Publications by authors named "Hem Chandra Jha"

54 Publications

Insights into and SARS-CoV-2 co-infection driven neurological manifestations.

Biosaf Health 2021 Apr 30. Epub 2021 Apr 30.

Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, India.

In malaria-endemic regions, people often get exposed to various pathogens simultaneously, generating co-infection scenarios. In such scenarios, overlapping symptoms pose serious diagnostic challenges. The delayed diagnosis may lead to an increase in disease severity and catastrophic events. Recent coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected various areas globally, including malaria-endemic regions. The and SARS-CoV-2 co-infection and its effect on the health are yet unexplored. We present a case report of a previously healthy, middle-aged individual from the malaria-endemic area who suffered SARS-CoV-2 and co-infection. The patient developed severe disease indications in the short time period. The patient showed neurological symptoms, altered hematological as well as liver-test parameters, and subsequent death in a narrow time-span. We hereby discuss the various aspects of this case regarding treatment and hematological parameters. Further, we have put forward perspectives related to the mechanism behind severity and neurological symptoms in this fatal parasite-virus co-infection case. In malaria-endemic regions, due to overlapping symptoms, suspected COVID-19 patients should also be monitored for diagnosis of malaria without any delay. The SARS-CoV-2 and co-infection could increase the disease severity in a short time span. In treatment, dexamethasone may not help in severe case having malaria as well as COVID-19 positive status and needs further exploration.
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http://dx.doi.org/10.1016/j.bsheal.2021.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084910PMC
April 2021

Glial cell response to Epstein-Barr Virus infection: A plausible contribution to virus-associated inflammatory reactions in the brain.

Virology 2021 Jul 21;559:182-195. Epub 2021 Apr 21.

Infection Bio-engineering Group, Discipline of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, India. Electronic address:

Epstein-Barr Virus (EBV) is clinically related to various neurological ailments. The manipulation of neural homeostasis through altered glial cells functions is enigmatic. We investigated EBV mediated nuances in glial cells through direct infection (group-1) or by supplementing them with EBV-infected lymphocytes (PBMCs) supernatant (group-3). Also, the cells were co-cultured with infected PBMCs (group-2). Upon confirmation of infection in U-87 MG through qRT-PCR, the gene expression of crucial molecules was analysed. We reported enhanced expression of IL6 in group-1 and 3 unlike group-2. PBMCs migrated and invaded the matrigel significantly when exposed to group-1 and 3 conditions. Thus, EBV may aid neuroinflammatory reactions through PBMCs infiltration. Also, the exposure of neurons to conditioned supernatant from group-2 caused reduced neuronal healing. Additionally, group-1 milieu contained chemical modulators that induced glial cells death and reduced NF-κB. Conclusively, the three modes of EBV infection can influence glial cells' functions to maneuver the microenvironment distinctly.
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http://dx.doi.org/10.1016/j.virol.2021.04.005DOI Listing
July 2021

A comparative analysis of COVID-19 outbreak on age groups and both the sexes of population from India and other countries.

J Infect Dev Ctries 2021 03 31;15(3):333-341. Epub 2021 Mar 31.

Discipline of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, India.

Introduction: The study of epidemiological outcomes of COVID-19 in the affected countries needs to be conducted to implement an effective strategy.

Methodology: Our study included age and sex-based analysis of epidemiological data of infected and deceased patients from various countries. The patient data was graphically depicted with the slope's calculation to describe a gradual or steep spread of the disease along with subsequent rise or fall in the death reports.

Results: Population groups of 20-49 years of age and 50 years-above were highly vulnerable to infection. Interestingly, 20-49 years of age group was most affected in India. However, higher population of the deceased were reported in the 50 years-above in all countries. India and South Korea demonstrated a gradual appearance of COVID-19 positive cases than other countries illustrated by reduced slope %. Further the highest percentage of infected people and deaths were reported from the densely populated states of India. We observed a sex independent prevalence of COVID-19. The BCG and JE vaccine are unique in the vaccination regime of India and South Korea.

Conclusions: Reduced ACE-2 expression in the children's nasal epithelium may be responsible for reduced SARS-CoV-2 susceptibility. Countries showed varying patterns in COVID-19 spread and associated mortality. It may be influenced by factors, such as screening strategy, countries demography, implementation of lockdown, etc. Due to limited evidence, it would be difficult to point to the influence of the virus on either sexes. Although vaccines may stimulate non-specific immunity, experimental proofs are needed to demonstrate the potential of any vaccine against SARS-CoV-2.
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http://dx.doi.org/10.3855/jidc.13698DOI Listing
March 2021

Mutational analysis of structural proteins of SARS-CoV-2.

Heliyon 2021 Mar 20;7(3):e06572. Epub 2021 Mar 20.

Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Indore, India.

SARS-CoV-2 transmissibility is higher than that of other human coronaviruses; therefore, it poses a threat to the populated communities. We investigated mutations among envelope (E), membrane (M), and spike (S) proteins from different isolates of SARS-CoV-2 and plausible signaling influenced by mutated virus in a host. We procured updated protein sequences from the NCBI virus database. Mutations were analyzed in the retrieved sequences of the viral proteins through multiple sequence alignment. Additionally, the data was subjected to ScanPROSITE to analyse if the mutations generated a relevant sequence for host signaling. Unique mutations in E, M, and S proteins resulted in modification sites like PKC phosphorylation and N-myristoylation sites. Based on structural analysis, our study revealed that the D614G mutation in the S protein diminished the interaction with T859 and K854 of adjacent chains. Moreover, the S protein of SARS-CoV-2 consists of an Arg-Gly-Asp (RGD) tripeptide sequence, which could potentially interact with various members of integrin family receptors. RGD sequence in S protein might aid in the initial virus attachment. We speculated crucial host pathways which the mutated isolates of SARS-CoV-2 may alter like PKC, Src, and integrin mediated signaling pathways. PKC signaling is known to influence the caveosome/raft pathway which is critical for virus entry. Additionally, the myristoylated proteins might activate NF-κB, a master molecule of inflammation. Thus the mutations may contribute to the disease pathogenesis and distinct lung pathophysiological changes. Further the frequently occurring mutations in the protein can be studied for possible therapeutic interventions.
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http://dx.doi.org/10.1016/j.heliyon.2021.e06572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980187PMC
March 2021

An Update on Antiviral Therapy Against SARS-CoV-2: How Far Have We Come?

