Toll-like Receptors are Key Participants in Innate Immune Responses

Arancibia, Sergio; Beltrán, Caroll J.; Aguirre, Isidora; Silva, Paulina; Peralta, Alexis; Malinarich, Frano; Hermoso, Marcela A.

doi:10.4067/s0716-97602007000200001

Cited by 245 publications

(155 citation statements)

References 129 publications

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“…One possible explanation is that the Pdi-dependent ability of S. iniae to form longer chains reduces the efficiency of phagocytic uptake and clearance. Another possible explanation for this decreased survival is that deacetylation of S. iniae cell surface molecules introduces significant changes in molecular patterns that are otherwise easily recognized by the host immune system, thus allowing WT S. iniae to survive and persist in vivo (Arancibia et al, 2007;Nigro et al, 2008). In examining specific potential effectors of phagocytic killing, we have found no difference in the kinetics of the killing of WT and Dpdi by hydrogen peroxide (a component of the oxidative burst) and the cationic HSB AMP moronecidin.…”

Section: Discussionmentioning

confidence: 99%

The novel polysaccharide deacetylase homologue Pdi contributes to virulence of the aquatic pathogen Streptococcus iniae

et al. 2010

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The aquatic zoonotic pathogen Streptococcus iniae represents a threat to the worldwide aquaculture industry and poses a risk to humans who handle raw fish. Because little is known about the mechanisms of S. iniae pathogenesis or virulence factors, we established a highthroughput system combining whole-genome pyrosequencing and transposon mutagenesis that allowed us to identify virulence proteins, including Pdi, the polysaccharide deacetylase of S. iniae, that we describe here. Using bioinformatics tools, we identified a highly conserved signature motif in Pdi that is also conserved in the peptidoglycan deacetylase PgdA protein family. A Dpdi mutant was attenuated for virulence in the hybrid striped bass model and for survival in whole fish blood. Moreover, Pdi was found to promote bacterial resistance to lysozyme killing and the ability to adhere to and invade epithelial cells. On the other hand, there was no difference in the autolytic potential, resistance to oxidative killing or resistance to cationic antimicrobial peptides between S. iniae wild-type and Dpdi. In conclusion, we have demonstrated that pdi is involved in S. iniae adherence and invasion, lysozyme resistance and survival in fish blood, and have shown that pdi plays a role in the pathogenesis of S. iniae. Identification of Pdi and other S. iniae virulence proteins is a necessary initial step towards the development of appropriate preventive and therapeutic measures against diseases and economic losses caused by this pathogen. INTRODUCTIONIn the past few decades, the pathogen Streptococcus iniae has emerged as a major hindrance to aquaculture operations worldwide (Agnew & Barnes, 2007), causing economic losses measured in hundreds of millions of dollars annually. In addition, S. iniae has established itself as a zoonotic risk, especially in areas of the world that preferentially prepare and consume raw fish (Lau et al., 2003). To date, at least 25 human cases of invasive streptococcal infection attributed to S. iniae have been confirmed in the USA, Canada, China and Taiwan, many of which were in immunocompromised patients (Agnew & Barnes, 2007;Sun et al., 2007;Weinstein et al., 1997); since there is currently no prospective epidemiological surveillance for human S. iniae infections, the true number may be much higher (Facklam et al., 2005;Lau et al., 2006).In spite of the economic and human health risks that S. iniae presents, a fully assembled genome sequence for this emerging pathogen is not yet available, and very little is known about its disease mechanisms. To better understand the molecular genetic basis of virulence in this versatile pathogen, we created a library of randomly generated transposon mutants that we screened for virulence Abbreviations: AMP, antimicrobial peptide; HSB, hybrid striped bass, i.p., intraperitoneal; PIA, polysaccharide intercellular adhesin, WT, wild-type.3These authors contributed equally to this work.The GenBank/EMBL/DDBJ accession number for the pdi sequence of Streptococcus iniae is FJ664396.Four supplementary f...

