Aberrant systemic complement levels and altered acute-phase inflammatory responses attribute to varying grades of dengue disease severity

BackgroundDengue virus (DENV) infection poses a serious health burden across the tropical and sub-tropical regions. Dengue manifestations range from asymptomatic and subclinical to severe disease with plasma leakage and organ dysfunction. The role of complement factors and acute-phase proteins in clinical dengue remains unclear. MethodsOf the enrolled 156 participants, 114 were confirmed clinical dengue cases and 42 healthy controls. We performed serological profiling of NS1, anti-DENV IgM, and anti-DENV IgG, and measured serum acute-phase reactants, clinico-laboratory parameters, and viral load. These parameters were used for classification of disease severity in the patients namely, dengue with warning signs (DWS+, n=35), dengue without warning signs (DWS-, n=74), and severe dengue (SD, n=5) in accordance with the 2009 WHO guidelines. Levels of complement factors C1Inh, C1q, C2, C3a, C3b, MBL, C5a, and CR1 were assessed using commercial ELISA. The concentrations of these complement factors were correlated with various acute-phase proteins, clinical laboratory parameters, grades of dengue disease severity, and platelet counts. ResultsSerological classification revealed 104 patients were IgM positive, 35 were IgG positive, 24 were NS1 positive, and 26 were secondary dengue samples. There was a significant alteration in early classical complement pathway proteins C1Inh, C1q, and C2. The levels of downstream complement products and CR1 remained largely unchanged across both varying grades of dengue severity and primary/secondary stratification. MBL showed significant variation between the severity groups but did not differ within primary and secondary dengue samples. Univariate analysis revealed that NS1 positivity, IgG positivity, age, urea, and CR1 were factors correlated with the severity, but further multivariate analysis showed CR1 as the only independent predictor among complement factors that correlated negatively with dengue severity. Platelet counts had a negative association with RDW and basophils, and a strong positive correlation with uric acid levels. ConclusionOur findings demonstrate that aberrant complement activation contributes to varying grades of dengue severity. Moreover, CR1 may serve as a possible predictor of dengue severity. Author summaryDengue is a mosquito-borne tropical viral infection that can range in severity from asymptomatic to life-threatening manifestations. The human immune system represents a key determinant of dengue disease progression and severity. However, the specific mechanism that makes a subset of individuals in the population relatively severely ill is seldom understood. The complement system represents a key component of the natural immune system, which can help fend off infection but can also injures the host by exaggerating inflammation if not properly controlled. Here, we studied the role of certain important complement proteins and laboratory analytes in patients with dengue infection of varying grades of disease severity. We found that alteration of certain complement proteins i.e., C1Inh, C1q, and C2, depended on the severity of dengue infection. Notably, we found that the complement receptor 1 was inversely correlated with disease severity. We also observed associations between platelet counts and certain hematologic markers, including a strong positive correlation with uric acid. We concluded the role of aberrant complement activation, and identified CR1 (CD35) as a predictor of dengue disease severity.