Front Pharmacol 2021 8;12:632677. Epub 2021 Mar 8.

Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Indore, India.

COVID-19 pandemic has spread worldwide at an exponential rate affecting millions of people instantaneously. Currently, various drugs are under investigation to treat an enormously increasing number of COVID-19 patients. This dreadful situation clearly demands an efficient strategy to quickly identify drugs for the successful treatment of COVID-19. Hence, drug repurposing is an effective approach for the rapid discovery of frontline arsenals to fight against COVID-19. Successful application of this approach has resulted in the repurposing of some clinically approved drugs as potential anti-SARS-CoV-2 candidates. Several of these drugs are either antimalarials, antivirals, antibiotics or corticosteroids and they have been repurposed based on their potential to negate virus or reduce lung inflammation. Large numbers of clinical trials have been registered to evaluate the effectiveness and clinical safety of these drugs. Till date, a few clinical studies are complete and the results are primary. WHO also conducted an international, multi-country, open-label, randomized trials-a solidarity trial for four antiviral drugs. However, solidarity trials have few limitations like no placebos were used, additionally any drug may show effectiveness for a particular population in a region which may get neglected in solidarity trial analysis. The ongoing randomized clinical trials can provide reliable long-term follow-up results that will establish both clinical safety and clinical efficacy of these drugs with respect to different regions, populations and may aid up to worldwide COVID-19 treatment research. This review presents a comprehensive update on majorly repurposed drugs namely chloroquine, hydroxychloroquine, remdesivir, lopinavir-ritonavir, favipiravir, ribavirin, azithromycin, umifenovir, oseltamivir as well as convalescent plasma therapy used against SARS-CoV-2. The review also summarizes the data recorded on the mechanism of anti-SARS-CoV-2 activity of these repurposed drugs along with the preclinical and clinical findings, therapeutic regimens, pharmacokinetics, and drug-drug interactions.
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http://dx.doi.org/10.3389/fphar.2021.632677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982669PMC
March 2021

The interrelation of COVID-19 and neurological modalities.

Neurol Sci 2021 06 12;42(6):2157-2160. Epub 2021 Mar 12.

Infection Bio-engineering Group, Discipline of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Indore, Madhya Pradesh, 453552, India.

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http://dx.doi.org/10.1007/s10072-021-05177-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953374PMC
June 2021

A review of the presence of SARS-CoV-2 RNA in wastewater and airborne particulates and its use for virus spreading surveillance.

Environ Res 2021 05 25;196:110929. Epub 2021 Feb 25.

LAR(5) Laboratory - Dipartimento di Ingegneria - University of Perugia, via G. Duranti 93, 06125, Perugia, Italy. Electronic address:

According to the WHO, on October 16, 2020, the spreading of the SARS-CoV-2, responsible for the COVID-19 pandemic, reached 235 countries and territories, and resulting in more than 39 million confirmed cases and 1.09 million deaths globally. Monitoring of the virus outbreak is one of the main activities pursued to limiting the number of infected people and decreasing the number of deaths that have caused high pressure on the health care, social, and economic systems of different countries. Wastewater based epidemiology (WBE), already adopted for the surveillance of life style and health conditions of communities, shows interesting features for the monitoring of the COVID-19 diffusion. Together with wastewater, the analysis of airborne particles has been recently suggested as another useful tool for detecting the presence of SARS-CoV-2 in given areas. The present review reports the status of research currently performed concerning the monitoring of SARS-CoV-2 spreading by WBE and airborne particles. The former have been more investigated, whereas the latter is still at a very early stage, with a limited number of very recent studies. Nevertheless, the main results highlights in both cases necessitate more research activity for better understating and defining the biomarkers and the related sampling and analysis procedures to be used for this important aim.
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http://dx.doi.org/10.1016/j.envres.2021.110929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906514PMC
May 2021

Correction for Pei et al., "Epstein-Barr Virus Facilitates Expression of KLF14 by Regulating the Cooperative Binding of the E2F-Rb-HDAC Complex in Latent Infection".

J Virol 2021 Jan 28;95(4). Epub 2021 Jan 28.

Department of Otorhinolaryngology-Head and Neck Surgery, and Microbiology, the Tumor Virology Program, Abramson Comprehensive Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA

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http://dx.doi.org/10.1128/JVI.02197-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851551PMC
January 2021

analysis of antiviral phytochemicals efficacy against Epstein-Barr virus glycoprotein H.

J Biomol Struct Dyn 2021 Jan 13:1-14. Epub 2021 Jan 13.

Discipline of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Indore, India.

