TREM-1 Amplifies Corneal Inflammation after Pseudomonas aeruginosa Infection by Modulating Toll-Like Receptor Signaling and Th1/Th2-Type Immune Responses

Wu, Minhao; Peng, Anping; Sun, Mingxia; Deng, Qiuchan; Hazlett, Linda D.; Yuan, Jing; Liu, Xialin; Gao, Qianying; Feng, Lianqiang; He, Jun; Zhang, Ping; Huang, Xi

doi:10.1128/iai.00144-11

Cited by 70 publications

(76 citation statements)

References 43 publications

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“…Previous animal studies of TREM-1 blockade suggested that modulation of the TREM-1 pathway can decrease inflammation without sacrificing bacterial control upon infection (23)(24)(25)(26)(27)(28)(29). We initially hypothesized that TREM-1 deficiency would decrease inflammation and improve survival in a murine KPLA model.…”

Section: Discussionmentioning

confidence: 99%

“…Initial findings established TREM-1 as an amplifier of the systemic inflammatory response syndrome associated with sepsis. The apparent detrimental effects of overstimulation through TREM-1 and the survival advantage of modulating TREM-1 signaling have been shown in various murine bacterial infection models (23)(24)(25)(26)(27)(28)(29). However, recent findings suggested TREM-1 signaling is necessary for successful antimicrobial responses in sepsis and pneumonia murine models (30,31), indicating that inappropriate modulation of the TREM-1 pathway could have profound effects on septic patients and may be detrimental.…”

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confidence: 96%

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TREM-1 Promotes Survival during Klebsiella pneumoniae Liver Abscess in Mice

Lin

Tseng²,

Yeh

et al. 2014

Infect Immun

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g Klebsiella pneumoniae liver abscess (KPLA) is prevalent in East Asia. Liver abscess can develop after translocation of K. pneumoniae from a patient's bowel into the liver via the portal circulation. TREM-1 (triggering receptor expressed on myeloid cells 1) amplifies inflammatory signaling during infection, but its role in KPLA is poorly understood. We used an animal study to characterize the role of TREM-1 in KPLA. We compared survival rates, bacterial burdens in tissues, inflammatory cytokine levels, and histology findings between wild-type and Trem-1 knockout (KO) mice after oral inoculation of capsular type K1 K. pneumoniae. Translocation of K. pneumoniae to mesenteric lymph nodes and liver was examined, and intestinal permeability, antimicrobial peptide expression, and the clearance of K. pneumoniae in the small intestine were determined. In the absence of TREM-1, KPLA model mice showed increased K. pneumoniae dissemination, enhanced liver and systemic inflammation, and reduced survival. Impaired bacterial clearance in the small intestine causes enhanced K. pneumoniae translocation, which renders Trem-1 KO mice more susceptible to K. pneumoniae oral infection. In conclusion, TREM-1-mediated bacterial clearance in the small intestine is an important immune response against K. pneumoniae. TREM-1 deficiency enhances K. pneumoniae translocation in the small intestine and increases mortality rates in mice with KPLA.

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Section: Discussionmentioning

confidence: 99%

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confidence: 96%

TREM-1 Promotes Survival during Klebsiella pneumoniae Liver Abscess in Mice

Lin

Tseng²,

Yeh

et al. 2014

Infect Immun

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“…S. suis serotype 2 strain 05ZY (also known as SC-19) was isolated from the brain of a diseased piglet during the outbreak of S. suis diseases in China in 2005. The strain expresses muramidase-released protein, extracellular protein factor, and suilysin and is highly pathogenic to mice and pigs, causing STSLS (42,43). RAW264.7 mouse macrophage cells were purchased from ATCC (TIB-71) and maintained in Dulbecco's modified Eagle's medium supplemented with 10% fetal calf serum at 37°C and 5% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

TREM-1 Signaling Promotes Host Defense during the Early Stage of Infection with Highly Pathogenic Streptococcus suis

et al. 2015

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c Infection with highly pathogenic Streptococcus suis can cause septic shock, which is characterized by high levels of inflammatory cytokines and a high mortality rate. Our previous study indicated that TREM-1 (triggering receptor expressed on myeloid cells 1) was upregulated in swine spleen cells in response to S. suis infection. The role of TREM-1 signaling in enhancement of the proinflammatory response promoted us to examine its effect on the outcome of S. suis infection. In the present study, the recombinant extracellular domain of TREM-1 (rTREM-1) and an agonistic TREM-1 antibody were used to inhibit and activate TREM-1 signaling to evaluate its role in neutrophil activation, pathogen clearance, proinflammatory cytokine response, and the outcome of highly pathogenic S. suis infection in a mouse model. Blockage of TREM-1 signaling caused a more severe proinflammatory response to S. suis infection and increased the mortality rate, while its activation had the opposite effect. Blockage or activation of TREM-1 signaling lowered or raised the number of neutrophils in the blood, which correlated well with host clearance of S. suis. In conclusion, the TREM-1-mediated innate immune response played an essential role in the activation of neutrophils and S. suis clearance, which further reduced severe inflammation and finally benefited the outcome of the infection. Streptococcus suis is a major swine pathogen that is responsible for severe economic losses in the pork industry and also represents a significant threat to human health (1-3). Infection of humans could cause meningitis, sepsis, arthritis, endocarditis, and endophthalmitis, and the pooled case-fatality rate is 12.8% (4). The two large-scale human S. suis epidemics in China (the first was 25 cases with 14 deaths in Jiangsu in 1998, and the second was 204 cases with 38 deaths in Sichuan in 2005) have raised people's awareness of the public health threat (3, 5, 6). To date, more than 1,500 human infections have been reported worldwide (4). In addition, S. suis has also been identified as the third most common cause of community-acquired bacterial meningitis in Hong Kong and as the leading and second most common cause of adult meningitis in Vietnam and Thailand, respectively (3,7,8). S. suis is known to constitute a high risk of infection for occupationally exposed people (9-11), but it could also cause severe infection in people who lack contact with swine and pork-derived products (12, 13). Human S. suis isolates showed high adhesion to intestinal epithelial cells, suggesting that it should be considered a foodborne pathogen (14). Furthermore, S. suis infection is very dangerous for cancer patients (15), alcoholics (16), and splenectomy patients (17, 18). S. suis infection may also cause adverse clinical outcomes for people with influenza (19,20).A few comprehensive studies have been performed that yielded many advances in epidemiology, population genomics, serotyping, molecular diagnostics, the characterization of potential virulence factors, host-pathogen i...

