Abstract:
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-γ 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.
journal_name
PLoS Negl Trop Disjournal_title
PLoS neglected tropical diseasesauthors
Araújo EF,Loures FV,Bazan SB,Feriotti C,Pina A,Schanoski AS,Costa TA,Calich VLdoi
10.1371/journal.pntd.0003330subject
Has Abstractpub_date
2014-11-20 00:00:00pages
e3330issue
11eissn
1935-2727issn
1935-2735pii
PNTD-D-14-01165journal_volume
8pub_type
杂志文章abstract:BACKGROUND:Ecological determinants of most emerging vector-borne diseases are understudied, particularly for neglected tropical disease. Moreover, although socioeconomic impacts can have significant downstream effects on human risks to vector-borne diseases via a change in land cover, particularly facilitating the inva...
journal_title:PLoS neglected tropical diseases
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abstract:BACKGROUND:Cure after treatment for human African trypanosomiasis (HAT) is assessed by examination of the cerebrospinal fluid every 6 months, for a total period of 2 years. So far, no markers for cure or treatment failure have been identified in blood. Trypanosome-specific antibodies are detectable in blood by the Card...
journal_title:PLoS neglected tropical diseases
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journal_title:PLoS neglected tropical diseases
pub_type: 临床试验,杂志文章
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journal_title:PLoS neglected tropical diseases
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abstract::West Nile Fever is a zoonotic disease caused by a mosquito-borne flavivirus, WNV. By its clinical sensitivity to the disease, the horse is a useful sentinel of infection. Because of the virus' low-level, short-term viraemia in horses, the primary tools used to diagnose WNV are serological tests. Inter-laboratory profi...
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journal_title:PLoS neglected tropical diseases
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abstract:BACKGROUND:Cystic echinococcosis (CE) is a neglected parasitic zoonosis with considerable socioeconomic impact on affected pastoral communities. CE is endemic throughout the Mediterranean, including Morocco, where the Mid Atlas is the most prevalent area for both human and animal infection. The highest hospital annual ...
journal_title:PLoS neglected tropical diseases
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journal_title:PLoS neglected tropical diseases
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pub_type: 临床试验,杂志文章,随机对照试验
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journal_title:PLoS neglected tropical diseases
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abstract:BACKGROUND:Dengue is a mosquito-borne viral disease caused by the four dengue viruses (DENV-1 to 4) that can also be transmitted by blood transfusion and organ transplantation. The distribution of DENV in the components of blood from infected donors is poorly understood. METHODS:We used an in-house TaqMan qRT-PCR assa...
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