Histocompatibility locus antigens regions contribute to the ethnicity bias of Epstein-Barr virus-associated nasopharyngeal carcinoma in higher-incidence populations.

Nasopharyngeal carcinoma (NPC) is one the most confusing and rare malignancy in most part of the world with significantly high occurrence in some populations of Southeast Asia, North Africa and Alaska. Apart from the dietary and environmental factors, NPC is well-associated with Epstein-Barr virus (EBV) infection in these ethnic groups. However, the internal molecular mechanism(s) for such association in specific populations is not known till date. Polymorphisms in the genes of histocompatibility locus antigens (HLA) are reported in NPC, but association of any particular polymorphism with ethnicity is not established yet. Here, we report a set of HLA polymorphisms in EBV-infected NPC samples from Northeast Indian population. These polymorphisms might play an important role for the lack of proper immune function against EBV infection and thus, eventually, for NPC generation in endemic populations like those of Northeast India.

Altered proteome in translation initiation fidelity defective eIF5G31R mutant causes oxidative stress and DNA damage.

The recognition of the AUG start codon and selection of an open reading frame (ORF) is fundamental to protein biosynthesis. Defect in the fidelity of start codon selection adversely affect proteome and have a pleiotropic effect on cellular function. Using proteomic techniques, we identified differential protein abundance in the translation initiation fidelity defective eIF5G31R mutant that initiates translation using UUG codon in addition to the AUG start codon. Consistently, the eIF5G31R mutant altered proteome involved in protein catabolism, nucleotide biosynthesis, lipid biosynthesis, carbohydrate metabolism, oxidation-reduction pathway, autophagy and re-programs the cellular pathways. The utilization of the upstream UUG codons by the eIF5G31R mutation caused downregulation of uridylate kinase expression, sensitivity to hydroxyurea, and DNA damage. The eIF5G31R mutant cells showed lower glutathione levels, high ROS activity, and sensitivity to H2O2.

Delineation of altered brain proteins associated with furious rabies virus infection in dogs by quantitative proteomics.

Rabies is a fatal zoonotic disease caused by rabies virus (RABV). Despite the existence of control measures, dog-transmitted human rabies accounts for ˃95% reported cases due to unavailability of sensitive diagnostic methods, inadequate understanding of disease progression and absence of therapeutics. In addition, host factors and their role in RABV infection are poorly understood. In this study, we used 8-plex iTRAQ coupled with HRMS approach to identify differentially abundant proteins (DAPs) of dog brain associated with furious rabies virus infection. Total 40 DAPs including 26 down-regulated and 14 up-regulated proteins were statistically significant in infected samples. GO annotation and IPA showed that calcium signaling and calcium transport, efficient neuronal function, metabolic pathway associated proteins were mostly altered during this infection. Total 34 proteins including 10 down-regulated proteins pertaining to calcium signaling and calcium transport pathways were successfully verified by qRT-PCR and two proteins were verified by western blot, thereby suggesting these pathways may play an important role in this infection. This study provides the map of altered brain proteins and some insights into the molecular pathophysiology associated with furious rabies virus infection. However, further investigations are required to understand their role in disease mechanism. SIGNIFICANCE: Transmission of rabies by dogs poses the greatest hazard world-wide and the rare survival of post-symptomatic patients as well as severe neurological and immunological problems pose a question to understand the molecular mechanism involved in rabies pathogenesis. However, information regarding host factors and their function in RABV infection is still inadequate. Our study has used an advanced quantitative proteomics approach i.e. 8-plex iTRAQ coupled with HRMS and identified 40 DAPs in furious rabies infected dog brain tissues compared to the controls. Further analysis showed that calcium signaling and transport pathway, efficient neuronal functions and metabolic pathway associated brain proteins were most altered during furious rabies virus infection. This data provides a map of altered brain proteins which may have role in furious rabies virus infection. Hence, this will improve our understanding of the molecular pathogenesis of RABV infection.

Lifestyle, Epstein-Barr virus infection, and other factors could impede nasopharyngeal cancer survivorship: a five-year cross-sectional study in North Eastern India.

Nasopharyngeal Carcinoma (NPC) is one of the leading cancers in India's north-eastern (NE) region affecting a section of the population each year. A proportion of the NPC cases are observed to recur even after therapy, indicating the involvement of other factors. We aimed to explore the NPC and Epstein-Barr virus (EBV) burden in the NE region and investigate the prognostic factors for the NPC patients' poor survival and recurrence. NPC patients' information was obtained from different state hospitals between 2014 and 2019. PCR and Sanger sequencing were performed to detect EBV types. Statistical analysis, including forest plot analysis, Kaplan-Mayer survival plot, Log-rank test, cox hazard regression, and Aalen's additive regression model, were performed to determine prognostic factors for the NPC patients' lower survival and recurrence. We observed an increased incidence of NPC and EBV infection in the past five years. Step-wise statistical analyses pointed out that variable such as non-professionals (B = 1.02, HR = 2.8, 95%CI = 1.5,4.9) workers (B = 0.92, HR = 2.5, 95%CI = 1.4,4.4), kitchen cum bedroom (B = 0.61, HR = 1.8, 95%CI = 1.2,2.8), mosquito repellent (B = 0.60, HR = 1.7, 95%CI = 1.1,2.7), nasal congestion (B = 0.60, HR = 1.8, 95%CI = 1.2,2.8), lower haemoglobin level (B = 0.92, HR = 2.5, 95%CI = 1.3,4.9), tumor stage IV (B = 2.8, HR = 1.8, 95%CI = 1.6,14.3), N2 (B = 1.4, HR = 4.0, 95%CI = 1.8,9.1), N3 (B = 1.9, HR = 6.4, 95%CI = 2.8,15.3), and M+ (B = 2.02, HR = 7.5, 95%CI = 4.1,13.7) revealed significant correlation with NPC patients' poor prognosis (p < 0.05). The presence of viral factors also showed a significant association with NPC patients' decreased survival. We concluded that factors related to day-to-day life with EBV infection could be the individual predictor for NPC incidence, lower survival, and disease recurrence. Supplementary Information: The online version contains supplementary material available at 10.1007/s13337-022-00789-5.

