There is a fundamental gap in our understanding of how animal virus interactions with cell surface receptors facilitate a productive infection. Bindin of viruses, such as herpesviruses, to the cell surface can occur at 40C in an energy independent manner. In contrast, entry into cells and subsequent transfer of capsids to the vicinity of the nucleus are an active, energy dependent phenomenon, and thus must require host-cell signaling pathways. Our central hypothesis is that KSHV has evolved to utilize its interactions with receptors to manipulate the host's pre-existing signal cascades to mediate entry and infection of target cells. Our ongoing studies support this hypothesis. We have shown that during infection of endothelial (HMVEC-d) cells, the initial attachment of KSHV occurs via heparan sulfate (HS) followed by a temporal interaction with integrins (?3?1,??V??3, and ?V??5) and xCT molecules. KSHV binding resulted in the activation of FAK, Src, PI3-K, Rho-GTPases, Dia-2, Ezrin, PKC-?, ERK1/2 and NF-?B signal molecules. These molecules play roles in KSHV entry (FAK, Src, PI3-K, Rho-GTPases), acetylation of microtubules (MT) (RhoA-GTPase) that facilitates the transport of KSHV capsid toward the nucleus via dynein motors, and viral gene expression (ERK1/2 and NF-?B). Although lipid raft (LR) disruption resulted in increased Src activation and virus entry, we observed the inhibition of viral gene expression, PI3K, RhoA, Dia-2 and NF?B activation, MT acetylation and nuclear delivery of viral DNA which suggested that LRs play roles in entry in cells and modulates selected signal molecules. We have also demonstrated that c-Cbl play a role in KSHV macropinocytosis. To further test our hypothesis, we have formulated three major interlinked, focused specific aims which will decipher the mechanisms by which c-Cbl facilitate KSHV entry, the role of major adaptor molecules in KSHV infection and decipher how c-Cbl dictates the fate of macropinosomes containing KSHV. These studies are significant since such comprehensive understanding of early events of KSHV infection will provide novel targets to block the initiation of target cell infection by KSHV and te associated diseases.

Public Health Relevance

Kaposi's sarcoma associated herpesvirus (KSHV) is etiologically associated with Kaposi's sarcoma and primary effusion lymphoma. The proposed studies will investigate early events of in vitro infection by KSHV. These studies are significant since such comprehensive understanding of early events of KSHV infection will provide novel targets to block the initiation of target cell infection by KSHV and the associated diseases.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA168472-03
Application #
8616737
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2012-04-01
Project End
2017-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
3
Fiscal Year
2014
Total Cost
$310,970
Indirect Cost
$109,695
Name
Rosalind Franklin University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
069501252
City
North Chicago
State
IL
Country
United States
Zip Code
60064
Bandyopadhyay, Chirosree; Veettil, Mohanan Valiya; Dutta, Sujoy et al. (2014) p130Cas scaffolds the signalosome to direct adaptor-effector cross talk during Kaposi's sarcoma-associated herpesvirus trafficking in human microvascular dermal endothelial cells. J Virol 88:13858-78
Veettil, Mohanan Valiya; Bandyopadhyay, Chirosree; Dutta, Dipanjan et al. (2014) Interaction of KSHV with host cell surface receptors and cell entry. Viruses 6:4024-46
Bandyopadhyay, Chirosree; Valiya-Veettil, Mohanan; Dutta, Dipanjan et al. (2014) CIB1 synergizes with EphrinA2 to regulate Kaposi's sarcoma-associated herpesvirus macropinocytic entry in human microvascular dermal endothelial cells. PLoS Pathog 10:e1003941
Gjyshi, Olsi; Bottero, Virginie; Veettil, Mohanan Valliya et al. (2014) Kaposi's sarcoma-associated herpesvirus induces Nrf2 during de novo infection of endothelial cells to create a microenvironment conducive to infection. PLoS Pathog 10:e1004460
Valiya Veettil, Mohanan; Dutta, Dipanjan; Bottero, Virginie et al. (2014) Glutamate secretion and metabotropic glutamate receptor 1 expression during Kaposi's sarcoma-associated herpesvirus infection promotes cell proliferation. PLoS Pathog 10:e1004389
Singh, Vivek Vikram; Dutta, Dipanjan; Ansari, Mairaj Ahmed et al. (2014) Kaposi's sarcoma-associated herpesvirus induces the ATM and H2AX DNA damage response early during de novo infection of primary endothelial cells, which play roles in latency establishment. J Virol 88:2821-34
Ansari, Mairaj Ahmed; Singh, Vivek Vikram; Dutta, Sujoy et al. (2013) Constitutive interferon-inducible protein 16-inflammasome activation during Epstein-Barr virus latency I, II, and III in B and epithelial cells. J Virol 87:8606-23
Paul, Arun George; Chandran, Bala; Sharma-Walia, Neelam (2013) Cyclooxygenase-2-prostaglandin E2-eicosanoid receptor inflammatory axis: a key player in Kaposi's sarcoma-associated herpes virus associated malignancies. Transl Res 162:77-92
Paul, Arun George; Chandran, Bala; Sharma-Walia, Neelam (2013) Concurrent targeting of eicosanoid receptor 1/eicosanoid receptor 4 receptors and COX-2 induces synergistic apoptosis in Kaposi's sarcoma-associated herpesvirus and Epstein-Barr virus associated non-Hodgkin lymphoma cell lines. Transl Res 161:447-68
Dutta, Dipanjan; Chakraborty, Sayan; Bandyopadhyay, Chirosree et al. (2013) EphrinA2 regulates clathrin mediated KSHV endocytosis in fibroblast cells by coordinating integrin-associated signaling and c-Cbl directed polyubiquitination. PLoS Pathog 9:e1003510

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