Dengue, caused by dengue virus (DENV), constitutes a public health emergency of international concern. DENV infection in humans results in a spectrum of outcomes ranging from asymptomatic to undifferentiated fever, mild form of the disease namely dengue fever (DF) to severe forms including dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) that may be fatal . The outcome of DENV infection is determined by multiple factors including viral virulence, host genetics and host immune responses .
Among the various components of host immune responses, T cells, antibodies, cytokine storm and complement factors contribute to the pathogenesis of dengue . Epidemiological studies have shown an association between DHF/DSS and secondary DENV infection. Preexisting antibodies and cross reactive T cell responses induced by the primary infection is believed to exacerbate the disease during secondary infection [3, 4]. Proinflammatory cytokines namely interleukin-8 (IL-8), tumor necrosis factor-α and interferon-γ and anti inflammatory cytokine IL-10 also contribute to dengue disease pathogenesis [5–11]. Activation of T cells, antibodies and cytokines are influenced by various immunomodulators. Increase or decrease in the levels of these immunomodulators influences the outcome of viral infections .
Vitamin D is a potent immunomodulator affecting both innate and adaptive immune responses. Vitamin D binds to Vitamin D receptor (VDR), translocates to the nucleus and influences gene expression. Vitamin D enhances the phagocytic capacity of macrophages and induces antimicrobial peptide gene expression contributing to innate immune responses . Vitamin D inhibits T-helper 1 (Th1) cell and cytotoxic T cell responses. It decreases B-cell proliferation, plasma-cell differentiation and IgG secretion . Vitamin D also enhances Th2 cytokine and IL-10 responses [15, 16]. Vitamin D deficiency increases the risk of cancer, tuberculosis, as well as influenza and human immunodeficiency virus infection [12, 17, 18]. Vitamin D has been reported to influence the expression of DENV receptors in immune cells [19–21]. A study from Vietnam has shown the association of vitamin D receptor gene polymorphisms with susceptibility to DHF .
One of the major pathways of complement activation is initiated by binding of the virus to mannose binding lectin (MBL). MBL is a pattern recognition molecule that recognizes specific sugar molecules present on the surface of microorganisms including DENV [23, 24]. Point mutations in the MBL2 gene lead to reduced concentrations of functional oligomers. Genetically determined variation in serum concentrations of MBL has been shown to influence the susceptibility to infectious, autoimmune and cardiovascular diseases . Alleles of MBL2 gene that are associated with higher concentrations of functional MBL, have been shown to be associated with thrombocytopenia in dengue infected patients . MBL concentrations were also found to be increased in acute samples of DHF cases as compared to DF cases .
Since MBL and Vitamin D are known to influence innate and adaptive immune responses and DENV pathogenesis is immune mediated, we hypothesized that altered levels of plasma vitamin D and MBL might be associated with dengue disease severity. Therefore, we investigated the levels of plasma vitamin D and MBL in dengue infected patients in the context of disease severity and immune status.