Abstract
Human Cytomegalovirus has been implicated as a probable cause for the development of hepatic cholestasis among neonates. Our study tried to ascertain the exact demographic, biochemical and immunological markers to differentially diagnose patients with HCMV associated intrahepatic and extrahepatic cholestasis and also decipher the phylogenetic variability among the viral strains infecting the two groups. A total of 110 neonates collected over a span of 2 years were selected for the study classified into four different groups based on the presence of hepatic cholestasis and active HCMV infection. Our analysis predicted that total Cholesterol, GGT, ALP and TNFα were the only significant biological markers with exact cut-off scores, capable of distinguishing between HCMV associated intrahepatic and extrahepatic cholestasis. We confirmed that in patients belonging to both of these groups, the inflammasome is activated and the extent of this activation is more or less same except for the initial activators NLRP3 and AIM2 respectively. When we performed two separate phylogenetic analyses with HCMV gM and gN gene sequences, we found that in both cases the sequences from the IHC and EHC groups formed almost separate phylogenetic clusters. Our study has shown that the HCMV clinical strains infecting at intrahepatic and extrahepatic sites are phylogenetically segregated as distinct clusters. These two separate groups show different physiological as well as immunological modulations while infecting a similar host.
Highlights
TNFα Tumor necrosis factor alpha IFNγ Interferon gamma IL6 Interlukin 6 IL10 Interlukin 10 IL1β Interlukin 1 beta TGFβ Transforming growth factor beta Interlukin 1 Receptor antagonist (IL1Ra) Interlukin 1 receptor antagonist IL18 Interlukin 18 IL8 Interlukin 8 C-reactive protein (CRP) C-Reactive protein MCP1 Monocyte chemoattractant protein 1 MIP1α Macrophage inflammatory protein 1-alpha IL2 Interlukin 2 RIG1 Retinoic acid-inducible gene 1 RANTES Regulated on Activation Normal T Cell Expressed and Secreted (RANTES) NLRP1 NLR family pyrin domain containing 1 NLRP3 NLR family pyrin domain containing 3 NLRC4 NLR family CARD domain-containing protein 4 AIM2 Absent in melanoma 2 IFI16 Interferon gamma inducible protein 16 ASC Apoptosis-associated speck-like protein containing a CARD domain ROC Receiver-operating characteristic AUC Area under the curve analysis of variance (ANOVA) Analysis of variance
Reduced head circumference was observed in case of patients with active Human cytomegalovirus (HCMV) infection i.e. both group 1 and group 2 compared to patients without HCMV infection i.e. group 3 and group 4
In this study we have shown that HCMV infection is associated with both intrahepatic and extrahepatic cholestasis in neonates and specified only four biomarkers (Cholesterol, GGT, ALP and TNFα) with exact cut-off values to distinguish between them thereby minimizing the labor, time constraint and cost of detection
Summary
TNFα Tumor necrosis factor alpha IFNγ Interferon gamma IL6 Interlukin 6 IL10 Interlukin 10 IL1β Interlukin 1 beta TGFβ Transforming growth factor beta IL1Ra Interlukin 1 receptor antagonist IL18 Interlukin 18 IL8 Interlukin 8 CRP C-Reactive protein MCP1 Monocyte chemoattractant protein 1 MIP1α Macrophage inflammatory protein 1-alpha IL2 Interlukin 2 RIG1 Retinoic acid-inducible gene 1 RANTES Regulated on Activation Normal T Cell Expressed and Secreted (RANTES) NLRP1 NLR family pyrin domain containing 1 NLRP3 NLR family pyrin domain containing 3 NLRC4 NLR family CARD domain-containing protein 4 AIM2 Absent in melanoma 2 IFI16 Interferon gamma inducible protein 16 ASC Apoptosis-associated speck-like protein containing a CARD domain ROC Receiver-operating characteristic AUC Area under the curve ANOVA Analysis of variance. Inflammatory response pathways play a major role in the etiology of hepatic cholestasis and since HCMV infections in neonates triggers a major immune response it is likely that this causes or aggravates the development of hepatic cholestasis[7,8]. Excessive inflammatory responses can promote secretion of more proinflammatory cytokines, to amplify inflammatory damage and liver fibrosis[9] These responses can subsequently activate the inflammasome complex causing extensive liver fibrosis and cirrhosis[10,11]. An important route of innate immunity, the first line of defence against HCMV relies on the multimeric protein complex called inflammasome[12,13] This complex is formed by different sensor and adaptor proteins which together converts the inactive pro-caspase-1 into its active protease form. We would decipher the pattern of variability in the phylogenetic lineage of the HCMV clinical strains inducing intrahepatic and extrahepatic cholestasis with respect to specific viral genes
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