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Section: Discussionmentioning

confidence: 99%

The novel polysaccharide deacetylase homologue Pdi contributes to virulence of the aquatic pathogen Streptococcus iniae

et al. 2010

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“…TLR4 activation by endogenous agonist like HMGB1, released by injured or necrotic cells, has been implicated in the pathogenesis of injury-driven disorders such as atherosclerosis and restenosis (12,(28)(29)(30). The TLR4/MD2 receptor complex utilizes the adapter molecule MyD88 and TIR domain-containing adapter-inducing interferon-β signaling adapters to induce expression of cytokines and chemokines (31). Previous studies implicated MyD88 in IH formation following periadventitial cuff placement on the carotid artery (15) and the inward remodeling induced by the changes of hemodynamic forces on conduit arteries (17).…”

Section: Saquinavir Inhibits Cathepsin L Activity and Intimal Hyperplmentioning

confidence: 99%

Cathepsin L Promotes Vascular Intimal Hyperplasia after Arterial Injury

Cai

Zhong

et al. 2017

Mol Med

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The inflammatory pathways that drive the development of intimal hyperplasia (IH) following arterial injury are not fully understood. We hypothesized that the lysosomal cysteine protease cathepsin L activates processes leading to IH after arterial injury. Using a mouse model of wire-induced carotid artery injury, we showed that cathepsin L activity peaks at d 7 and remains elevated for 28 d. Genetic deletion of cathepsin L prevented IH and monocyte recruitment in the carotid wall. The injury-induced increases in cathepsin L mRNA and activity were mitigated in mice with myeloid-specific deletion of toll-like receptor 4 (TLR4) or myeloid differentiation primary response gene 88 (MyD88). We further discovered that the HIV protease inhibitor saquinavir (SQV), which is known to block recombinant mouse cathepsin L activity in vitro, prevented IH after arterial injury. SQV also suppressed LPS (TLR4 agonist)-induced monocyte adhesion to endothelial monolayers. These findings establish cathepsin L as a critical regulator of the inflammation that leads to IH and that the TLR4-MyD88 pathway in myeloid lineages regulates cathepsin L expression in the vessel wall following wire injury. The Food and Drug Administration-approved drug SQV blocks IH though mechanisms that may include the suppression of cathepsin L.

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“…However, the same Th1 response may also contribute to the Chlamydia-induced inflammatory pathologies. Because MyD88 is a critical signaling adaptor molecule required by many pattern recognition receptors for initiating inflammatory responses (12) and may also directly or indirectly affect T cell responses during adaptive immunity (13)(14)(15), we evaluated the role of MyD88-mediated signaling in C. muridarum urogenital tract infection in the current study.…”

mentioning

confidence: 99%

Mice Deficient in MyD88 Develop a Th2-Dominant Response and Severe Pathology in the Upper Genital Tract following Chlamydia muridarum Infection

Chen

Lei

Chang

et al. 2010

The Journal of Immunology

110

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MyD88, a key adaptor molecule required for many innate immunity receptor-activated signaling pathways, was evaluated in a Chlamydia muridarum urogenital tract infection model. Compared with wild-type mice, MyD88 knockout (KO) mice failed to produce significant levels of inflammatory cytokines in the genital tract during the first week of chlamydial infection. MyD88 KO mice developed a Th2-dominant whereas wild-type mice developed a Th1/Th17-dominant immune response after chlamydial infection. Despite the insufficient production of early inflammatory cytokines and lack of Th1/Th17-dominant adaptive immunity, MyD88 KO mice appeared to be as resistant to chlamydial intravaginal infection as wild-type mice based on the number of live organisms recovered from vaginal samples. However, significantly high numbers of chlamydial organisms were detected in the upper genital tract tissues of MyD88 KO mice. Consequently, MyD88 KO mice developed more severe pathology in the upper genital tract. These results together have demonstrated that MyD88-dependent signaling pathway is not only required for inflammatory cytokine production in the early phase of host response to chlamydial infection but also plays a critical role in the development of Th1/Th17 adaptive immunity, both of which may be essential for limiting ascending infection and reducing pathology of the upper genital tract by chlamydial organisms.

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Toll-like Receptors are Key Participants in Innate Immune Responses

Cited by 245 publications

References 129 publications

The novel polysaccharide deacetylase homologue Pdi contributes to virulence of the aquatic pathogen Streptococcus iniae

The novel polysaccharide deacetylase homologue Pdi contributes to virulence of the aquatic pathogen Streptococcus iniae

Cathepsin L Promotes Vascular Intimal Hyperplasia after Arterial Injury

Mice Deficient in MyD88 Develop a Th2-Dominant Response and Severe Pathology in the Upper Genital Tract following Chlamydia muridarum Infection

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