Epstein-Barr virus is a tumor-associated, enveloped virus with glycoprotein receptor gHgL on its surface. gH attaches to epithelial or B cells and mediates internalization. Till date, no specific anti-EBV FDA approved drug is available. Targeting gH may aid in designing virus-specific therapeutics and reducing the drug induced complications in host. We investigated the influence of antiviral phytochemicals on gH using computational approaches. Through molecular docking, we performed binding energy analysis of cellocidin, bruceantin, EGCG, formononetin and sesquiterpene lactones with gH DII/DIII interface, crucial for gH functions. Further, to cause any perturbations in the protein function, the molecules must bind stably to gH. Bruceantin and EGCG interacted with high affinities to gH. Simulation of these two molecules revealed stable binding with gH throughout 100 ns moreover, van der Waal interactions stabilized overall binding. Mutation of amino acids like V265, L269, L315, I423, I459, L474 and F475 involved in stable binding to gH was predicted deleterious to protein function. We obtained no difference in RMSD between these two ligands and minor deviations in the RMSF were noticed compared to gH. Conclusively, our study provided insights into the potential of bruceantin and EGCG to target gH. Different amino acids are involved in binding of each ligand to gH, engagement of certain amino acids may affect the virus binding with epithelial or B cells. The interaction of the ligand with gH may trap it in its native conformation or induce structural flexibility thereby inhibiting the interaction with host receptors or other glycoproteins.Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2020.1871074DOI Listing
January 2021

Erratum for Jha et al., "Gammaherpesvirus Infection of Human Neuronal Cells".

mBio 2021 Jan 5;12(1). Epub 2021 Jan 5.

Department of Microbiology and the Tumor Virology Program, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA

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http://dx.doi.org/10.1128/mBio.02981-20DOI Listing
January 2021

Epstein-Barr virus infection modulates blood-brain barrier cells and its co-infection with Plasmodium falciparum induces RBC adhesion.

Pathog Dis 2021 01;79(1)

Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Indore 453552, India.

Plasmodium falciparum infection-mediated Epstein-Barr virus (EBV) reactivation is well established in malaria-endemic countries. We hypothesize that, during malaria onset, the reactivated EBV can infect human brain microvascular endothelial cells (HBECs). This may cause severe cerebral manifestations. We infected HBECs with EBV in vitro. The subsequent gene expression pattern of EBV, inflammatory and endothelial markers was analysed using qRT-PCR. Further, a wound-healing assay for cells maintaining blood-brain barrier (BBB) integrity was performed to investigate the effect of EBV-infected HBECs secretions. The RBC adhesion assay was conducted to assess RBC attachment onto HBECs during EBV and P. falciparum mono- and co-infection. Our experiments revealed that EBV infection of HBECs significantly elevated several inflammatory (TNFα, CCL2) and endothelial (integrin β3, PECAM, VEGFA, VWF, claudin-5, cx37) markers. The EBV-infected HBECs secretion significantly reduced migration of HBECs, glial and neuronal cells. Additionally, EBV-P. falciparum co-infection significantly (P < 0.05) enhanced RBC adhesion to HBECs compared to mono-infection scenarios. Conclusively, the EBV infection of HBECs led to endothelial activation and modulated the BBB microenvironment. The EBV-P. falciparum co-infection scenario increased RBC adhesion on ECs which is a hallmark of cerebral malaria. Together with malaria, EBV infection can aid in exacerbation of cerebral malaria pathology.
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http://dx.doi.org/10.1093/femspd/ftaa080DOI Listing
January 2021

Recent updates on COVID-19: A holistic review.

Heliyon 2020 Dec 11;6(12):e05706. Epub 2020 Dec 11.

Discipline of Biosciences and Biomedical Engineering, Indian Institute of Technology, Indore, India.

Coronaviruses are large positive-sense RNA viruses with spike-like peplomers on their surface. The family's strains infect different animals and are popularly associated with several outbreaks, namely SARS and MERS epidemic. COVID-19 is one such recent outbreak caused by SARS-CoV-2 identified first in Wuhan, China. COVID-19 was declared a pandemic by WHO on 11 March 2020. Our review provides information covering various facets of the disease starting from its origin, transmission, mutations in the virus to pathophysiological changes in the host upon infection followed by diagnostics and possible therapeutics available to tackle the situation. We have highlighted the zoonotic origin of SARS-CoV-2, known to share 96.2% nucleotide similarity with bat coronavirus. Notably, several mutations in SARS-CoV-2 spike protein, nucleocapsid protein, PLpro, and ORF3a are reported across the globe. These mutations could alter the usual receptor binding function, fusion process with the host cell, virus replication, and the virus's assembly. Therefore, studying these mutations could help understand the virus's virulence properties and design suitable therapeutics. Moreover, the aggravated immune response to COVID-19 can be fatal. Hypertension, diabetes, and cardiovascular diseases are comorbidities substantially associated with SARS-CoV-2 infection. The review article discusses these aspects, stating the importance of various comorbidities in disease outcomes. Furthermore, medications' unavailability compels the clinicians to opt for atypical drugs like remdesivir, chloroquine, etc. The current diagnostics of COVID-19 include qRT-PCR, CT scan, serological tests, etc. We have described these aspects to expose the information to the scientific community and to accelerate the research.
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http://dx.doi.org/10.1016/j.heliyon.2020.e05706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7729279PMC
December 2020

Erratum for Pandey et al., "Epigenetic Regulation of Tumor Suppressors by Helicobacter pylori Enhances EBV-Induced Proliferation of Gastric Epithelial Cells".

mBio 2020 Dec 15;11(6). Epub 2020 Dec 15.

Departments of Otorhinolaryngology-Head and Neck Surgery, and Microbiology, the Tumor Virology Program, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA

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http://dx.doi.org/10.1128/mBio.03074-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773999PMC
December 2020

Temporal Raman Spectroscopy for Monitoring Replication Kinetics of Epstein-Barr Virus Infection in Glial Cells.

ACS Omega 2020 Nov 4;5(45):29547-29560. Epub 2020 Nov 4.

Discipline of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Simrol, 453552 Indore, India.