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“…For example, the corneal scarification model involves scratching through both the corneal epithelium and the basal lamina of mouse corneas to allow bacteria direct access to the underlying corneal stroma, an event required for triggering of visible corneal pathology (keratitis). Consequently, the model is well suited to studying what occurs after bacteria have gained access into the corneal stroma, and much has been learned through its utilization for that purpose (31)(32)(33)(34)(35). Indeed, we have used it to show that the T3SS can participate in keratitis caused by P. aeruginosa (28,30,36).…”

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The Importance of the Pseudomonas aeruginosa Type III Secretion System in Epithelium Traversal Depends upon Conditions of Host Susceptibility

et al. 2015

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Pseudomonas aeruginosa is invasive or cytotoxic to host cells, depending on the type III secretion system (T3SS) effectors encoded. While the T3SS is known to be involved in disease in vivo, how it participates remains to be clarified. Here, mouse models of superficial epithelial injury (tissue paper blotting with EGTA treatment) and immunocompromise (MyD88 deficiency) were used to study the contribution of the T3SS transcriptional activator ExsA to epithelial traversal. Corneas of excised eyeballs were inoculated with green fluorescent protein (GFP)-expressing PAO1 or isogenic exsA mutants for 6 h ex vivo before bacterial traversal and epithelial thickness were quantified by using imaging. In the blotting-EGTA model, exsA mutants were defective in capacity for traversal. Accordingly, an ϳ16-fold variability in exsA expression among PAO1 isolates from three sources correlated with epithelial loss. In contrast, MyD88؊/؊ epithelia remained susceptible to P. aeruginosa traversal despite exsA mutation. Epithelial lysates from MyD88 ؊/؊ mice had reduced antimicrobial activity compared to those from wild-type mice with and without prior antigen challenge, particularly 30-to 100-kDa fractions, for which mass spectrometry revealed multiple differences, including (i) lower baseline levels of histones, tubulin, and lumican and (ii) reduced glutathione S-transferase, annexin, and dermatopontin, after antigen challenge. Thus, the importance of ExsA in epithelial traversal by invasive P. aeruginosa depends on the compromise enabling susceptibility, suggesting that strategies for preventing infection will need to extend beyond targeting the T3SS. The data also highlight the importance of mimicking conditions allowing susceptibility in animal models and the need to monitor variability among bacterial isolates from different sources, even for the same strain. P seudomonas aeruginosa remains a leading cause of respiratory infections, septicemia, and urinary tract and burn wound infections (1-4). It is also the most common cause of corneal infection associated with contact lens wear (5, 6). Our research has shown that clinical and laboratory isolates of P. aeruginosa can be divided into invasive or cytotoxic strains based upon how they interact with host cells (7). Invasive strains can survive and replicate inside epithelial cells dependent on the type III secretion system (T3SS) effector ExoS (8-10), while cytotoxic strains instead encode ExoU, which can induce rapid death of intoxicated host cells (11,12). While details of how invasive and cytotoxic strains impact host cells vary, both types can cause human disease, and they can each be virulent in animal models of infection (13-15).Several in vivo models exist for studying P. aeruginosa pathogenicity. They include Caenorhabditis elegans (16-18) and Drosophila melanogaster (19), in addition to mouse models of pneumonia with sepsis (20-22), burn wound infection with sepsis (23-25), and gastrointestinal colonization and sepsis (26,27) and corneal scarification models (28)(29)(30)...

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TREM-1 Amplifies Corneal Inflammation after Pseudomonas aeruginosa Infection by Modulating Toll-Like Receptor Signaling and Th1/Th2-Type Immune Responses

Cited by 70 publications

References 43 publications

TREM-1 Promotes Survival during Klebsiella pneumoniae Liver Abscess in Mice

TREM-1 Promotes Survival during Klebsiella pneumoniae Liver Abscess in Mice

TREM-1 Signaling Promotes Host Defense during the Early Stage of Infection with Highly Pathogenic Streptococcus suis

The Importance of the Pseudomonas aeruginosa Type III Secretion System in Epithelium Traversal Depends upon Conditions of Host Susceptibility

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