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Article ; Online: The Kaposi's sarcoma progenitor enigma: KSHV-induced MEndT-EndMT axis.

Naipauer, Julian / Mesri, Enrique A

2023 Volume 29, Issue 3, Page(s) 188–200

Abstract: Endothelial-to-mesenchymal transition has been described in tumors as a source of mesenchymal stroma, while the reverse process has been proposed in tumor vasculogenesis and angiogenesis. A human oncogenic virus, Kaposi's sarcoma herpes virus (KSHV), can ...

Abstract	Endothelial-to-mesenchymal transition has been described in tumors as a source of mesenchymal stroma, while the reverse process has been proposed in tumor vasculogenesis and angiogenesis. A human oncogenic virus, Kaposi's sarcoma herpes virus (KSHV), can regulate both processes in order to transit through this transition 'boulevard' when infecting KS oncogenic progenitor cells. Endothelial or mesenchymal circulating progenitor cells can serve as KS oncogenic progenitors recruited by inflammatory cytokines because KSHV can reprogram one into the other through endothelial-to-mesenchymal and mesenchymal-to-endothelial transitions. Through these novel insights, the identity of the potential oncogenic progenitor of KS is revealed while gaining knowledge of the biology of the mesenchymal-endothelial differentiation axis and pointing to this axis as a therapeutic target in KS.
MeSH term(s)	Humans ; Sarcoma, Kaposi/drug therapy ; Sarcoma, Kaposi/pathology ; Herpesvirus 8, Human/physiology ; Cell Differentiation
Language	English
Publishing date	2023-01-10
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2036490-8
ISSN	1471-499X ; 1471-4914
ISSN (online)	1471-499X
ISSN	1471-4914
DOI	10.1016/j.molmed.2022.12.003
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Article ; Online: 2-Deoxy-d-glucose exploits increased glucose metabolism in cancer and viral-infected cells: Relevance to its use in India against SARS-CoV-2.

Mesri, Enrique A / Lampidis, Theodore J

IUBMB life

2021 Volume 73, Issue 10, Page(s) 1198–1204

Abstract: Mechanisms discovered to drive increased glucose metabolism in cancer cells are found to be similar to those in viral-infected cells. In this mini review, we summarize the major pathways by which the sugar analog, 2-Deoxy-d-glucose, has been shown to ... ...

Abstract	Mechanisms discovered to drive increased glucose metabolism in cancer cells are found to be similar to those in viral-infected cells. In this mini review, we summarize the major pathways by which the sugar analog, 2-Deoxy-d-glucose, has been shown to exploit increased glucose metabolism in cancer and how this information applies to viral-infected cells. Moreover, we highlight the relevance of these findings to the emergency approval of 2-Deoxy-d-glucose in India to be used against SARS-CoV-2, the virus responsible for COVID-19.
MeSH term(s)	COVID-19/metabolism ; COVID-19/virology ; Deoxyglucose/pharmacology ; Glucose/metabolism ; Humans ; India ; Neoplasms/metabolism ; SARS-CoV-2/drug effects ; SARS-CoV-2/isolation & purification ; SARS-CoV-2/pathogenicity
Chemical Substances	Deoxyglucose (9G2MP84A8W) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2021-09-02
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, P.H.S. ; Review
ZDB-ID	1492141-8
ISSN	1521-6551 ; 1521-6543
ISSN (online)	1521-6551
ISSN	1521-6543
DOI	10.1002/iub.2546
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Article ; Online: Unbiased Screening of Activated Receptor Tyrosine Kinases (RTKs) in Tumor Extracts Using a Mouse Phospho-RTK Array Kit.

Naipauer, Julian / Cavallin, Lucas E / Mesri, Enrique A

Bio-protocol

2020 Volume 9, Issue 8

Abstract: Kaposi's sarcoma (KS) herpesvirus (KSHV) is a virus that causes KS, an angiogenic AIDS-associated spindle-cell neoplasm, by activating host oncogenic signaling cascades through autocrine and paracrine mechanisms. Many host signaling cascades co-opted by ... ...

