Apolipoprotein A1 levels and its association with NS1 in the pathogenesis of acute dengue

Abstract

AbstractBackgroundThe dengue NS1 antigen is a secretory protein and was shown to associate with apolipoprotein A1 (ApoA1). Therefore, we sought to investigate the changes in ApoA1 levels in patients with varying severity of acute dengue and then proceeded to investigate how ApoA1 and NS1 interactions affect cytokine production from primary human monocytes.Methodology/Principal FindingsSerial measurements of ApoA1, viral loads, NS1 antigen levels and lipid profiles were done in adult patients with dengue fever (DF= 21) and dengue haemorrhagic fever (DHF =28). To investigate the effect of ApoA1-NS1 interactions in cytokine production from primary human monocytes, cells were harvested from healthy individuals (n=6) and co-cultured with varying concentrations of ApoA1 and levels of IL-6 and TNF-α measured in culture supernatants.The ApoA1 levels were significantly lower in patients with DHF on day 5 of illness (p=0.04) compared to those with DF. ApoA1 levels did not show any correlation with either the NS1 antigen levels or the viral loads in patients with DF or DHF, although they did significantly and inversely correlate with liver transaminases, AST (Spearmans R=-0.55, p <0.0001) and ALT (Spearmans R=-0.49, p<0.0001) in patients with DF. However, a significant correlation was not seen between ApoA1 levels and AST levels (Spearmans R=-0.45, p=0.09) in patients with DHF and ALT levels (Spearman’s R=0.0.5, p=0.64). HDL and LDL levels were significantly lower on day 5 of the illness in patients with DHF compared to those with DF. Co-culture of NS1 and ApoA1 resulted in an increased IL-6 production (but not TNFα) in culture supernatants in a dose dependent manner.Conclusions/SignificanceHDL, LDL and ApoA1 levels were significantly lower in those who have severe dengue, especially in the critical phase and ApoA1 levels inversely correlated with the extent of rise in liver enzymes. While co-culture of ApoA1 with NS1 in primary human monocytes induced high IL-6 levels in a dose dependent manner, this was not seen for TNFα suggesting that the interaction of ApoA1 with NS1 could give rise to different outcomes.Author summaryThe dengue NS1 antigen is a secretory protein and was shown to associate with apolipoprotein A1 (ApoA1). Therefore, we sought to investigate the changes in ApoA1 levels in patients with varying severity of acute dengue and then proceeded to investigate how ApoA1 and NS1 interactions affect cytokine production from primary human monocytes. Serial measurements of ApoA1, viral loads, NS1 antigen levels and lipid profiles were done in adult patients with dengue fever (DF) and dengue haemorrhagic fever (DHF). HDL, LDL and ApoA1 levels were significantly lower in those who have severe dengue, especially in the critical phase and ApoA1 levels inversely correlated with the extent of rise in liver enzymes. While co-culture of ApoA1 with NS1 in primary human monocytes induced high IL-6 levels in a dose dependent manner, this was not seen for TNFα, suggesting that the interaction of ApoA1 with NS1 could give rise to different outcomes.