Subversion of Host Innate Immunity by Human Papillomavirus Oncoproteins

The growth of human papillomavirus (HPV)-transformed cells depends on the ability of the viral oncoproteins E6 and E7, especially those from high-risk HPV16/18, to manipulate the signaling pathways involved in cell proliferation, cell death, and innate immunity. Emerging evidence indicates that E6/E7 inhibition reactivates the host innate immune response, reversing what until then was an unresponsive cellular state suitable for viral persistence and tumorigenesis. Given that the disruption of distinct mechanisms of immune evasion is an attractive strategy for cancer therapy, the race is on to gain a better understanding of E6/E7-induced immune escape and cancer progression. Here, we review recent literature on the interplay between E6/E7 and the innate immune signaling pathways cGAS/STING/TBK1, RIG-I/MAVS/TBK1, and Toll-like receptors (TLRs). The overall emerging picture is that E6 and E7 have evolved broad-spectrum mechanisms allowing for the simultaneous depletion of multiple rather than single innate immunity effectors. The cGAS/STING/TBK1 pathway appears to be the most heavily impacted, whereas the RIG-I/MAVS/TBK1, still partially functional in HPV-transformed cells, can be activated by the powerful RIG-I agonist M8, triggering the massive production of type I and III interferons (IFNs), which potentiates chemotherapy-mediated cell killing. Overall, the identification of novel therapeutic targets to restore the innate immune response in HPV-transformed cells could transform the way HPV-associated cancers are treated

HPV-induced field cancerisation: Transformation of adult tissue stem cell into cancer stem cell

Field cancerisation was originally described as a basis for multiple head and neck squamous cell carcinoma (HNSCC) and is a pre-malignant phenomenon that is frequently attributable to oncogenic human papillomavirus (HPV) infection. Our work on β-HPV-induced cutaneous squamous cell carcinomas identified a novel Lrig1+ hair follicle junctional zone keratinocyte stem cell population as the basis for field cancerisation. Herein, we describe the ability for HPV to infect adult tissue stem cells in order to establish persistent infection and induce their proliferation and displacement resulting in field cancerisation. By review of the HPV literature, we reveal how this mechanism is conserved as the basis of field cancerisation across many tissues. New insights have identified the capacity for HPV early region genes to dysregulate adult tissue stem cell self-renewal pathways ensuring that the expanded population preserve its stem cell characteristics beyond the stem cell niche. HPV-infected cells acquire additional transforming mutations that can give rise to intraepithelial neoplasia (IEN), from environmental factors such as sunlight or tobacco induced mutations in skin and oral cavity, respectively. With establishment of IEN, HPV viral replication is sacrificed with loss of the episome, and the tissue is predisposed to multiple cancer stem cell-driven carcinomas

High prevalence of human cytomegalovirus in a population of periodontally healthy subjects

Background: Human cytomegalovirus (HCMV) appears to be more frequent in periodontally affected patients than in healthy control groups. Based on this assumption, it has been suggested that HCMV may play a role in the pathogenesis of periodontal disease. Objective: The objective of this uncontrolled study was to assess the occurrence of HCMV in a large unselected population of periodontally healthy subjects. Study Design: Fifty consecutive periodontally healthy patients satisfied the inclusion criteria. Two samples of gingival crevicular fluids were taken from two non-bleeding on probing sites for each patient. Samples were collected from the anterior and the posterior area. Polymerase chain reaction (PCR) was used to identify the presence of HCMV. Results: HCMV was detected in 17 (33%) out of 50 participants. Ten subjects showed presence of HCMV on both anterior and posterior sites, whereas the remaining 7 only had HCMV present in the anterior sites. No differences were noticed between HCMV positive and HCMV negative in terms of smoking (p = 0.33), drinking habits (p=0,94) or the presence of prosthodontic restorations (p= 0,89). Conclusions: HCMV was detected in a high proportion of periodontally healthy subjects. Its presence was not found to be influenced by smoking or drinking habits

Fenologia e comportamento reprodutivo de pêssego no centro-leste da Argentina

Na região centro-leste do estado de Santa Fé, Argentina, para a expansão dos frutais é preciso introduzir variedades de baixo requerimento de frio. O objetivo deste estudo foi caracterizar o comportamento durante as fases de crescimento e frutificação de variedades de pêssego (Prunus persica L. Batsch) e nectarina com requerimentos de frio que variam entre 150-650 horas de frio (CH). As variedades de pêssego de baixa necessidade de frio (;500 CH). As variedades de maior necessidade de frio tiveram a vantagem da floração, e o estabelecimento dos frutos aconteceu depois do período de risco de geadas. Porém, essas variedades não têm satisfeita sua necessidade de frio, apresentando comportamento vegetativo e reprodutivo inadequado. As variedades de baixa necessidade de frio brotaram entre 4 a 31 de julho e o período de plena floração aconteceu entre 14 de julho a 4 de agosto. A colheita de fruta começou em 19 de outubro com o cv. 'Flordastar', e sua duração foi de 58 dias. Para as variedades de baixa necessidade de frio o período de colheita foi dez dias mais curto.In Santa Fe, the central-east area of Argentina, the expansion of fruit tree crops requires the introduction and evaluation of low chilling varieties. The aims of this study was to characterize the phenological behaviour and the reproductive traits of peach (Prunus persica L. Batsch) and nectarine varieties with chilling requirements ranging from 150 to 650 chilling hours (CH). Low chilling varieties (;500 CH). The phenology of high chilling requirement varieties had the advantage that blooming and fruit set happened after the period of late frost occurrence. However, they did not satisfy their chilling requirement, showing an inadequate vegetative and reproductive behaviour. Low chilling varieties began to sprout during July, and the period of full bloom occurred from July 14th to August 4th. Fruit harvest was initiated on October 19th with the cv. 'Flordastar' and it extended for 58 days. However, on low chilling varieties the harvest time was reduced in ten days. Flower density, fruit set and fruit yield showed a negative relationship with the chilling requirement of the variety