Raman spectroscopy can be used as a tool to study virus entry and pathogen-driven manipulation of the host efficiently. To date, Epstein-Barr virus (EBV) entry and altered biochemistry of the glial cell upon infection are elusive. In this study, we detected biomolecular changes in human glial cells, namely, HMC-3 (microglia) and U-87 MG (astrocytes), at two variable cellular locations (nucleus and periphery) by Raman spectroscopy post-EBV infection at different time points. Two possible phenomena, one attributed to the response of the cell to viral attachment and invasion and the other involved in duplication of the virus followed by egress from the host cell, are investigated. These changes corresponded to unique Raman spectra associated with specific biomolecules in the infected and the uninfected cells. The Raman signals from the nucleus and periphery of the cell also varied, indicating differential biochemistry and signaling processes involved in infection progression at these locations. Molecules such as cholesterol, glucose, hyaluronan, phenylalanine, phosphoinositide, etc. are associated with the alterations in the cellular biochemical homeostasis. These molecules are mainly responsible for cellular processes such as lipid transport, cell proliferation, differentiation, and apoptosis in the cells. Raman signatures of these molecules at distinct time points of infection indicated their periodic involvement, depending on the stage of virus infection. Therefore, it is possible to discern the details of variability in EBV infection progression in glial cells at the biomolecular level using time-dependent Raman scattering.
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http://dx.doi.org/10.1021/acsomega.0c04525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7676301PMC
November 2020

Impact of Gastrointestinal Symptoms in COVID-19: a Molecular Approach.

SN Compr Clin Med 2020 Nov 4:1-12. Epub 2020 Nov 4.

Infection Bioengineering Group, Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Simrol, Madhya Pradesh 453552 Indore, India.

The pandemic of novel coronavirus disease (COVID-19) caused by the Severe Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) creates an immense menace to public health worldwide. Currently, the World Health Organization (WHO) has recognized the novel coronavirus as the main cause of global pandemic. Patients infected with this virus generally show fever, nausea, and respiratory illness, while some patients also manifest gastrointestinal symptoms such as abdominal pain, vomiting, and diarrhea. Traces of SARS-CoV-2 RNA have been found in gastrointestinal cells. Further angiotensin converting enzyme 2 (ACE2) the known receptor for the virus is extensively expressed in these cells. This implies that gastrointestinal tract can be infected and can also present them as a replication site for SARS-CoV-2, but since this infection may lead to multiple organ failure, therefore identification of another receptor is a plausible choice. This review aims to provide comprehensive information about probable receptors such as sialic acid and CD147 which may facilitate the virus entry. Several potential targets are mentioned which can be used as a therapeutic approach for COVID-19 and associated GI disorders. The gut microbiomes are responsible for high levels of interferon-gamma which causes hyper-inflammation and exacerbates the severity of the disease. Briefly, this article highlights the gut microbiome's relation and provides potential diagnostic approaches like RDT and LC-MS for sensitive and specific identification of viral proteins. Altogether, this article reviews epidemiology, probable receptors and put forward the tentative ideas of the therapeutic targets and diagnostic methods for COVID-19 with gastrointestinal aspect of disease.
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http://dx.doi.org/10.1007/s42399-020-00619-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609378PMC
November 2020

SARS-CoV-2, an Underestimated Pathogen of the Nervous System.

SN Compr Clin Med 2020 Sep 28:1-10. Epub 2020 Sep 28.

Infection Bio-engineering Group, Discipline of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Lab No. 302, School Building, Indore, Madhya Pradesh 453552 India.

Numerous clinical studies have reported neurological symptoms in COVID-19 patients since the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), apart from the atypical signs of pneumonia. Angiotensin-converting enzyme-2 (ACE-2), a potential receptor for SARS-CoV-2 entry, is expressed on various brain cells and cerebral parts, i.e., subfornical organ, paraventricular nucleus, nucleus of the tractus solitarius, and rostral ventrolateral medulla, as well as in non-cardiovascular areas such as the motor cortex and raphe. The resident CNS cells like astrocytes and microglia also express ACE-2, thus highlighting the vulnerability of the nervous system to SARS-CoV-2 infection. Additionally, transmembrane serine protease 2 (TMPRSS2) and furin facilitate virus entry into the host. Besides, the probable routes of virus entry into the nervous system include the hematogenic pathway, through the vagus, the olfactory nerve, or the enteric nervous system. However, the trajectory of SARS-CoV-2 to the brain needs investigation. Furthermore, a Th17-mediated cytokine storm is seen in COVID-19 cases with higher levels of IL-1β/2/7/8/9/10/17, GM-CSF, IFN-γ, TNF-α, CXCL-10, MCP1, and MIP1α/β. Some cytokines can cross the blood-brain barrier and activate the brain's immune cells to produce neural cytokines, leading to neuronal dysfunctions. Nonetheless, most of the neurological conditions developed due to viral infections may not have effective and registered treatments. Although, some antivirals may inhibit the virus-mediated pathogenesis and prove to be suitable in COVID-19 treatment. Therefore, clinicians' and researchers' collective expertise may unravel the potential of SARS-CoV-2 infection to prevent short-term and long-term CNS damage.
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http://dx.doi.org/10.1007/s42399-020-00522-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7520376PMC
September 2020

Status of kinases in Epstein-Barr virus and Helicobacter pylori Coinfection in gastric Cancer cells.

BMC Cancer 2020 Sep 29;20(1):925. Epub 2020 Sep 29.

The Discipline of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Room no. 302, School Building, IIT Indore, Khandwa Road, Simrol, Indore, 453552, India.

Background: Helicobacter pylori (H. pylori) and Epstein - Barr virus (EBV) plays a significant role in aggressive gastric cancer (GC). The investigation of genes associated with these pathogens and host kinases may be essential to understand the early and dynamic progression of GC.

Aim: The study aimed to demonstrate the coinfection of EBV and H. pylori in the AGS cells through morphological changes, expression of the kinase and the probable apoptotic pathways.

Methods: Genomic DNA isolation of H. pylori and its characterization from clinical samples were performed. RT-qPCR of kinases was applied to scrutinize the gene expression of kinases in co-infected GC in a direct and indirect (separated through insert size 0.45 μm) H. pylori infection set up. Morphological changes in co-infected GC were quantified by measuring the tapering ends of gastric epithelial cells. Gene expression profiling of apoptotic genes was assessed through RT-qPCR.

