličtina
Zdroj: Brain, behavior, and immunity [Brain Behav Immun] 2023 Nov; Vol. 114, pp. 275-286. Date of Electronic Publication: 2023 Aug 28.
DOI: 10.1016/j.bbi.2023.08.026
Abstrakt: Background: Sex-determined differences are rarely addressed in the management of diseases, despite well-known contrasting outcomes between female and male patients. In COVID-19 there is a remarkable disparity, with higher rates of mortality and more severe acute disease in men compared to women, who are mostly affected by long COVID-19. Furthermore, whether androgens play a protective or detrimental role in COVID-19 is still a matter of debate. Hence, the adequate management of the disease, especially regarding men presenting acute disease aggravation, still needs important data to elucidate the interplay between sex hormones and host immune responses that drive the worse evolution in male patients.
Methods: A cohort of 92 controls and 198 non-severe and severe COVID-19 patients, from both sexes, was assessed for clinical outcomes, plasma steroids, gonadotropins, sex hormone binding globulin (SHBG) and immune mediators, before vaccination. These data were correlated with the global gene expression of blood leukocytes. The androgen receptor (AR) signaling pathway was investigated by transcriptomics and tracheal aspirate was obtained from severe patients for SARS-COV-2 quantification in the respiratory tract. The interplay among clinical, endocrine and immunological data deciphered the sex differences in COVID-19. Importantly, statistical analyses, using 95% confidence interval, considered confounding factors such as age and comorbidities, to definitely parse the role of androgens in the disease outcome.
Results: There were notable contrasting levels of testosterone and dihydrotestosterone (DHT) throughout the disease course in male but not female patients. Inflammatory mediators presented significant negative correlations with testosterone, which was partially dependent on age and diabetes in men. Male subjects with severe COVID-19 had a significant up regulation of the AR signaling pathway, including modulation of TMPRSS2 and SRD5A1 genes, which are related to the viral infection and DHT production. Indeed, men had a higher viral load in the tracheal aspirate and levels of DHT were associated with increased relative risk of death. In contrast, the testosterone hormone, which was notably reduced in severe disease, was significantly related with susceptibility to COVID-19 worsening in male patients. Secondary hypogonadism was ruled out in the male severe COVID-19 subjects, as FSH, LH, and SHBG levels were not significantly altered. Instead, these subjects tended to have increased gonadotropin levels. Most interestingly, in this study we identified, for the first time, combined sets of clinical and immunoendocrine parameters that together predicted progression from non-severe to severe COVID-19 in men. One of the limitations of our study was the low or undetectable levels of DHT in many patients. Then, the evaluation of enzymes related to biosynthesis and signaling by androgens was mandatory and reiterated our findings.
Conclusions: These original results unraveled the disease immunoendocrine regulation, despite vaccination or comorbidities and pointed to the fundamental divergent role of the androgens testosterone and DHT in the determination of COVID-19 outcomes in men. Therefore, sex-specific management of the dysregulated responses, treatments or public health measures should be considered for the control of COVID-19 pandemic.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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