An Integrated View of Virus-Triggered Cellular Plasticity Using Boolean Networks.

Virus-related mortality and morbidity are due to cell/tissue damage caused by replicative pressure and resource exhaustion, e.g., HBV or HIV; exaggerated immune responses, e.g., SARS-CoV-2; and cancer, e.g., EBV or HPV. In this context, oncogenic and other types of viruses drive genetic and epigenetic changes that expand the tumorigenic program, including modifications to the ability of cancer cells to migrate. The best-characterized group of changes is collectively known as the epithelial-mesenchymal transition, or EMT. This is a complex phenomenon classically described using biochemistry, cell biology and genetics. However, these methods require enormous, often slow, efforts to identify and validate novel therapeutic targets. Systems biology can complement and accelerate discoveries in this field. One example of such an approach is Boolean networks, which make complex biological problems tractable by modeling data ("nodes") connected by logical operators. Here, we focus on virus-induced cellular plasticity and cell reprogramming in mammals, and how Boolean networks could provide novel insights into the ability of some viruses to trigger uncontrolled cell proliferation and EMT, two key hallmarks of cancer.

Epithelial-to-mesenchymal transition induced by virus / Transición epitelio-mesénquima inducida por virus

RESUMEN La Transición Epitelio-Mesénquima (EMT) es un proceso de diferenciación altamente conservado en vertebrados. Este ocurre en células epiteliales con la activación progresiva de la pérdida de la polaridad, la adquisición de motilidad individual y la capacidad invasiva a otros tejidos. La EMT es un proceso normal durante el desarrollo; no obstante, en condiciones patológicas está relacionada con la inducción de metástasis, lo cual representa una vía alterna al desarrollo de procesos oncogénicos tempranos. Aunque la EMT es activada principalmente por factores de crecimiento, también se puede desencadenar por infecciones de patógenos intracelulares mediante la activación de rutas moleculares inductoras de este proceso. Por lo tanto, una infección bacteriana o viral pueda generar predisposición al desarrollo de tumores. Nuestro interés está enfocado principalmente en caracterizar la relación virus-hospedero, y en el caso de los virus, varios ya se han descrito como inductores de la EMT. En este artículo de revisión se describen el fenómeno de la plasticidad celular y la ocurrencia detallada del proceso de EMT, los patógenos virales reportados como inductores, los mecanismos moleculares usados para ello y las vías de regulación mediante miRNAs. Por último, se discute cómo esta relación virus-hospedero puede explicar la patogénesis de la enfermedad causada por Dengue virus, favoreciendo la identificación de blancos moleculares para terapia, estrategia conocida como Antivirales dirigidos a blancos celulares o HTA (Host-targeting antivirals).

ABSTRACT Epithelial-to-Mesenchymal Transition (EMT) is a highly conserved dedifferentiation process in vertebrates. This process occurs in epithelial cells activating progressive loss of cell polarity, acquisition of individual motility and invasive capacity to other tissues. EMT is a normal process during development process, however, in pathological conditions is related to the induction of metastasis, which represents an alternative path to the development of early oncogenic processes. Although, EMT is mainly activated by growth factors, it can also be triggered by intracellular-pathogen-infections by activating molecular pathways that induce this process. Therefore, a bacterial or viral infection may generate predisposition to the development of tumors. Our interest is mainly focused on characterizing the host-virus relationship, and in the case of viruses, several have already been described as EMT inductors. In this review, phenomenon of cellular plasticity, detailed occurrence of the EMT, viral pathogens reported as inducers, the molecular mechanisms, and the regulatory pathways through miRNAs are described. Finally, we discuss how this host-virus relationship may explain the pathogenesis of the disease caused by Dengue virus, favoring the identification of molecular targets for therapy, a strategy known as Host-Targeting Antivirals (HTA).