Abstract	Kaposi's sarcoma (KS) herpesvirus (KSHV) is a virus that causes KS, an angiogenic AIDS-associated spindle-cell neoplasm, by activating host oncogenic signaling cascades through autocrine and paracrine mechanisms. Many host signaling cascades co-opted by KSHV including PI3K/AKT/mTORC, NFkB and Notch are critical for cell-specific mechanisms of transformation and their identification is paving the way to therapeutic target discovery. Analysis of the molecular KS signature common to human KS tumors and our mouse KS-like tumors showed consistent expression of KS markers VEGF and PDGF receptors with upregulation of other angiogenesis ligands and their receptors
Language	English
Publishing date	2020-08-24
Publishing country	United States
Document type	Journal Article
ZDB-ID	2833269-6
ISSN	2331-8325 ; 2331-8325
ISSN (online)	2331-8325
ISSN	2331-8325
DOI	10.21769/bioprotoc.3216
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Article: A major role for Nrf2 transcription factors in cell transformation by KSHV encoded oncogenes.

Sapochnik, Daiana / Raimondi, Ana R / Medina, Victoria / Naipauer, Julian / Mesri, Enrique A / Coso, Omar

Frontiers in oncology

2022 Volume 12, Page(s) 890825

Abstract: Kaposi's sarcoma (KS) is the most common tumor in AIDS patients. The highly vascularized patient's skin lesions are composed of cells derived from the endothelial tissue transformed by the KSHV virus. Heme oxygenase-1 (HO-1) is an enzyme upregulated by ... ...

Abstract	Kaposi's sarcoma (KS) is the most common tumor in AIDS patients. The highly vascularized patient's skin lesions are composed of cells derived from the endothelial tissue transformed by the KSHV virus. Heme oxygenase-1 (HO-1) is an enzyme upregulated by the Kaposi´s sarcoma-associated herpesvirus (KSHV) and highly expressed in human Kaposi Sarcoma (KS) lesions. The oncogenic G protein-coupled receptor (KSHV-GPCR or vGPCR) is expressed by the viral genome in infected cells. It is involved in KS development, HO-1 expression, and vascular endothelial growth factor (VEGF) expression. vGPCR induces HO-1 expression and HO-1 dependent transformation through the Ga13 subunit of heterotrimeric G proteins and the small GTPase RhoA. We have found several lines of evidence supporting a role for Nrf2 transcription factors and family members in the vGPCR-Ga13-RhoA signaling pathway that converges on the HO-1 gene promoter. Our current information assigns a major role to ERK1/2MAPK pathways as intermediates in signaling from vGPCR to Nrf2, influencing Nrf2 translocation to the cell nucleus, Nrf2 transactivation activity, and consequently HO-1 expression. Experiments in nude mice show that the tumorigenic effect of vGPCR is dependent on Nrf2. In the context of a complete KSHV genome, we show that the lack of vGPCR increased cytoplasmic localization of Nrf2 correlated with a downregulation of HO-1 expression. Moreover, we also found an increase in phospho-Nrf2 nuclear localization in mouse KS-like KSHV (positive) tumors compared to KSHV (negative) mouse KS-like tumors. Our data highlights the fundamental role of Nrf2 linking vGPCR signaling to the HO-1 promoter, acting upon not only HO-1 gene expression regulation but also in the tumorigenesis induced by vGPCR. Overall, these data pinpoint this transcription factor or its associated proteins as putative pharmacological or therapeutic targets in KS.
Language	English
Publishing date	2022-09-21
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2022.890825
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Article ; Online: Oral and anal microbiome from HIV-exposed individuals: role of host-associated factors in taxa composition and metabolic pathways.

Lacunza, Ezequiel / Fink, Valeria / Salas, María E / Canzoneri, Romina / Naipauer, Julián / Williams, Sion / Coso, Omar / Sued, Omar / Cahn, Pedro / Mesri, Enrique A / Abba, Martín C

NPJ biofilms and microbiomes

2023 Volume 9, Issue 1, Page(s) 48

Abstract: Evidence indicates that the microbiome plays a significant role in HIV immunopathogenesis and associated complications. This study aimed to characterize the oral and anal microbiome of Men who have Sex with Men (MSM) and Transgender Women (TGW), with and ...

