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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

Disease Tolerance Mediated by Phosphorylated indoleamine-2,3 Dioxygenase confers resistance to a Primary Fungal Pathogen

Texto completo
Autor(es):
de Araujo, Eliseu Frank [1] ; Loures, Flavio Vieira [1] ; Feriotti, Claudia [1] ; Costa, Tania [1] ; Vacca, Carmine [2] ; Puccetti, Paolo [2] ; Romani, Luigina [2] ; Garcia Calich, Vera Lucia [1]
Número total de Autores: 8
Afiliação do(s) autor(es):
[1] Univ Sao Paulo, Inst Biomed Sci, Dept Immunol, Sao Paulo - Brazil
[2] Univ Perugia, Dept Expt Med, Perugia - Italy
Número total de Afiliações: 2
Tipo de documento: Artigo Científico
Fonte: FRONTIERS IN IMMUNOLOGY; v. 8, NOV 13 2017.
Citações Web of Science: 1
Resumo

Resistance to primary fungal pathogens is usually attributed to the proinflammatory mechanisms of immunity conferred by interferon-gamma activation of phagocytes that control microbial growth, whereas susceptibility is attributed to anti-inflammatory responses that deactivate immunity. This study challenges this paradigm by demonstrating that resistance to a primary fungal pathogen such as Paracoccidiodes brasiliensis can be mediated by disease tolerance, a mechanism that preserves host fitness instead of pathogen clearance. Among the mechanisms of disease tolerance described, a crucial role has been ascribed to the enzyme indoleamine-2,3 dioxygenase (IDO) that concomitantly controls pathogen growth by limiting tryptophan availability and reduces tissue damage by decreasing the inflammatory process. Here, we demonstrated in a pulmonary model of paracoccidioidomycosis that IDO exerts a dual function depending on the resistant pattern of hosts. IDO activity is predominantly enzymatic and induced by IFN-gamma signaling in the pulmonary dendritic cells (DCs) from infected susceptible (B10.A) mice, whereas phosphorylated IDO (pIDO) triggered by TGF-beta activation of DCs functions as a signaling molecule in resistant mice. IFN-gamma signaling activates the canonical pathway of NF-kappa B that promotes a proinflammatory phenotype in B10. A DCs that control fungal growth but ultimately suppress T cell responses. In contrast, in A/J DCs IDO promotes a tolerogenic phenotype that conditions a sustained synthesis of TGF-beta and expansion of regulatory T cells that avoid excessive inflammation and tissue damage contributing to host fitness. Therefore, susceptibility is unexpectedly mediated by mechanisms of proinflammatory immunity that are usually associated with resistance, whereas genetic resistance is based on mechanisms of disease tolerance mediated by pIDO, a phenomenon never described in the protective immunity against primary fungal pathogens. (AU)

Processo FAPESP: 13/02396-9 - O papel do inflamassoma NLRP3 na paracoccidioidomicose pulmonar
Beneficiário:Claudia Feriotti
Linha de fomento: Bolsas no Brasil - Pós-Doutorado
Processo FAPESP: 14/18668-0 - A importância do receptor para aril hidrocarboneto (AhR) na regulação da resposta imune e na resistência de hospedeiros à paracoccidioidomicose pulmonar
Beneficiário:Eliseu Frank de Araujo
Linha de fomento: Bolsas no Brasil - Pós-Doutorado
Processo FAPESP: 11/51258-2 - Influência da enzima indolamina-2,3-dioxigenase (IDO) na diferenciação e função das células dendríticas e T reguladoras na paracoccidiodomicose pulmonar de camundongos resistentes e suscetíveis ao P. brasiliensis
Beneficiário:Vera Lucia Garcia Calich
Linha de fomento: Auxílio à Pesquisa - Regular