Cutting edge: TLR9 and TLR2 signaling together account for MyD88-dependent control of parasitemia in

Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
The Journal of Immunology (Impact Factor: 5.36). 10/2006; 177(6):3515-9. DOI: 10.4049/jimmunol.177.6.3515
Source: PubMed

ABSTRACT Activation of innate immune cells by Trypanosoma cruzi-derived molecules such as GPI anchors and DNA induces proinflammatory cytokine production and host defense mechanisms. In this study, we demonstrate that DNA from T. cruzi stimulates cytokine production by APCs in a TLR9-dependent manner and synergizes with parasite-derived GPI anchor, a TLR2 agonist, in the induction of cytokines by macrophages. Compared with wild-type animals, T. cruzi-infected Tlr9(-/-) mice displayed elevated parasitemia and decreased survival. Strikingly, infected Tlr2(-/-)Tlr9(-/-) mice developed a parasitemia equivalent to animals lacking MyD88, an essential signaling molecule for most TLR, but did not show the acute mortality displayed by MyD88(-/-) animals. The enhanced susceptibility of Tlr9(-/-) and Tlr2(-/-)Tlr9(-/-) mice was associated with decreased in vivo IL-12/IFN-gamma responses. Our results reveal that TLR2 and TLR9 cooperate in the control of parasite replication and that TLR9 has a primary role in the MyD88-dependent induction of IL-12/IFN-gamma synthesis during infection with T. cruzi.

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Available from: Romina S Goldszmid, Aug 15, 2015
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    • "For example, two Glycosylphosphatidylinositol (GPI) -anchored proteins isolated from parasite species, Toxoplasma gondii [8] and Trypanosoma cruzi [9] can be recognized by TLR2 and/or TLR4. Moreover, DNA from T. cruzi and profilin-like protein from T. gondii can induce the expressions of TLR9 and TLR11 [10] [11]. In fish, at least 17 TLR types have been identified, including many so-called " non-mammalian " TLRs (TLR18-TLR27) [12]. "
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    ABSTRACT: Toll-like receptors (TLR) are key components of innate immunity that play significant roles in immune defense against pathogens invasion. Recent frequent outbreaks of the "white spot disease" caused by parasitic infection in farmed Tibetan fishes had resulted in great economic losses. However, to our knowledge, the roles of TLRs in mediating immune response to parasitic infection in Tibetan fishes remain to be determined. Here, we performed data-mining on a widely-farmed Tibetan fish (Gymnocypris przewalskii or Gp) transcriptome to determine the genetic variation and expression pattern of TLRs. We totally obtained 14 GpTLRs and identified 5 with a complete coding sequence. Phylogenetic analysis verified their identities and supported the classification of TLRs into six families as in other vertebrates. The TLR family motifs, such as leucine rich repeat (LRR) and Toll/interleukin (IL)-1 receptor (TIR) domain, are conserved in GpTLR1-5. Selective pressure test demonstrated that all known GpTLRs are under purifying selection, except GpTLR4 underwent positive selection. Further, site model analysis suggested that 11 positively selected sites are found in LRR domain of GpTLR4. Three positively selected sites are located on outside surface of TLR4 3D structure, indicating that function of GpTLR4 may be affected. Tissue specific expression analysis showed all GpTLRs are present in gill, head-kidney and spleen but the relative abundance varied among tissues. In response to parasite Ichthyophthirius multifiliis infection, 5 GpTLR (GpTLR1, -2, -4, -9 and -20) expressions were induced. Intriguingly, GpTLR4 was significantly up-regulated in gills, while GpTLR19 and GpTLR21 unexpectedly showed no any change. In summary, these results revealed the first genomic resources of TLR family and several parasitic infection responsive TLRs in Tibetan fish. These findings provide key information for future studies aiming to understand the molecular mechanisms underlying the immune response to pathogen invasion in Tibetan fishes. Copyright © 2015. Published by Elsevier Ltd.
    Fish &amp Shellfish Immunology 10/2015; 46(2):334–345. DOI:10.1016/j.fsi.2015.06.023 · 3.03 Impact Factor
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    • "Innate immune responses play critical roles in the control of parasite spreading and host survival. Toll-like receptor (TLR) family of pattern recognition receptors (PRRs) plays a central role in the recognition of T. cruzi by the immune system [2]; TLR4 [3], TLR2 [4] [5] [6], TLR9 [7], and TLR7 [8] initiate a signaling cascade that culminates in the activation of proinflammatory genes which are important for resistance to T. cruzi infection [9]. NOD1, a member of the cytosolic NOD-like receptor (NLR) family, also plays a role in controlling T. cruzi infection; Nod1−/− mice were shown to be very susceptible to T. cruzi, succumbing to the infection and displaying higher parasitemia and parasite loads in the spleen and heart tissues [10]. "
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    ABSTRACT: Trypanosoma cruzi infection was studied in mouse lines selected for maximal (AIRmax) or minimal (AIRmin) acute inflammatory reaction and for high (HIII) or low (LIII) antibody (Ab) responses to complex antigens. Resistance was associated with gender (females) and strain-the high responder lines AIRmax and HIII were resistant. The higher resistance of HIII as compared to LIII mice extended to higher infective doses and was correlated with enhanced production of IFN-γ and nitric oxide production by peritoneal and lymph node cells, in HIII males and females. We also analyzed the involvement of previously mapped Ab and T. cruzi response QTL with the survival of Selection III mice to T. cruzi infections in a segregating backcross [F1(HIII×LIII) ×LIII] population. An Ab production QTL marker mapping to mouse chromosome 1 (34.8 cM) significantly cosegregated with survival after acute T. cruzi infections, indicating that this region also harbors genes whose alleles modulate resistance to acute T. cruzi infection.
    Mediators of Inflammation 08/2014; 2014:952857. DOI:10.1155/2014/952857 · 3.24 Impact Factor
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    • "Cytokines and TLRs influence each other and it is no wonder of a pleiotropic effect since cytokines and TLRs interact in complex networks (Uddin et al., 2011). TLR9 and TLR2 signaling together account for MyD88-dependent control of parasitemia (Bafica et al., 2006). Therefore, closer locations of TLRs and IL2 QTLs along with WBC QTLs may be an active region, which is involved in execution of a large dependent complex mechanism to build up the innate and acquired immunity of an individual. "
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    ABSTRACT: The purpose of this study was to detect significant SNPs for blood components that were related to immunity using high single nucleotide polymorphism (SNP) density panels in a Korean native pig (KNP)Yorkshire (YK) cross population. A reciprocal design of KNPYK produced 249 individuals that were genotyped for a total of 46,865 available SNPs in the Illumina porcine 60K beadchip. To perform whole genome association analysis (WGA), phenotypes were regressed on each SNP under a simple linear regression model after adjustment for sex and slaughter age. To set up a significance threshold, 0.1% point-wise p value from F distribution was used for each SNP test. Among the significant SNPs for a trait, the best set of SNP markers were determined using a stepwise regression procedure with the rates of inclusion and exclusion of each SNP out of the model at 0.001 level. A total of 54 SNPs were detected; 10, 6, 4, 4, 5, 4, 5, 10, and 6 SNPs for neutrophil, lymphocyte, monocyte, eosinophil, basophil, atypical lymph, immuno-globulin, insulin, and insulin-like growth factor-I, respectively. Each set of significant SNPs per trait explained 24 to 42% of phenotypic variance. Several pleiotropic SNPs were detected on SSCs 4, 13, 14 and 15.
    Asian Australasian Journal of Animal Sciences 12/2012; 25(12). DOI:10.5713/ajas.2012.12503 · 0.56 Impact Factor
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