Maria Massucci (Karolinska Institutet, Sweden)
“A Role of Bacterial Co-Infection in the Pathogenesis of NPC?”
in immunosuppressive considerations. EBV positivity
1. Immunotherapy blasting clymohoma (60&)
CNS localization (100%)
3. Post-transplant lymphoma (100%)
4. Lymphoma of the elderly (100%)
5. Leiomyosarcoma (smooth muscles)
[evidence suggesting the involvement of bacterial infections in NPC pathogenesis]
• NPC is often associated with chronic bacteria infections of the nasopharynx sand oral cavity
• Poor oral hygiene is a risk factor for NPC
• Bacterial-induced inflammation may alter the activation/differentiation of epithelial cells
• Bacterial metabolites can modulate
Periodontitis. (High virus titers of EBV and CMV)
Virulence factors of oral pathogenic bacteria
Exposure to live bacteria supernatants promotes EBV reactivation and activates BZLF1, BMRF1.. lytic reactivation
CDT promotes virus reactivation.
– CDT is a toxin heat-sensitive
– Also induces DNA damage (H2AX)
– Cytolethal distending toxin (a trim ethic toxins, CdtB: active subunit, homologous to DNAse 1, CdtA/CdtC binding to the cell
– Chronic intoxication promotes the establishment of a malignant phenotype (form cell Fock, constitutive activity on p38 pathway
Question does intoxication of other
– CDT intoxicating enhances the susceptibility of epithelial cells to EBV infection
– AGS cell line , ITGVB1
– CDT intoxication promotes the long-term survival of EBV infected cells (day 12). CDT 1 ug/ml). Cytokine involved?
– CT intoxicating enhances DNA damage in EBV infected cells
Question: how can virus reactivation promote oncogenesis?
Evidence:
– elevated antibody tigers to viral antigens have diagnostic and prognostic value in NPC and other ENV associated malignancies
– elevated virus load often observed before the onset of this ease
– Elevated virus utters required for the development of malignancies ion animal models
– Lytic proteins packed into exosome may ave the way for oncogenesis
BPLF1 (3149 aa)
– EBV largest tegument protein required for efficient virus assembly
– Expressed during productive infection and delivered into infected cell
Cellular targets of BPLF1
– DUB PCNA, DUB TRAF6, DUB Rad18 DeNedd Cullins
– BP:LF1 interacting proteins identified by mass spectrometry
– 14-3-3 interacting protein of BPLF1 , 8 members, shared interactomes of 14-3-3 and BPLF1, TRIM25+14-3-3 interaction regulated the type I IFN response (interaction is independent of BPLF1 catalytic domain
– Catalytically active BPLF1 inhibits the IFN response
(IFNb RIG4, M
BPLF1 part goes TRM25 ubiquitination activity
Activated RIG0I is recruited to the trios but is not ubiquitinated
BPLF1 homologs share the effect (the easiest in CMV homologous)
BPLF1 D86-90R mustang does not inhibit the IFN response
Summary an outlook
– different types of bacterial products affect the interaction of EBV with epithelial cells
– Intoxicating with sub-lethal amounts of CDT enhances the susceptibility of epithelial cells to EBV infection
– Viral products that are delivered by the incoming virions play roles in regulating IFN response