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1.
J Clin Immunol ; 41(7): 1607-1620, 2021 10.
Article in English | MEDLINE | ID: covidwho-1298388

ABSTRACT

The complement system, a network of highly-regulated proteins, represents a vital part of the innate immune response. Over-activation of the complement system plays an important role in inflammation, tissue damage, and infectious disease severity. The prevalence of MERS-CoV in Saudi Arabia remains significant and cases are still being reported. The role of complement in Middle East Respiratory Syndrome coronavirus (MERS-CoV) pathogenesis and complement-modulating treatment strategies has received limited attention, and studies involving MERS-CoV-infected patients have not been reported. This study offers the first insight into the pulmonary expression profile including seven complement proteins, complement regulatory factors, IL-8, and RANTES in MERS-CoV infected patients without underlying chronic medical conditions. Our results significantly indicate high expression levels of complement anaphylatoxins (C3a and C5a), IL-8, and RANTES in the lungs of MERS-CoV-infected patients. The upregulation of lung complement anaphylatoxins, C5a, and C3a was positively correlated with IL-8, RANTES, and the fatality rate. Our results also showed upregulation of the positive regulatory complement factor P, suggesting positive regulation of the complement during MERS-CoV infection. High levels of lung C5a, C3a, factor P, IL-8, and RANTES may contribute to the immunopathology, disease severity, ARDS development, and a higher fatality rate in MERS-CoV-infected patients. These findings highlight the potential prognostic utility of C5a, C3a, IL-8, and RANTES as biomarkers for MERS-CoV disease severity and mortality. To further explore the prediction of functional partners (proteins) of highly expressed proteins (C5a, C3a, factor P, IL-8, and RANTES), the computational protein-protein interaction (PPI) network was constructed, and six proteins (hub nodes) were identified.


Subject(s)
Chemokine CCL5/genetics , Chemokine CCL5/metabolism , Complement C3a/metabolism , Complement C5a/metabolism , Coronavirus Infections/diagnosis , Interleukin-8/metabolism , Lung/metabolism , Middle East Respiratory Syndrome Coronavirus/physiology , Aged , Biomarkers/metabolism , Complement C3a/genetics , Complement C5a/genetics , Coronavirus Infections/metabolism , Coronavirus Infections/mortality , Female , Humans , Interleukin-8/genetics , Male , Middle Aged , Prognosis , Severity of Illness Index , Survival Analysis , Up-Regulation
2.
J Autoimmun ; 117: 102595, 2021 02.
Article in English | MEDLINE | ID: covidwho-1014585

ABSTRACT

BACKGROUND: Genetic variation at a multigene cluster at chromosome 3p21.31 and the ABO blood group have been associated with the risk of developing severe COVID-19, but the mechanism remains unclear. Complement activation has been associated with COVID-19 severity. OBJECTIVE: The aim of this study was to examine whether chromosome 3p21.31 and the ABO variants are linked to the activation of the complement cascade in COVID-19 patients. METHODS: We considered 72 unrelated European hospitalized patients with genetic data and evaluation of circulating C5a and soluble terminal complement complex C5b-9 (SC5b-9). Twenty-six (36.1%) patients carried the rs11385942 G>GA variant and 44 (66.1%) non-O blood group associated with increased risk of severe COVID-19. RESULTS: C5a and SC5-b9 plasma levels were higher in rs11385949 GA carriers than in non-carriers (P = 0.041 and P = 0.012, respectively), while C5a levels were higher in non-O group than in O group patients (P = 0.019). The association between rs11385949 and SC5b-9 remained significant after adjustment for ABO and disease severity (P = 0.004) and further correction for C5a (P = 0.018). There was a direct relationship between upper airways viral load and SC5b-9 in carriers of the rs11385949 risk allele (P = 0.032), which was not observed in non-carriers. CONCLUSIONS: The rs11385949 G>GA variant, tagging the chromosome 3 gene cluster variation and predisposing to severe COVID-19, is associated with enhanced complement activation, both with C5a and terminal complement complex, while non-O blood group with C5a levels. These findings provide a link between genetic susceptibility to more severe COVID-19 and complement activation.


Subject(s)
ABO Blood-Group System/genetics , COVID-19/genetics , Chromosomes, Human, Pair 3/genetics , Complement Activation/genetics , Genotype , Multigene Family/genetics , Aged , Complement C5a/genetics , Disease Progression , Female , Gene Frequency , Genetic Association Studies , Genetic Predisposition to Disease , Hospitalization , Humans , Male , Middle Aged , Polymorphism, Single Nucleotide , Risk , SARS-CoV-2/physiology , Viral Load
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