Descrizione del progetto
Meccanismi di modulazione della risposta macrofagica mediata da virus
I virus modulano le risposte delle cellule mieloidi, compromettendo i fenotipi dei macrofagi, e dati recenti suggeriscono che questa compromissione può verificarsi anche senza la presenza di una replicazione del virus in queste cellule. Il rhinovirus umano (HRV) compromette le risposte dei macrofagi all’infezione batterica attraverso la sottoregolazione della secrezione di citochine. La comprensione dei meccanismi impiegati dai virus per modulare le risposte macrofagiche potrebbe offrire opzioni terapeutiche per prevenire la patogenesi associata ai virus. Il progetto MacroRhino, finanziato dal programma di azioni Marie Skłodowska-Curie, intende scoprire se l’HRV può replicarsi nei macrofagi alveolari e chiarire i meccanismi mediati dall’HRV della compromissione dei macrofagi. I ricercatori svilupperanno un nuovo modello di cellule simili ai macrofagi alveolari del polmone umano, derivate da cellule staminali pluripotenti indotte, per ricapitolare la fisiologia dell’organo e il fenotipo dei macrofagi residenti.
Obiettivo
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.
Campo scientifico
Parole chiave
Programma(i)
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme
Meccanismo di finanziamento
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European FellowshipsCoordinatore
75006 Paris
Francia