Results: An interleukin-2-inducible T-cell kinase (ITK) showed significant upregulation with indirect H. pylori infection. Moreover, Ephrin type-B receptor six precursors (EPHB6) and Tyrosine-protein kinase Fyn (FYN) showed significant upregulation with direct coinfection. The tapering ends in AGS cells were found to be extended after 12 h. A total of 24 kinase genes were selected, out of which EPHB6, ITK, FYN, and TYK2 showed high expression as early as 12 h. These kinases may lead to rapid morphological changes in co-infected gastric cells. Likewise, apoptotic gene expression such as APAF-1 and Bcl2 family genes such as BAD, BID, BIK, BIM, BAX, AND BAK were significantly down-regulated in co-infected AGS cells.

Conclusion: All the experiments were performed with novel isolates of H. pylori isolated from central India, for the functional assessment of GC. The effect of coinfection with EBV was more profoundly observed on morphological changes in AGS cells at 12 h as quantified by measuring the tapering of ends. This study also identifies the kinase and apoptotic genes modulated in co-infected cells, through direct and indirect approaches. We report that ITK, EPHB6, TYK2, FYN kinase are enhanced, whereas apoptotic genes such as APAF-1, BIK, FASL, BAX are significantly down-regulated in AGS cells coinfected with EBV and H. pylori.
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http://dx.doi.org/10.1186/s12885-020-07377-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523314PMC
September 2020

Comorbidity Assessment Is Essential During COVID-19 Treatment.

Front Physiol 2020 4;11:984. Epub 2020 Aug 4.

Discipline of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Indore, India.

Coronavirus disease 2019 (COVID-19) caused by SARS-CoV2 is associated with various comorbidities; cardiovascular diseases, hypertension, diabetes, liver, lung diseases, and neurological ailments. The majority of the dysfunctions mentioned above are often associated with endothelial deterioration, indicating that endothelium can be the target of SARS-CoV2. Our study is an exclusive observational study that quantitatively analyses COVID-19 related comorbidities. We retrieved the data of % population of COVID-19 hospitalized and deceased patients with associated comorbidities from publicly accessible portals of the five European countries. A two tailed -test enabled us to determine the significant proportions of deaths compared to hospitalized patients with associated comorbidity. Our study revealed that deaths associated with cardiovascular diseases and diabetes are highly significant ( < 0.0001) compared to hospitalized in countries like Italy, France, and Spain unlike the Netherlands. Deaths from kidney diseases (Italy- < 0.0001; Sweden- < 0.0001; Netherlands- = 0.0001; France- = 0.0033) and neurological ailments (France- = 0.0001; Netherlands- < 0.0001) are significantly higher than the total hospitalized patients affected by the particular comorbidity. We have noted that deaths due to liver diseases are least associated with COVID-19 among all comorbidities. Intriguingly, immunodeficiency shows mixed outcomes in death proportions compared to the hospital admitted individuals. Besides, the treatment regime involves drugs like losartan, ACE inhibitors, angiotensin-receptor blockers, Remdesivir, Chloroquine, Hydroxychloroquine, etc. may modulate the severity of the comorbidities. These comorbidities can create chaos in the existing healthcare system and may worsen the disease outcome.
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http://dx.doi.org/10.3389/fphys.2020.00984DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7438844PMC
August 2020

Epstein-Barr Virus Facilitates Expression of KLF14 by Regulating the Cooperative Binding of the E2F-Rb-HDAC Complex in Latent Infection.

J Virol 2020 10 27;94(22). Epub 2020 Oct 27.

Department of Otorhinolaryngology-Head and Neck Surgery, and Microbiology, the Tumor Virology Program, Abramson Comprehensive Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA

Epstein-Barr virus (EBV) was discovered as the first human tumor virus more than 50 years ago. EBV infects more than 90% of the human population worldwide and is associated with numerous hematologic malignancies and epithelial malignancies. EBV establishes latent infection in B cells, which is the typical program seen in lymphomagenesis. Understanding EBV-mediated transcription regulatory networks is one of the current challenges that will uncover new insights into the mechanism of viral-mediated lymphomagenesis. Here, we describe the regulatory profiles of several cellular factors (E2F6, E2F1, Rb, HDAC1, and HDAC2) together with EBV latent nuclear antigens using next-generation sequencing (NGS) analysis. Our results show that the E2F-Rb-HDAC complex exhibits similar distributions in genomic regions of EBV-positive cells and is associated with oncogenic super-enhancers involving long-range regulatory regions. Furthermore, EBV latent antigens cooperatively hijack this complex to bind at KLFs gene loci and facilitate gene expression in lymphoblastoid cell lines (LCLs). These results demonstrate that EBV latent antigens can function as master regulators of this multisubunit repressor complex (E2F-Rb-HDAC) to reverse its suppressive activities and facilitate downstream gene expression that can contribute to viral-induced lymphomagenesis. These results provide novel insights into targets for the development of new therapeutic interventions for treating EBV-associated lymphomas. Epstein-Barr virus (EBV), as the first human tumor virus, infects more than 90% of the human population worldwide and is associated with numerous human cancers. Exploring EBV-mediated transcription regulatory networks is critical to understand viral-associated lymphomagenesis. However, the detailed mechanism is not fully explored. Now we describe the regulatory profiles of the E2F-Rb-HDAC complex together with EBV latent antigens, and we found that EBV latent antigens cooperatively facilitate KLF14 expression by antagonizing this multisubunit repressor complex in EBV-positive cells. This provides potential therapeutic targets for the treatment of EBV-associated cancers.
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http://dx.doi.org/10.1128/JVI.01209-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592212PMC
October 2020

Quassinoid analogs with enhanced efficacy for treatment of hematologic malignancies target the PI3Kγ isoform.

