PMID- 20008536
OWN - NLM
STAT- MEDLINE
DCOM- 20100326
LR  - 20211020
IS  - 1098-5522 (Electronic)
IS  - 0019-9567 (Print)
IS  - 0019-9567 (Linking)
VI  - 78
IP  - 3
DP  - 2010 Mar
TI  - Toll-like receptor 4 signaling leads to severe fungal infection associated with 
      enhanced proinflammatory immunity and impaired expansion of regulatory T cells.
PG  - 1078-88
LID - 10.1128/IAI.01198-09 [doi]
AB  - Toll-like receptors (TLRs) present in innate immune cells recognize pathogen 
      molecular patterns and influence immunity to control the host-parasite 
      interaction. The objective of this study was to characterize the involvement of 
      TLR4 in the innate and adaptive immunity to Paracoccidioides brasiliensis, the 
      most important primary fungal pathogen of Latin America. We compared the 
      responses of C3H/HeJ mice, which are naturally defective in TLR4 signaling, with 
      those of C3H/HePas mice, which express functional receptors, after in vitro and 
      in vivo infection with P. brasiliensis. Unexpectedly, we verified that 
      TLR4-defective macrophages infected in vitro with P. brasiliensis presented 
      decreased fungal loads associated with impaired synthesis of nitric oxide, 
      interleukin-12 (IL-12), and macrophage chemotactic protein 1 (MCP-1). After 
      intratracheal infection with 1 million yeasts, TLR4-defective mice developed 
      reduced fungal burdens and decreased levels of pulmonary nitric oxide, 
      proinflammatory cytokines, and antibodies. TLR4-competent mice produced elevated 
      levels of IL-12 and tumor necrosis factor alpha (TNF-alpha), besides cytokines of 
      the Th17 pattern, indicating a proinflammatory role for TLR4 signaling. The more 
      severe infection of TLR4-normal mice resulted in increased influx of activated 
      macrophages and T cells to the lungs and progressive control of fungal burdens 
      but impaired expansion of regulatory T cells (Treg cells). In contrast, 
      TLR4-defective mice were not able to clear their diminished fungal burdens 
      totally, a defect associated with deficient activation of T-cell immunity and 
      enhanced development of Treg cells. These divergent patterns of immunity, 
      however, resulted in equivalent mortality rates, indicating that control of 
      elevated fungal growth mediated by vigorous inflammatory reactions is as 
      deleterious to the hosts as low fungal loads inefficiently controlled by limited 
      inflammatory reactions.
FAU - Loures, Flavio V
AU  - Loures FV
AD  - Departamento de Imunologia, Instituto de Ciencias Biomedicas da Universidade de 
      Sao Paulo, CEP 05508-900, Sao Paulo, SP, Brazil.
FAU - Pina, Adriana
AU  - Pina A
FAU - Felonato, Maira
AU  - Felonato M
FAU - Araujo, Eliseu F
AU  - Araujo EF
FAU - Leite, Katia R M
AU  - Leite KR
FAU - Calich, Vera L G
AU  - Calich VL
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20091214
PL  - United States
TA  - Infect Immun
JT  - Infection and immunity
JID - 0246127
RN  - 0 (Cytokines)
RN  - 0 (Inflammation Mediators)
RN  - 0 (Tlr4 protein, mouse)
RN  - 0 (Toll-Like Receptor 4)
SB  - IM
MH  - Animals
MH  - Colony Count, Microbial
MH  - Cytokines/metabolism
MH  - Inflammation Mediators/*metabolism
MH  - Lung/microbiology/pathology
MH  - Mice
MH  - Mice, Inbred C3H
MH  - Paracoccidioides/*immunology/pathogenicity
MH  - Paracoccidioidomycosis/*immunology/pathology
MH  - *Signal Transduction
MH  - Survival Analysis
MH  - T-Lymphocyte Subsets/*immunology
MH  - Toll-Like Receptor 4/deficiency/*immunology
PMC - PMC2825906
EDAT- 2009/12/17 06:00
MHDA- 2010/03/27 06:00
PMCR- 2010/09/01
CRDT- 2009/12/17 06:00
PHST- 2009/12/17 06:00 [entrez]
PHST- 2009/12/17 06:00 [pubmed]
PHST- 2010/03/27 06:00 [medline]
PHST- 2010/09/01 00:00 [pmc-release]
AID - IAI.01198-09 [pii]
AID - 1198-09 [pii]
AID - 10.1128/IAI.01198-09 [doi]
PST - ppublish
SO  - Infect Immun. 2010 Mar;78(3):1078-88. doi: 10.1128/IAI.01198-09. Epub 2009 Dec 
      14.