Abstract	Evidence indicates that the microbiome plays a significant role in HIV immunopathogenesis and associated complications. This study aimed to characterize the oral and anal microbiome of Men who have Sex with Men (MSM) and Transgender Women (TGW), with and without HIV. One hundred and thirty oral and anal DNA-derived samples were obtained from 78 participants and subjected to shotgun metagenomics sequencing for further microbiome analysis. Significant differences in the microbiome composition were found among subjects associated with HIV infection, gender, sex behavior, CD4+ T-cell counts, antiretroviral therapy (ART), and the presence of HPV-associated precancerous anal lesions. Results confirm the occurrence of oncogenic viromes in this high HIV-risk population. The oral microbiome in HIV-associated cases exhibited an enrichment of bacteria associated with periodontal disease pathogenesis. Conversely, anal bacteria showed a significant decrease in HIV-infected subjects (Coprococcus comes, Finegoldia magna, Blautia obeum, Catenibacterium mitsuokai). TGW showed enrichment in species related to sexual transmission, which concurs that most recruited TGW are or have been sex workers. Prevotella bivia and Fusobacterium gonidiaformans were positively associated with anal precancerous lesions among HIV-infected subjects. The enrichment of Holdemanella biformis and C. comes was associated with detectable viral load and ART-untreated patients. Metabolic pathways were distinctly affected by predominant factors linked to sexual behavior or HIV pathogenesis. Gene family analysis identified bacterial gene signatures as potential prognostic and predictive biomarkers for HIV/AIDS-associated malignancies. Conclusions: Identified microbial features at accessible sites are potential biomarkers for predicting precancerous anal lesions and therapeutic targets for HIV immunopathogenesis.
MeSH term(s)	Male ; Humans ; Female ; HIV Infections/complications ; Homosexuality, Male ; Sexual and Gender Minorities ; Microbiota ; Metabolic Networks and Pathways
Language	English
Publishing date	2023-07-12
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2817021-0
ISSN	2055-5008 ; 2055-5008
ISSN (online)	2055-5008
ISSN	2055-5008
DOI	10.1038/s41522-023-00413-4
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Article: Kaposi's Sarcoma-Associated Herpesvirus-Encoded Viral IL-6 (vIL-6) Enhances Immunoglobulin Class-Switch Recombination.

Rosario, Santas A / Santiago, Gabriel E / Mesri, Enrique A / Verdun, Ramiro E

Frontiers in microbiology

2018 Volume 9, Page(s) 3119

Abstract: Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic gamma-herpesvirus that causes AIDS-associated Kaposi sarcoma (KS) and several lymphoproliferative disorders. During the humoral immune response antigen-activated mature B cells acquire ... ...

Abstract	Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic gamma-herpesvirus that causes AIDS-associated Kaposi sarcoma (KS) and several lymphoproliferative disorders. During the humoral immune response antigen-activated mature B cells acquire functional diversification by immunoglobulin heavy chain (IgH) class-switch recombination (CSR). CSR is initiated by activation-induced cytidine deaminase (AID) which targets highly repetitive switch (S)-regions to mediate DNA double-stranded breaks (DSBs) in the IgH locus facilitating intramolecular recombination. Here we show that in the context of cytokine stimulation, CSR is enhanced in murine B cells exposed only to replication-competent KSHV in an environment of KSHV infection, which coincided with elevated AID transcripts. Using murine splenic B cells and the mouse lymphoma CH12F3-2 CSR system, we identified that vIL-6, but not murine IL-6, increased class-switching, which correlated with upregulated AID expression. Together, these data suggest a regulatory role for KSHV vIL-6 in functionally modulating B cell biology by promoting CSR, which may in part explain how KSHV infection influences humoral immunity and affect KSHV pathogenesis.
Language	English
Publishing date	2018-12-18
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2587354-4
ISSN	1664-302X
ISSN	1664-302X
DOI	10.3389/fmicb.2018.03119
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Article ; Online: Oral and anal microbiome from HIV-exposed individuals

Ezequiel Lacunza / Valeria Fink / María E. Salas / Romina Canzoneri / Julián Naipauer / Sion Williams / Omar Coso / Omar Sued / Pedro Cahn / Enrique A. Mesri / Martín C. Abba

npj Biofilms and Microbiomes, Vol 9, Iss 1, Pp 1-

role of host-associated factors in taxa composition and metabolic pathways

2023 Volume 15

Abstract: Abstract Evidence indicates that the microbiome plays a significant role in HIV immunopathogenesis and associated complications. This study aimed to characterize the oral and anal microbiome of Men who have Sex with Men (MSM) and Transgender Women (TGW), ...

Abstract	Abstract Evidence indicates that the microbiome plays a significant role in HIV immunopathogenesis and associated complications. This study aimed to characterize the oral and anal microbiome of Men who have Sex with Men (MSM) and Transgender Women (TGW), with and without HIV. One hundred and thirty oral and anal DNA-derived samples were obtained from 78 participants and subjected to shotgun metagenomics sequencing for further microbiome analysis. Significant differences in the microbiome composition were found among subjects associated with HIV infection, gender, sex behavior, CD4+ T-cell counts, antiretroviral therapy (ART), and the presence of HPV-associated precancerous anal lesions. Results confirm the occurrence of oncogenic viromes in this high HIV-risk population. The oral microbiome in HIV-associated cases exhibited an enrichment of bacteria associated with periodontal disease pathogenesis. Conversely, anal bacteria showed a significant decrease in HIV-infected subjects (Coprococcus comes, Finegoldia magna, Blautia obeum, Catenibacterium mitsuokai). TGW showed enrichment in species related to sexual transmission, which concurs that most recruited TGW are or have been sex workers. Prevotella bivia and Fusobacterium gonidiaformans were positively associated with anal precancerous lesions among HIV-infected subjects. The enrichment of Holdemanella biformis and C. comes was associated with detectable viral load and ART-untreated patients. Metabolic pathways were distinctly affected by predominant factors linked to sexual behavior or HIV pathogenesis. Gene family analysis identified bacterial gene signatures as potential prognostic and predictive biomarkers for HIV/AIDS-associated malignancies. Conclusions: Identified microbial features at accessible sites are potential biomarkers for predicting precancerous anal lesions and therapeutic targets for HIV immunopathogenesis.
Keywords	Microbial ecology ; QR100-130
Language	English
Publishing date	2023-07-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
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Article ; Online: A role of hypoxia-inducible factor 1 alpha in Murine Gammaherpesvirus 68 (MHV68) lytic replication and reactivation from latency.

López-Rodríguez, Darlah M / Kirillov, Varvara / Krug, Laurie T / Mesri, Enrique A / Andreansky, Samita

PLoS pathogens

2019 Volume 15, Issue 12, Page(s) e1008192

Abstract: The hypoxia-inducible factor 1 alpha (HIF1α) protein and the hypoxic microenvironment are critical for infection and pathogenesis by the oncogenic gammaherpesviruses (γHV), Kaposi sarcoma herpes virus (KSHV) and Epstein-Barr virus (EBV). However, ... ...

Abstract	The hypoxia-inducible factor 1 alpha (HIF1α) protein and the hypoxic microenvironment are critical for infection and pathogenesis by the oncogenic gammaherpesviruses (γHV), Kaposi sarcoma herpes virus (KSHV) and Epstein-Barr virus (EBV). However, understanding the role of HIF1α during the virus life cycle and its biological relevance in the context of host has been challenging due to the lack of animal models for human γHV. To study the role of HIF1α, we employed the murine gammaherpesvirus 68 (MHV68), a rodent pathogen that readily infects laboratory mice. We show that MHV68 infection induces HIF1α protein and HIF1α-responsive gene expression in permissive cells. siRNA silencing or drug-inhibition of HIF1α reduce virus production due to a global downregulation of viral gene expression. Most notable was the marked decrease in many viral genes bearing hypoxia-responsive elements (HREs) such as the viral G-Protein Coupled Receptor (vGPCR), which is known to activate HIF1α transcriptional activity during KSHV infection. We found that the promoter of MHV68 ORF74 is responsive to HIF1α and MHV-68 RTA. Moreover, Intranasal infection of HIF1αLoxP/LoxP mice with MHV68 expressing Cre- recombinase impaired virus expansion during early acute infection and affected lytic reactivation in the splenocytes explanted from mice. Low oxygen concentrations accelerated lytic reactivation and enhanced virus production in MHV68 infected splenocytes. Thus, we conclude that HIF1α plays a critical role in promoting virus replication and reactivation from latency by impacting viral gene expression. Our results highlight the importance of the mutual interactions of the oxygen-sensing machinery and gammaherpesviruses in viral replication and pathogenesis.
MeSH term(s)	Animals ; Gene Expression Regulation, Viral/physiology ; Herpesviridae Infections/metabolism ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Mice ; Rhadinovirus/metabolism ; Virus Latency/physiology ; Virus Replication/physiology
Chemical Substances	Hif1a protein, mouse ; Hypoxia-Inducible Factor 1, alpha Subunit
Language	English
Publishing date	2019-12-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1008192
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Article ; Online: Glucose and mannose analogs inhibit KSHV replication by blocking N-glycosylation and inducing the unfolded protein response.

