Area:
Virology Biology, Biochemistry
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High-probability grants
According to our matching algorithm, John G. Purdy is the likely recipient of the following grants.
Years |
Recipients |
Code |
Title / Keywords |
Matching score |
2021 |
Purdy, John Gerard |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Mechanisms of Human Cytomegalovirus Reprogramming of Lipid Metabolism
PROJECT SUMMARY Human cytomegalovirus (HCMV) is a herpesvirus that causes disease and death in the immunocompromised and is a leading cause of congenital disabilities. HCMV replication requires lipids. Since HCMV does not encode a metabolic network, virus replication depends on host lipid metabolism. However, little is known about how HCMV reprograms host metabolism to ensure lipids required for virus replication are made. Our overall goal is to understand the virus-host interactions that regulate lipid synthesis essential for HCMV replication. Recently, we showed that HCMV infection results in an increase in lipid synthesis and a rise in lipid abundances. Here we demonstrate that HCMV infection induces the synthesis of at least 20 previously undescribed lipids unique to infected cells. Most of these unique lipids are phospholipids with very long-chain fatty acid tails (PL-VLCFAs). The PL-VLCFAs discussed in this application are understudied in general and unstudied in HCMV biology beyond our work. While shorter FA tails have been well-studied, we know little about lipids with VLCFAs tails that are as long as those we observe in HCMV infection, including how they will behave in a biological membrane. The molecular mechanisms underlying this HCMV-induced expansion in the host lipidome and the functional roles of the newly generated lipids are largely unknown. We discovered that HCMV pUL37x1 and pUL38 proteins promote PL-VLCFA synthesis, laying the foundation for understanding the mechanisms by which HCMV reprograms lipid synthesis. pUL37x1 and pUL38 induce Ca2+ and mTOR signaling, respectively. We have preliminary data suggesting that stress responses related to these signaling pathways contribute to HCMV remodeling of lipids. We hypothesize that pUL37x1 and pUL38 use Ca2+ and mTOR signaling to promote the synthesis of PC-VLCFAs required for HCMV replication. We will test this hypothesis by determining the mechanisms by which pUL37x1 and pUL38 promote synthesis of PL-VLCFAs (Aim 1) and defining the PL-VLCFA synthesis enzymes required for HCMV replication and the role of PL-VLCFAs in infection (Aim 2). These studies will determine the mechanisms by which HCMV interacts with the host to create a unique lipid environment advancing our knowledge of HCMV reprogramming of metabolism. Furthermore, these studies will define the biological functions of PC-VLCFAs in HCMV replication and further our understanding of lipids required for HCMV infection. Determining the mechanisms involved in HCMV-induced reprogramming of lipid metabolism and functions of PC-VLCFAs will advance knowledge in HCMV biology needed to identify new targets for treating infection.
|
0.948 |
2021 |
Purdy, John Gerard |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Metabolite-Mediated Signaling in Cell-to-Cell Spread of Human Cytomegalovirus
Human cytomegalovirus (HCMV) establishes a life-long persistent infection by evading the immune system, in part, by direct cell-to-cell viral spread. In solid organ or stem cell transplant recipients, HCMV spread leads to end-organ diseases that can cause death. During pregnancy, HCMV spread causes congenital infection and is a leading cause of congenital disabilities. No HCMV treatment offers a cure, and there is no vaccine. Thus, there is a need for new treatments to limit infection based on novel discoveries in HCMV biology. Viral proteins required for HCMV cell-to-cell spread are known, but the host processes involved in HCMV cell-to-cell spread have received less attention. Clinical strains of HCMV spread most efficiently through cell-to-cell means, but the molecular mechanisms?including host metabolic ones?essential to HCMV cell-to-cell spread are largely unknown. Understanding host mechanisms regulating cell-to-cell spread may lead to new understandings of how to reduce HCMV infection. Our research has uncovered a novel role of metabolite signaling in promoting HCMV spread. This project's overall goal is to mechanistically understand virus-host interactions regulating metabolite signaling essential to HCMV cell-to-cell spread. We found a metabolite in tryptophan metabolism?kynurenine (KYN)?enhances HCMV spread. In addition to its metabolic role, KYN is a signaling messenger. KYN signals through aryl hydrocarbon receptor (AhR). We show that activation of AhR supports HCMV replication. Moreover, we found that hypoxia-inducible factor 1? (HIF1?), through its metabolic regulatory function, limits the production of KYN and suppresses HCMV infection. We hypothesize that metabolite-mediated signaling from infected cells to uninfected cells promotes HCMV cell-to-cell spread, which is attenuated by a HIF1?-dependent cellular response. The proposed research will determine molecular mechanisms involved in the enhancement of HCMV infection by KYN-metabolite signaling (aim 1) and define virus-host interactions regulating HIF1? attenuation of HCMV cell-to-cell spread (aim 2). The experimental approach will integrate virus assays, CRISPR/Cas9 engineering, and untargeted metabolomics to understand HCMV biology. Our findings will provide a mechanistic understanding of metabolite signaling and AhR activity in promoting HCMV cell-to-cell spread and the HIF1?-dependent host-response that targets metabolite signaling to reduce infection. Our studies will advance our knowledge in an understudied area of HCMV research that will provide significant steps-forward in developing novel strategies to treat HCMV infection and limit HCMV-related disease.
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0.948 |