BAX -248 G>A and BCL2 -938 C>A Variant Lowers the Survival in Patients with Nasopharyngeal Carcinoma and Could be Associated with Tissue-Specific Malignancies: A Multi-Method Approach.

BACKGROUND: The association of BAX -248 G>A and BCL2 -938 C>A with different cancers created conflicts.  We studied the correlation and the effect of these polymorphisms in patients with Nasopharyngeal Carcinoma (NPC).  Methods: PCR-RFLP and Sanger sequencing were used to detect polymorphisms. Statistical analysis including forest plot and Kaplan-Meier Log-rank test was conducted to investigate the association and effect of these SNPs on the NPC patients' survival. The computational study was performed to investigate the possible regulatory role between these polymorphisms and the poor survival of NPC patients. Meta-analysis was executed to check the tissue-specific association of these polymorphisms in the context of global cancer prognosis. RESULTS: We observed an increased and significant association of BAX -248 G>A [GA:OR=5.29, 95%CI=1.67,16.67, P=0.004; GA+AA:OR=5.71, 95%CI=1.82,17.90, P =0.002; A:OR=5.33, 95%CI=1.76,16.13, P=0.003], and BCL2 -938 C>A [CA:OR=2.26, 95%CI=1.03,4.96, P=0.04; AA:OR=3.56, 95%CI=0.97,13.05, P=0.05; CA+AA:OR=3.10, 95%CI=1.51,6.35, P=0.002; A:OR=2.90, 95% CI=1.59,5.29, P=0.0005] with the risk of NPC. Also, these SNPs were strongly correlated with poor survival in NPC patients (lower estimated survival mean, lower estimated proportion surviving at 5 years with p <0.05). The computational study showed that these SNPs altered the binding affinity of transcription factors HIF1, SP1, PAX3, PAX9 and CREB towards promoter (Lower p indicates strong affinity). The meta-analysis revealed the tissue-specific association of these polymorphisms. BAX -248 G>A showed a significant correlation with carcinomas [A vs G:OR=1.60, 95%CI=1.09,2.34, P=0.01; AA vs GG:OR=2.61, 95%CI=1.68,4.06, p <0.001; AA+GA vs GG:OR=1.53,95%CI=1.04,2.25, P=0.02); AA vs GG+GA:OR=2.53, 95%CI=1.65,3.87, p <0.001], and BCL2 -938 C>A with other malignancies [A vs C:OR=1.45, 95%CI=1.26,1.66, p <0.001; AA vs CC:OR=2.07, 95%CI: 1.15,3.72, P=0.01; AA+CA vs CC:OR=1.42, 95%CI=1.18,1.72, p <0.001; AA vs CC+CA:OR=1.89, 95%CI=1.02,3.50, P=0.04]. CONCLUSIONS: BAX -248 G>A and BCL2 -938 C>A was associated with poor survival in NPC patients. It may increase cancer susceptibility through transcriptional regulation. Moreover, these SNPs' effects could be tissue-specific.
.

TLR9 Polymorphisms Might Contribute to the Ethnicity Bias for EBV-Infected Nasopharyngeal Carcinoma.

Nasopharyngeal carcinoma (NPC) is a rare malignancy in most parts of the world, but is endemic in some ethnic groups. The association of NPC with the Epstein-Barr virus (EBV) is firmly established; however, the mechanism is still unclear. TLR9 is well known for its essential role in viral pathogen recognition and activation of innate immunity. Here, we report a set of TLR9 polymorphisms in the TIR-2 domain of the TLR9 protein collected from the EBV-infected NPC samples from northeast Indian populations sharing the aforesaid ethnicity. The occurrence of mutations is significantly high in these samples as we found a p value of <0.0001 at a significance level of 0.05. These might play an important role for the lack of function of TLR9 and thus for the higher occurrence of EBV-mediated NPC in such ethnic groups.

Kaposi sarcoma herpes virus latency associated nuclear antigen protein release the G2/M cell cycle blocks by modulating ATM/ATR mediated checkpoint pathway.

The Kaposi's sarcoma-associated herpesvirus infects the human population and maintains latency stage of viral life cycle in a variety of cell types including cells of epithelial, mesenchymal and endothelial origin. The establishment of latent infection by KSHV requires the expression of an unique repertoire of genes among which latency associated nuclear antigen (LANA) plays a critical role in the replication of the viral genome. LANA regulates the transcription of a number of viral and cellular genes essential for the survival of the virus in the host cell. The present study demonstrates the disruption of the host G2/M cell cycle checkpoint regulation as an associated function of LANA. DNA profile of LANA expressing human B-cells demonstrated the ability of this nuclear antigen in relieving the drug (Nocodazole) induced G2/M checkpoint arrest. Caffeine suppressed nocodazole induced G2/M arrest indicating involvement of the ATM/ATR. Notably, we have also shown the direct interaction of LANA with Chk2, the ATM/ATR signalling effector and is responsible for the release of the G2/M cell cycle block.