Schlesinger, Mariana / McDonald, Christian / Ahuja, Anuj / Alvarez Canete, Carolina Alejandra / Nuñez Del Prado, Zelmira / Naipauer, Julian / Lampidis, Theodore / Mesri, Enrique A

Journal of medical virology

2022 Volume 95, Issue 1, Page(s) e28314

Abstract: Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent for Kaposi's sarcoma (KS), an HIV/AIDS-associated malignancy. Effective treatments against KS remain to be developed. The sugar analog 2-deoxy- d-glucose (2-DG) is an anticancer ... ...

Abstract	Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent for Kaposi's sarcoma (KS), an HIV/AIDS-associated malignancy. Effective treatments against KS remain to be developed. The sugar analog 2-deoxy- d-glucose (2-DG) is an anticancer agent that is well-tolerated and safe in patients and was recently demonstrated to be a potent antiviral, including KSHV and severe acute respiratory syndrome coronavirus 2. Because 2-DG inhibits glycolysis and N-glycosylation, identifying its molecular targets is challenging. Here we compare the antiviral effect of 2-DG with 2-fluoro-deoxy- d-glucose, a glycolysis inhibitor, and 2-deoxy-fluoro- d-mannose (2-DFM), a specific N-glycosylation inhibitor. At doses similar to those clinically achievable with 2-DG, the three drugs impair KSHV replication and virion production in iSLK.219 cells via downregulation of viral structural glycoprotein expression (K8.1 and gB), being 2-DFM the most potent KSHV inhibitor. Consistently with the higher potency of 2-DFM, we found that d-mannose rescues KSHV glycoprotein synthesis and virus production, indicating that inhibition of N-glycosylation is the main antiviral target using d-mannose competition experiments. Suppression of N-glycosylation by the sugar drugs triggers ER stress. It activates the host unfolded protein response (UPR), counteracting KSHV-induced inhibition of the protein kinase R-like endoplasmic reticulum kinase branch, particularly activating transcription factor 4 and C/EBP homologous protein expression. Finally, we demonstrate that sugar analogs induce autophagy (a prosurvival mechanism) and, thus, inhibit viral replication playing a protective role against KSHV-induced cell death, further supporting their direct antiviral effect and potential therapeutic use. Our work identifies inhibition of N-glycosylation leading to ER stress and UPR as an antienveloped virus target and sugar analogs such as 2-DG and the newly identified 2-DFM as antiviral drugs.
MeSH term(s)	Humans ; Herpesvirus 8, Human/physiology ; Mannose/pharmacology ; Glucose ; Glycosylation ; COVID-19 ; Unfolded Protein Response ; Virus Replication ; Sarcoma, Kaposi ; Antiviral Agents/pharmacology
Chemical Substances	Mannose (PHA4727WTP) ; Glucose (IY9XDZ35W2) ; Antiviral Agents
Language	English
Publishing date	2022-11-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	752392-0
ISSN	1096-9071 ; 0146-6615
ISSN (online)	1096-9071
ISSN	0146-6615
DOI	10.1002/jmv.28314
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Article ; Online: Kaposi's sarcoma herpesvirus oncogenesis is a notch better in 3D.

Mesri, Enrique A / Cesarman, Ethel

Cell host & microbe

2011 Volume 10, Issue 6, Page(s) 529–531

Abstract: Culture of KSHV-infected lymphatic endothelial cells in 3D increases viral gene expression, leading to Notch-induced MT1-MMP-dependent endothelial-to-mesenchymal transition. This reproduces patterns of KSHV gene expression and presence of mesenchymal ... ...

Abstract	Culture of KSHV-infected lymphatic endothelial cells in 3D increases viral gene expression, leading to Notch-induced MT1-MMP-dependent endothelial-to-mesenchymal transition. This reproduces patterns of KSHV gene expression and presence of mesenchymal KSHV-infected cells found in KS lesions, narrowing the gap between in vitro systems of infection and KSHV tumorigenesis.
Language	English
Publishing date	2011-12-18
Publishing country	United States
Document type	Comment ; Journal Article
ZDB-ID	2278004-X
ISSN	1934-6069 ; 1931-3128
ISSN (online)	1934-6069
ISSN	1931-3128
DOI	10.1016/j.chom.2011.11.008
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