Commun Biol 2020 05 27;3(1):267. Epub 2020 May 27.

Departments of Otorhinolaryngology-Head and Neck Surgery, and Microbiology, and the Tumor Virology Program, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.

Development of novel PI3K inhibitors is an important strategy to overcome their resistance and poor tolerability in clinical trials. The quassinoid family member Brusatol shows specific inhibitory activity against hematologic malignancies. However, the mechanism of its anti-cancer activity is unknown. We investigated the anti-cancer activity of Brusatol on multiple hematologic malignancies derived cell lines. The results demonstrated that the PI3Kγ isoform was identified as a direct target of Brusatol, and inhibition was dramatically reduced on cells with lower PI3Kγ levels. Novel synthetic analogs were also developed and tested in vitro and in vivo. They shared comparable or superior potency in their ability to inhibit malignant hematologic cell lines, and in a xenograft transplant mouse model. One unique analog had minimal toxicity to normal human cells and in a mouse model. These new analogs have enhanced potential for development as a new class of PI3K inhibitors for treatment of hematologic malignancies.
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http://dx.doi.org/10.1038/s42003-020-0996-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253423PMC
May 2020

Shugoshin 1 is dislocated by KSHV-encoded LANA inducing aneuploidy.

PLoS Pathog 2018 09 13;14(9):e1007253. Epub 2018 Sep 13.

Departments of Otorhinolaryngology-Head and Neck Surgery, and Microbiology, the Tumor Virology Program, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States of America.

Shugoshin-1 (Sgo1) protects the integrity of the centromeres, and H2A phosphorylation is critical for this process. The mitotic checkpoint kinase Bub1, phosphorylates H2A and ensures fidelity of chromosome segregation and chromosome number. Oncogenic KSHV induces genetic alterations through chromosomal instability (CIN), and its essential antigen LANA regulates Bub1. We show that LANA inhibits Bub1 phosphorylation of H2A and Cdc20, important for chromosome segregation and mitotic signaling. Inhibition of H2A phosphorylation at residue T120 by LANA resulted in dislocation of Sgo1, and cohesin from the centromeres. Arrest of Cdc20 phosphorylation also rescued degradation of Securin and Cyclin B1 at mitotic exit, and interaction of H2A, and Cdc20 with Bub1 was inhibited by LANA. The N-terminal nuclear localization sequence domain of LANA was essential for LANA and Bub1 interaction, reversed LANA inhibited phosphorylation of H2A and Cdc20, and attenuated LANA-induced aneuploidy and cell proliferation. This molecular mechanism whereby KSHV-induced CIN, demonstrated that the NNLS of LANA is a promising target for development of anti-viral therapies targeting KSHV associated cancers.
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http://dx.doi.org/10.1371/journal.ppat.1007253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6136811PMC
September 2018

Metabolic reprogramming of Kaposi's sarcoma associated herpes virus infected B-cells in hypoxia.

PLoS Pathog 2018 05 10;14(5):e1007062. Epub 2018 May 10.

Departments of Otorhinolaryngology-Head and Neck Surgery and Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America.

Kaposi's sarcoma associated herpesvirus (KSHV) infection stabilizes hypoxia inducible factors (HIFs). The interaction between KSHV encoded factors and HIFs plays a critical role in KSHV latency, reactivation and associated disease phenotypes. Besides modulation of large-scale signaling, KSHV infection also reprograms the metabolic activity of infected cells. However, the mechanism and cellular pathways modulated during these changes are poorly understood. We performed comparative RNA sequencing analysis on cells with stabilized hypoxia inducible factor 1 alpha (HIF1α) of KSHV negative or positive background to identify changes in global and metabolic gene expression. Our results show that hypoxia induces glucose dependency of KSHV positive cells with high glucose uptake and high lactate release. We identified the KSHV-encoded vGPCR, as a novel target of HIF1α and one of the main viral antigens of this metabolic reprogramming. Bioinformatics analysis of vGPCR promoter identified 9 distinct hypoxia responsive elements which were activated by HIF1α in-vitro. Expression of vGPCR alone was sufficient for induction of changes in the metabolic phenotype similar to those induced by KSHV under hypoxic conditions. Silencing of HIF1α rescued the hypoxia associated phenotype of KSHV positive cells. Analysis of the host transcriptome identified several common targets of hypoxia as well as KSHV encoded factors and other synergistically activated genes belonging to cellular pathways. These include those involved in carbohydrate, lipid and amino acids metabolism. Further DNA methyltranferases, DNMT3A and DNMT3B were found to be regulated by either KSHV, hypoxia, or both synergistically at the transcript and protein levels. This study showed distinct and common, as well as synergistic effects of HIF1α and KSHV-encoded proteins on metabolic reprogramming of KSHV-infected cells in the hypoxia.
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http://dx.doi.org/10.1371/journal.ppat.1007062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5963815PMC
May 2018

Epigenetic Regulation of Tumor Suppressors by Enhances EBV-Induced Proliferation of Gastric Epithelial Cells.

mBio 2018 04 24;9(2). Epub 2018 Apr 24.

Departments of Otorhinolaryngology-Head and Neck Surgery, and Microbiology, the Tumor Virology Program, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA

and Epstein-Barr virus (EBV) are two well-known contributors to cancer and can establish lifelong persistent infection in the host. This leads to chronic inflammation, which also contributes to development of cancer. Association with increases the risk of gastric carcinoma, and coexistence with EBV enhances proliferation of infected cells. Further, -EBV coinfection causes chronic inflammation in pediatric patients. We have established an -EBV coinfection model system using human gastric epithelial cells. We showed that infection can increase the oncogenic phenotype of EBV-infected cells and that the cytotoxin-associated gene (CagA) protein encoded by stimulated EBV-mediated cell proliferation in this coinfection model system. This led to increased expression of DNA methyl transferases (DNMTs), which reprogrammed cellular transcriptional profiles, including those of tumor suppressor genes (TSGs), through hypermethylation. These findings provide new insights into a molecular mechanism whereby cooperativity between two oncogenic agents leads to enhanced oncogenic activity of gastric cancer cells. We have studied the cooperativity between and EBV, two known oncogenic agents. This led to an enhanced oncogenic phenotype in gastric epithelial cells. We now demonstrate that EBV-driven epigenetic modifications are enhanced in the presence of , more specifically, in the presence of its CagA secretory antigen. This results in increased proliferation of the infected gastric cells. Our findings now elucidate a molecular mechanism whereby expression of cellular DNA methyl transferases is induced influencing infection by EBV. Hypermethylation of the regulatory genomic regions of tumor suppressor genes results in their silencing. This drastically affects the expression of cell cycle, apoptosis, and DNA repair genes, which dysregulates their associated processes, and promotion of the oncogenic phenotype.
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http://dx.doi.org/10.1128/mBio.00649-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5915740PMC
April 2018

An essential EBV latent antigen 3C binds Bcl6 for targeted degradation and cell proliferation.

PLoS Pathog 2017 Jul 24;13(7):e1006500. Epub 2017 Jul 24.

Department of Otorhinolaryngology-Head and Neck Surgery, and Microbiology, the Tumor Virology Program, Abramson Comprehensive Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.

The latent EBV nuclear antigen 3C (EBNA3C) is required for transformation of primary human B lymphocytes. Most mature B-cell malignancies originate from malignant transformation of germinal center (GC) B-cells. The GC reaction appears to have a role in malignant transformation, in which a major player of the GC reaction is Bcl6, a key regulator of this process. We now demonstrate that EBNA3C contributes to B-cell transformation by targeted degradation of Bcl6. We show that EBNA3C can physically associate with Bcl6. Notably, EBNA3C expression leads to reduced Bcl6 protein levels in a ubiquitin-proteasome dependent manner. Further, EBNA3C inhibits the transcriptional activity of the Bcl6 promoter through interaction with the cellular protein IRF4. Bcl6 degradation induced by EBNA3C rescued the functions of the Bcl6-targeted downstream regulatory proteins Bcl2 and CCND1, which resulted in increased proliferation and G1-S transition. These data provide new insights into the function of EBNA3C in B-cell transformation during GC reaction, and raises the possibility of developing new targeted therapies against EBV-associated cancers.
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http://dx.doi.org/10.1371/journal.ppat.1006500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5524291PMC
July 2017

Status of Epstein-Barr Virus Coinfection with in Gastric Cancer.

J Oncol 2017 21;2017:3456264. Epub 2017 Mar 21.

Centre for Biosciences and Biomedical Engineering, Indian Institute of Technology, Indore, India.

Epstein-Barr virus is a ubiquitous human herpesvirus whose primary infection causes mononucleosis, Burkett's lymphoma, nasopharyngeal carcinoma, autoimmune diseases, and gastric cancer (GC). The persistent infection causes malignancies in lymph and epithelial cells. causes gastritis in human with chronic inflammation. This chronic inflammation is thought to be the cause of genomic instability. About 45%-word population have a probability of having both pathogens, namely, and EBV. Approximately 180 per hundred thousand population is developing GC along with many gastric abnormalities. This makes GC the third leading cause of cancer-related death worldwide. Although lots of research are carried out individually for EBV and , still there are very few reports available on coinfection of both pathogens. Recent studies suggested that EBV and coinfection increases the occurrence of GC as well as the early age of GC detection comparing to individual infection. The aim of this review is to present status on coinfection of both pathogens and their association with GC.
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http://dx.doi.org/10.1155/2017/3456264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5379099PMC
March 2017

EBV Nuclear Antigen 3C Mediates Regulation of E2F6 to Inhibit E2F1 Transcription and Promote Cell Proliferation.

PLoS Pathog 2016 08 22;12(8):e1005844. Epub 2016 Aug 22.

Department of Otorhinolaryngology-Head and Neck Surgery, and the Tumor Virology Program, Abramson Comprehensive Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.

Epstein-Barr virus (EBV) is considered a ubiquitous herpesvirus with the ability to cause latent infection in humans worldwide. EBV-association is evidently linked to different types of human malignancies, mainly of epithelial and lymphoid origin. Of interest is the EBV nuclear antigen 3C (EBNA3C) which is critical for EBV-mediated immortalization. Recently, EBNA3C was shown to bind the E2F1 transcription regulator. The E2F transcription factors have crucial roles in various cellular functions, including cell cycle, DNA replication, DNA repair, cell mitosis, and cell fate. Specifically, E2F6, one of the unique E2F family members, is known to be a pRb-independent transcription repressor of E2F-target genes. In our current study, we explore the role of EBNA3C in regulating E2F6 activities. We observed that EBNA3C plays an important role in inducing E2F6 expression in LCLs. Our study also shows that EBNA3C physically interacts with E2F6 at its amino and carboxy terminal domains and they form a protein complex in human cells. In addition, EBNA3C stabilizes the E2F6 protein and is co-localized in the nucleus. We also demonstrated that both EBNA3C and E2F6 contribute to reduction in E2F1 transcriptional activity. Moreover, E2F1 forms a protein complex with EBNA3C and E2F6, and EBNA3C competes with E2F1 for E2F6 binding. E2F6 is also recruited by EBNA3C to the E2F1 promoter, which is critical for EBNA3C-mediated cell proliferation. These results demonstrate a critical role for E2F family members in EBV-induced malignancies, and provide new insights for targeting E2F transcription factors in EBV-associated cancers as potential therapeutic intervention strategies.
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http://dx.doi.org/10.1371/journal.ppat.1005844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4993364PMC
August 2016

Major Histocompatibility Complex Class II HLA-DRα Is Downregulated by Kaposi's Sarcoma-Associated Herpesvirus-Encoded Lytic Transactivator RTA and MARCH8.

