Description du projet
Mécanismes de modulation de la réponse des macrophages par les virus
Les virus modulent les réponses des cellules myéloïdes, altérant ainsi les phénotypes des macrophages. Des données récentes sembler indiquer que cette altération peut se produire même sans la réplication virale dans ces cellules. Le rhinovirus humain (RVH) altère les réponses des macrophages à l’infection bactérienne par une régulation négative de la sécrétion de cytokines. La compréhension des mécanismes employés par les virus pour moduler les réponses des macrophages pourrait offrir des options thérapeutiques destinées à la prévention de la pathogenèse associée aux virus. Financé par le programme Actions Marie Skłodowska-Curie, le projet MacroRhino vise à découvrir si le RVH peut se répliquer dans les macrophages alvéolaires et à élucider les mécanismes d’altération des macrophages médiés par le RVH. Les chercheurs développeront un nouveau modèle de cellules semblables à des macrophages alvéolaires de poumon humain, dérivés de cellules souches pluripotentes induites, afin de reproduire la physiologie de l’organe et le phénotype des macrophages résidents.
Objectif
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.
Champ scientifique
Programme(s)
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme
Régime de financement
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European FellowshipsCoordinateur
75006 Paris
France