We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
TLR9 Activation Dampens the Early Inflammatory Response to Paracoccidioides brasiliensis, Impacting Host Survival.
- Authors
Menino, João Filipe; Saraiva, Margarida; Gomes-Alves, Ana G.; Lobo-Silva, Diogo; Sturme, Mark; Gomes-Rezende, Jéssica; Saraiva, Ana Laura; Goldman, Gustavo H.; Cunha, Cristina; Carvalho, Agostinho; Romani, Luigina; Pedrosa, Jorge; Castro, António Gil; Rodrigues, Fernando
- Abstract
Background: Paracoccidioides brasiliensis causes paracoccidioidomycosis, one of the most prevalent systemic mycosis in Latin America. Thus, understanding the characteristics of the protective immune response to P. brasiliensis is of interest, as it may reveal targets for disease control. The initiation of the immune response relies on the activation of pattern recognition receptors, among which are TLRs. Both TLR2 and TLR4 have been implicated in the recognition of P. brasiliensis and regulation of the immune response. However, the role of TLR9 during the infection by this fungus remains unclear. Methodology/Principal findings: We used in vitro and in vivo models of infection by P. brasiliensis, comparing wild type and TLR9 deficient (−/−) mice, to assess the contribution of TLR9 on cytokine induction, phagocytosis and outcome of infection. We show that TLR9 recognizes either the yeast form or DNA from P. brasiliensis by stimulating the expression/production of pro-inflammatory cytokines by bone marrow derived macrophages, also increasing their phagocytic ability. We further show that TLR9 plays a protective role early after intravenous infection with P. brasiliensis, as infected TLR9−/− mice died at higher rate during the first 48 hours post infection than wild type mice. Moreover, TLR9−/− mice presented tissue damage and increased expression of several cytokines, such as TNF-α and IL-6. The increased pattern of cytokine expression was also observed during intraperitoneal infection of TLR9−/− mice, with enhanced recruitment of neutrophils. The phenotype of TLR9−/− hosts observed during the early stages of P. brasiliensis infection was reverted upon a transient, 48 hours post-infection, neutrophil depletion. Conclusions/Significance: Our results suggest that TLR9 activation plays an early protective role against P. brasiliensis, by avoiding a deregulated type of inflammatory response associated to neutrophils that may lead to tissue damage. Thus modulation of TLR9 may be of interest to potentiate the host response against this pathogen. Author Summary: Paracoccidioides brasiliensis is an etiological agent of paracoccidioidomycosis, one of the most prevalent systemic mycosis in South America, affecting over 10 million people. One of the hallmark features of this fungus is its multinucleated nature, where a single P. brasiliensis cell can have from one to over 50 nuclei. Thus, fungal cell death may culminate in the release of large amounts of DNA and in the activation of the host innate immune system via toll like receptor (TLR) 9, a member of the TLR family. In this study, we evaluated the contribution of TLR9 activation during the infection by P. brasiliensis using an experimental model of P. brasiliensis infection of wild-type and TLR9−/− mice. We found that the lack of this receptor results in tissue damage and increased expression of cytokines, culminating in a higher death rate of TLR9−/− mice early post infection. This was mainly associated to neutrophils, as depletion of these cells, during the first 48 hours post-infection, converted the early response of TLR9−/− mice to infection to that of wild-type mice. Our work provides evidence for the protective effects of TLR9 activation during early stages of P. brasiliensis infection, highlighting the relevance of a balanced innate immune response to avoid tissue damage.
- Subjects
SOUTH America; PARACOCCIDIOIDOMYCOSIS; PARACOCCIDIOIDES brasiliensis; IMMUNOREGULATION; PATTERN perception receptors; INFLAMMATION; BONE marrow
- Publication
PLoS Neglected Tropical Diseases, 2013, Vol 7, Issue 7, p1
- ISSN
1935-2727
- Publication type
Article
- DOI
10.1371/journal.pntd.0002317