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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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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]
Total Authors: 8
[1] Univ Sao Paulo, Inst Biomed Sci, Dept Immunol, Sao Paulo - Brazil
[2] Univ Perugia, Dept Expt Med, Perugia - Italy
Total Affiliations: 2
Document type: Journal article
Source: FRONTIERS IN IMMUNOLOGY; v. 8, NOV 13 2017.
Web of Science Citations: 2

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)

FAPESP's process: 11/51258-2 - Influence of the enzyme indoleamine-2,3-dioxygenase (IDO) in the differentiation and function of dendritic cells and regulatory T cells in the pulmonary paracoccidioidomycosis of resistant and susceptible mice to P. brasiliensis infection
Grantee:Vera Lucia Garcia Calich
Support Opportunities: Regular Research Grants
FAPESP's process: 14/18668-0 - The importance of aryl hydrocarbon receptor (AhR) in the regulation of immune response and host resistance to pulmonary paracoccidioidomycosis
Grantee:Eliseu Frank de Araujo
Support Opportunities: Scholarships in Brazil - Post-Doctoral
FAPESP's process: 13/02396-9 - The role of the NLRP3 inflammasome in pulmonary paracoccidioidomycosis
Grantee:Claudia Feriotti
Support Opportunities: Scholarships in Brazil - Post-Doctoral