J Virol 2016 09 26;90(18):8047-58. Epub 2016 Aug 26.

Department of Otorhinolaryngology-Head and Neck Surgery and Tumor Virology Program, Abramson Comprehensive Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA

Unlabelled: Kaposi's sarcoma-associated herpesvirus (KSHV) maintains two modes of life cycle, the latent and lytic phases. To evade the attack of the cell host's immune system, KSHV switches from the lytic to the latent phase, a phase in which only a few of viral proteins are expressed. The mechanism by which KSHV evades the attack of the immune system and establishes latency has not been fully understood. Major histocompatibility complex class II (MHC-II) molecules are key components of the immune system defense mechanism against viral infections. Here we report that HLA-DRα, a member of the MHC-II molecules, was downregulated by the replication and transcription activator (RTA) protein encoded by KSHV ORF50, an important regulator of the viral life cycle. RTA not only downregulated HLA-DRα at the protein level through direct binding and degradation through the proteasome pathway but also indirectly downregulated the protein level of HLA-DRα by enhancing the expression of MARCH8, a member of the membrane-associated RING-CH (MARCH) proteins. Our findings indicate that KSHV RTA facilitates evasion of the virus from the immune system through manipulation of HLA-DRα.

Importance: Kaposi's sarcoma-associated herpesvirus (KSHV) has a causal role in a number of human cancers, and its persistence in infected cells is controlled by the host's immune system. The mechanism by which KSHV evades an attack by the immune system has not been well understood. This work represents studies which identify a novel mechanism by which the virus can facilitate evasion of an immune system. We now show that RTA, the replication and transcription activator encoded by KSHV (ORF50), can function as an E3 ligase to degrade HLA-DRα. It can directly bind and induce degradation of HLA-DRα through the ubiquitin-proteasome degradation pathway. In addition to the direct regulation of HLA-DRα, RTA can also indirectly downregulate the level of HLA-DRα protein by upregulating transcription of MARCH8. Increased MARCH8 results in the downregulation of HLA-DRα. Furthermore, we also demonstrate that expression of HLA-DRα was impaired in KSHV de novo infection.
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http://dx.doi.org/10.1128/JVI.01079-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5008100PMC
September 2016

An EBV recombinant deleted for residues 130-159 in EBNA3C can deregulate p53/Mdm2 and Cyclin D1/CDK6 which results in apoptosis and reduced cell proliferation.

Oncotarget 2016 Apr;7(14):18116-34

Department of Otorhinolaryngology and Tumor Virology Program, Abramson Cancer Center, Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA-19104, USA.

Epstein-Barr virus (EBV), a gamma herpes virus is associated with B-cell malignancies. EBNA-3C is critical for in vitro primary B-cell transformation. Interestingly, the N terminal domain of EBNA3C which contains residues 130-159, interacts with various cellular proteins, such as p53, Mdm2, CyclinD1/Cdk6 complex, and E2F1. In the current reverse genetics study, we deleted the residues 130-159 aa within EBNA3C open reading frame (ORF) by BACmid recombinant engineering methodology. Our experiments demonstrated that deletion of the 130-159 aa showed a reduction in cell proliferation. Also, this recombinant virus showed with higher infectivity of human peripheral blood mononuclear cells (PBMCs) compared to wild type EBV. PBMCs- infected with recombinant EBV deleted for 130-159 residues have differential expression patterns for the p53/Mdm2, CyclinD1/Cdk6 and pRb/E2F1 pathways compared to wild type EBV-infected PBMCs. PBMCs infected with recombinant virus showed increased apoptotic cell death which further resulted in activation of polymerase 1 (PARP1), an important contributor to apoptotic signaling. Interestingly, cells infected with this recombinant virus showed a dramatic decrease in chromosomal instability, indicated by the presence of increased multinucleation and micronucleation. In addition infection with recombinant virus have increased cells in G0/G1 phase and decreased cells in S-G2M phase when compared to wild type infected cells. Thus, these differences in signaling activities due to 29 amino acid residues of EBNA3C is of particular significance in deregulation of cell proliferation in EBV-infected cells.
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http://dx.doi.org/10.18632/oncotarget.7502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4951276PMC
April 2016

The Role of Gammaherpesviruses in Cancer Pathogenesis.

Pathogens 2016 Feb 6;5(1). Epub 2016 Feb 6.

Department of Microbiology and Tumor Virology Program, Abramson Comprehensive Cancer Center, Perelman School of Medicine at the University of Pennsylvania, 201E Johnson Pavilion, 3610, Hamilton Walk, Philadelphia, PA 19104, USA.

Worldwide, one fifth of cancers in the population are associated with viral infections. Among them, gammaherpesvirus, specifically HHV4 (EBV) and HHV8 (KSHV), are two oncogenic viral agents associated with a large number of human malignancies. In this review, we summarize the current understanding of the molecular mechanisms related to EBV and KSHV infection and their ability to induce cellular transformation. We describe their strategies for manipulating major cellular systems through the utilization of cell cycle, apoptosis, immune modulation, epigenetic modification, and altered signal transduction pathways, including NF-kB, Notch, Wnt, MAPK, TLR, etc. We also discuss the important EBV latent antigens, namely EBNA1, EBNA2, EBNA3's and LMP's, which are important for targeting these major cellular pathways. KSHV infection progresses through the engagement of the activities of the major latent proteins LANA, v-FLIP and v-Cyclin, and the lytic replication and transcription activator (RTA). This review is a current, comprehensive approach that describes an in-depth understanding of gammaherpes viral encoded gene manipulation of the host system through targeting important biological processes in viral-associated cancers.
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http://dx.doi.org/10.3390/pathogens5010018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4810139PMC
February 2016