Indoleamine 2,3-Dioxygenase Controls Fungal Loads and Immunity in Paracoccidioidomicosis but is More Important to Susceptible than Resistant Hosts

Autor(es)

Araujo, Eliseu F. ^[1] ; Loures, Flavio V. ^[1] ; Bazan, Silvia B. ^[1] ; Feriotti, Claudia ^[1] ; Pina, Adriana ^[1] ; Schanoski, Alessandra S. ^[1] ; Costa, Tania A. ^[1] ; Calich, Vera L. G. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Inst Ciencias Biomed, Dept Imunol, BR-05508 Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: PLoS Neglected Tropical Diseases; v. 8, n. 11 NOV 2014.
• Citações Web of Science: 14

Resumo

Background: Paracoccidioidomycosis, a primary fungal infection restricted to Latin America, is acquired by inhalation of fungal particles. The immunoregulatory mechanisms that control the severe and mild forms of paracoccidioidomycosis are still unclear. Indoleamine 2,3-dioxygenase (IDO), an IFN-gamma induced enzyme that catalyzes tryptophan metabolism, can control host-pathogen interaction by inhibiting pathogen growth, T cell immunity and tissue inflammation. Methodology/Principal Findings: In this study, we investigated the role of IDO in pulmonary paracoccidioidomycosis of susceptible and resistant mice. IDO was blocked by 1-methyl-dl-tryptophan (1MT), and fungal infection studied in vitro and in vivo. Paracoccidioides brasiliensis infection was more severe in 1MT treated than untreated macrophages of resistant and susceptible mice, concurrently with decreased production of kynurenines and IDO mRNA. Similar results were observed in the pulmonary infection. Independent of the host genetic pattern, IDO inhibition reduced fungal clearance but enhanced T cell immunity. The early IDO inhibition resulted in increased differentiation of dendritic and Th17 cells, accompanied by reduced responses of Th1 and Treg cells. Despite these equivalent biological effects, only in susceptible mice the temporary IDO blockade caused sustained fungal growth, increased tissue pathology and mortality rates. In contrast, resistant mice were able to recover the transitory IDO blockade by the late control of fungal burdens without enhanced tissue pathology. Conclusions/Significance: Our studies demonstrate for the first time that in pulmonary paracoccidioidomycosis, IDO is an important immunoregulatory enzyme that promotes fungal clearance and inhibits T cell immunity and inflammation, with prominent importance to susceptible hosts. In fact, only in the susceptible background IDO inhibition resulted in uncontrolled tissue pathology and mortality rates. Our findings open new perspectives to understand the immunopathology of paracoccidioidomycosis, and suggest that an insufficient IDO activity could be associated with the severe cases of human PCM characterized by inefficient fungal clearance and excessive inflammation. (AU)

• Processo FAPESP: 09/53045-6 - Influencia da enzima indolamina-2,3-dioxigenase na diferenciacao e funcao das celulas dendriticas e t reguladoras na paracoccidiodomicose pulmonar de camundongos resistentes e suscetiveis ao paracoc...
• Beneficiário: ELISEU FRANK DE ARAUJO
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 05/55327-8 - Caracterização da função das células dendríticas na paracoccidioidomicose pulmonar murina e na determinação dos padrões de susceptibilidade e resistência ao fungo
• Beneficiário: Adriana Pina
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 07/55124-5 - Caracterizacao dos receptores de macrofagos de camundongos resistentes e sesceptiveis ao paracoccidioides brasiliensis envolvidos na interacao com o fungo.
• Beneficiário: Claudia Feriotti
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 12/01765-8 - Caracterização das células t reguladoras na paracoccidioidomicose (pcm) pulmonar utilizando camundongos c57bl/6 transgênicos para a expressão de foxp3-gfp
• Beneficiário: Silvia Boschi Bazan
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 09/11503-8 - O papel das células T Natural Killer (NKT) na imunidade ao Paracoccidioides brasiliensis: da fisiologia à patologia
• Beneficiário: Alessandra Soares Schanoski
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 10/50111-5 - Influência dos receptores de imunidade inata (TLR2, TLR4 e Dectina-1) na indução do comportamento de células dendríticas e na determinação do padrão imunidade adaptativa dos hospedeiros contra o Paracoccidioides brasiliensis
• Beneficiário: Flávio Vieira Loures
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado