The hepatitis C virus (HCV) infects about 3% of the world's population and is the most common etiological agent associated with liver cirrhosis and hepatocellular carcinoma. Annually 3-4 million people acquire infection and 60-80% of the infected adults become chronically infected and suffers from chronic hepatitis, which then subsequently progresses into end-stage liver diseases such as liver fibrosis, cirrhosis and liver cancer. The mechanisms by which HCV causes chronic progressive liver damage are not completely characterized. The reliance of HCV on host lipids for all facets of its lifecycle and th concomitant modulation of the host lipid metabolism by the virus is a unique feature of HCV biology. HCV alters the lipid homeostasis leading to the accumulation of intracellular lipid droplets that manifests into `hepatosteatosis/fatty liver' a common phenotype associated with chronic HCV infection. Intriguingly, hepatosteatosis is associated with progression to end stage liver diseases and is often considered a prelude to liver fibrosis and cirrhosis. Hepatic inflammation during chronic HCV infection is considered to be the primary catalyst for liver disease and progression to liver cancer. Interestingly, recent studies imply an intricate connection between inflammatory signaling and host lipid metabolism. The role of chronic inflammation in HCV-infection associated alteration of hepatic lipid metabolism has not been studied so far. We recently showed that HCV promotes the activation of the NLRP3-inflammasome in infected hepatocytes, which likely contributes to chronic inflammation associated with infection. Inflammasome activation is conventionally considered to resolve the infection. In contrast, our preliminary studies reveal that HCV exploits the NLRP3-inflammasome to modulate lipid metabolism and to facilitate viral proliferation. In this proposal we will attempt to further explore and understand this intriguing relation between NLRP3-inflammasome and lipid metabolism during HCV infection. Based on our preliminary findings we hypothesize that HCV-induced NLRP3-inflammasome-mediates LDs biogenesis and facilitate HCV assembly and release. The objective of this study is to elucidate the underlying mechanisms associated with these processes. In pursuit of our objective we propose three specific aims;
in Aim 1, we will determine how NRLP3-inflammasome promotes SREBPs maturation and activity in HCV infected cells, in Aim 2, we will determine the role of the NLRP3-inflammasome in lipid droplets biogenesis, and in Aim 3, we will define the role of the NLRP3-inflammasome in HCV proliferation. The proposed research is highly significant and deals with the novel and uncharacterized link between inflammation and hepatic lipid metabolism in HCV infection and will unveil important clues enhance our understanding of HCV biology/life cycle and pathophysiology of liver diseases. The results obtained from the proposed studies will open potential new avenues for developing efficient therapy to HCV infection and associated liver diseases.
The proposed research has relevance to public health, because the fundamental mechanisms to be investigated are expected to contribute to understanding of how chronic inflammatory processes can regulate host cell lipid metabolism and HCV production. The proposed research is relevant to NIH mission that pertains to developing fundamental knowledge that will potentially help design the cost effective alternate strategies in the treatment of chronic hepatitis C infection. The proposed studies are of an important and under-investigated area of HCV research that is expected to provide novel strategies for targeting the cellular determinants to arrest the production of HCV and progression of liver diseases associated with chronic HCV-infection.
|Iqbal, Jawed; Sarkar-Dutta, Mehuli; McRae, Steven et al. (2018) Osteopontin Regulates Hepatitis C Virus (HCV) Replication and Assembly by Interacting with HCV Proteins and Lipid Droplets and by Binding to Receptors ?V?3 and CD44. J Virol 92:|
|McRae, Steven; Iqbal, Jawed; Sarkar-Dutta, Mehuli et al. (2016) The Hepatitis C Virus-induced NLRP3 Inflammasome Activates the Sterol Regulatory Element-binding Protein (SREBP) and Regulates Lipid Metabolism. J Biol Chem 291:3254-67|