Descripción del proyecto
Mecanismos de la modulación de la respuesta de los macrófagos mediada por virus
Los virus modulan las respuestas de las células mieloides al deteriorar los fenotipos de los macrófagos. Datos recientes sugieren que esta afectación puede ocurrir incluso sin la replicación del virus en estas células. El rinovirus humano (RVH) deteriora la respuesta de los macrófagos a infecciones bacterianas mediante la regulación a la baja de la secreción de citocinas. La comprensión de los mecanismos empleados por los virus para modular las respuestas de los macrófagos podría ofrecer opciones terapéuticas para prevenir la patogenia asociada a los virus. El equipo del proyecto MacroRhino, financiado por las Acciones Marie Skłodowska-Curie, tiene como objetivo descubrir si el RVH puede replicarse en los macrófagos alveolares y dilucidar los mecanismos de deterioro de los macrófagos mediados por el RVH. Los investigadores crearán un nuevo modelo de células similares a los macrófagos alveolares de los pulmones humanos derivadas de células madre pluripotentes inducidas y, con él, reproducirán la fisiología del órgano y el fenotipo de los macrófagos residentes.
Objetivo
A growing body of evidence suggest that viruses can modulate myeloid cells responses leading to long term impairment of monocytes/macrophages phenotypes. Whereas for virus directly infecting macrophages, the long-term effects on these cells function and phenotype have been extensively studied, for virus infecting other cell types, the effects on macrophages have been overlooked. Yet, recent data suggest that virus-mediated modulation of macrophages can even occurred when the virus do not replicate in these cells. Indeed, viruses have broader ways to modulate the innate immune responses than the one identified in permissive cells. Understanding the mechanisms of action employed by viruses to modulate macrophages responses could not only provide possible targets to eliminate the infection, but also offer therapeutic options to prevent/avoid virus-associated pathogenesis.
Human rhinovirus (HRV) impairs macrophages’ responses upon secondary challenge with bacteria. The host laboratory identified arpin as a critical factor targeted by HRV to alter the phagocytic activity of macrophages and showed that HRV16-treated macrophages present a “paralysed” phenotype in terms of cytokine secretion. The precise mechanisms governing the reprogramming of the macrophages are however not fully elucidated. Furthermore, it is still unclear whether HRV needs to replicate within macrophages to reprogram their phenotype and functions. Therefore, my objectives are to decipher (i) if HRV can replicate in alveolar macrophages and (ii) what are the HRV-mediated mechanisms leading to impaired macrophages’ functions.
Moreover, the models employed to study macrophages present advantages but do not recapitulate organ physiology, which plays a key role on the resident macrophage phenotype. Therefore, I will develop a model of human lung alveolar macrophage-like cell (LAML) derived from induced pluripotent stem cells (h-iPSC) to answer the above-mentioned objectives.
Ámbito científico
Palabras clave
Programa(s)
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme
Régimen de financiación
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European FellowshipsCoordinador
75006 Paris
Francia