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Central role of toll-like receptor 4 signaling and host defense in experimental pneumonia caused by Gram-negative bacteria.

ABSTRACT: Toll-like receptor 4 (TLR4) has been identified as a receptor for lipopolysaccharide. However, the precise role of TLR4 in regulating gene expression in response to an infection caused by gram-negative bacteria has not been fully elucidated. The role of TLR4 signaling in coordinating gene expression was assessed by gene expression profiling in lung tissue in a mouse model of experimental pneumonia with a low-dose infection of Klebsiella pneumoniae. We analyzed four mouse strains: C57BL/6 mice, which are resistant to bacterial dissemination; 129/SvJ mice, which are susceptible; C3H/HeJ mice, which are susceptible and have defective TLR4 signaling; and their respective control strain, C3H/HeN (intermediate resistance). At 4 h after infection, C57BL/6 and C3H/HeN mice demonstrated the greatest number of genes, with 67 shared induced genes which were TLR4 dependent and highly associated with the resistance phenotype. These genes included cytokine and chemokine genes required for neutrophil activation or recruitment, growth factor receptors, MyD88 (a critical adaptor protein for TLR signaling), and adhesion molecules. TLR4 signaling accounted for over 74% of the gene expression in the C3H background. These data suggest that early TLR4 signaling controls the vast majority of gene expression in the lung in response to an infection caused by gram-negative bacteria and that this subsequent gene expression determines survival of the host.

SUBMITTER: Schurr JR

PROVIDER: S-EPMC538991 | biostudies-literature | 2005 Jan

REPOSITORIES: biostudies-literature

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Central role of toll-like receptor 4 signaling and host defense in experimental pneumonia caused by Gram-negative bacteria.

Schurr Jill R JR Young Erana E Byrne Pat P Steele Chad C Shellito Judd E JE Kolls Jay K JK

Infection and immunity 20050101 1

Toll-like receptor 4 (TLR4) has been identified as a receptor for lipopolysaccharide. However, the precise role of TLR4 in regulating gene expression in response to an infection caused by gram-negative bacteria has not been fully elucidated. The role of TLR4 signaling in coordinating gene expression was assessed by gene expression profiling in lung tissue in a mouse model of experimental pneumonia with a low-dose infection of Klebsiella pneumoniae. We analyzed four mouse strains: C57BL/6 mice, w ...[more]

PMID: 15618193

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Project description:BackgroundToll-like receptors (TLRs) are essential in host defense against pathogens by virtue of their capacity to detect microbes and initiate the immune response. TLR2 is seen as the most important receptor for gram-positive bacteria, while TLR4 is regarded as the gram-negative TLR. Melioidosis is a severe infection caused by the gram-negative bacterium, Burkholderia pseudomallei, that is endemic in Southeast Asia. We aimed to characterize the expression and function of TLRs in septic melioidosis.Methods and findingsPatient studies: 34 patients with melioidosis demonstrated increased expression of CD14, TLR1, TLR2, and TLR4 on the cell surfaces of monocytes and granulocytes, and increased CD14, TLR1, TLR2, TLR4, LY96 (also known as MD-2), TLR5, and TLR10 mRNA levels in purified monocytes and granulocytes when compared with healthy controls. In vitro experiments: Whole-blood and alveolar macrophages obtained from TLR2 and TLR4 knockout (KO) mice were less responsive to B. pseudomallei in vitro, whereas in the reverse experiment, transfection of HEK293 cells with either TLR2 or TLR4 rendered these cells responsive to this bacterium. In addition, the lipopolysaccharide (LPS) of B. pseudomallei signals through TLR2 and not through TLR4. Mouse studies: Surprisingly, TLR4 KO mice were indistinguishable from wild-type mice with respect to bacterial outgrowth and survival in experimentally induced melioidosis. In contrast, TLR2 KO mice displayed a markedly improved host defenses as reflected by a strong survival advantage together with decreased bacterial loads, reduced lung inflammation, and less distant-organ injury.ConclusionsPatients with melioidosis displayed an up-regulation of multiple TLRs in peripheral blood monocytes and granulocytes. Although both TLR2 and TLR4 contribute to cellular responsiveness to B. pseudomallei in vitro, TLR2 detects the LPS of B. pseudomallei, and only TLR2 impacts on the immune response of the intact host in vivo. Inhibition of TLR2 may be a novel treatment strategy in melioidosis.

Project description:BACKGROUND:Host sexual dimorphism is being increasingly recognized to generate strong differences in the outcome of infectious disease, but the mechanisms underlying immunological differences between males and females remain poorly characterized. Here, we used Drosophila melanogaster to assess and dissect sexual dimorphism in the innate response to systemic bacterial infection. RESULTS:We demonstrated sexual dimorphism in susceptibility to infection by a broad spectrum of Gram-positive and Gram-negative bacteria. We found that both virgin and mated females are more susceptible than mated males to most, but not all, infections. We investigated in more detail the lower resistance of females to infection with Providencia rettgeri, a Gram-negative bacterium that naturally infects D. melanogaster. We found that females have a higher number of phagocytes than males and that ablation of hemocytes does not eliminate the dimorphism in resistance to P. rettgeri, so the observed dimorphism does not stem from differences in the cellular response. The Imd pathway is critical for the production of antimicrobial peptides in response to Gram-negative bacteria, but mutants for Imd signaling continued to exhibit dimorphism even though both sexes showed strongly reduced resistance. Instead, we found that the Toll pathway is responsible for the dimorphism in resistance. The Toll pathway is dimorphic in genome-wide constitutive gene expression and in induced response to infection. Toll signaling is dimorphic in both constitutive signaling and in induced activation in response to P. rettgeri infection. The dimorphism in pathway activation can be specifically attributed to Persephone-mediated immune stimulation, by which the Toll pathway is triggered in response to pathogen-derived virulence factors. We additionally found that, in absence of Toll signaling, males become more susceptible than females to the Gram-positive Enterococcus faecalis. This reversal in susceptibility between male and female Toll pathway mutants compared to wildtype hosts highlights the key role of the Toll pathway in D. melanogaster sexual dimorphism in resistance to infection. CONCLUSION:Altogether, our data demonstrate that Toll pathway activity differs between male and female D. melanogaster in response to bacterial infection, thus identifying innate immune signaling as a determinant of sexual immune dimorphism.

Project description:IntroductionVentilator-associated pneumonias (VAPs) are a complication of mechanical ventilation in the intensive care unit (ICU) that increase length of stay, morbidity, and mortality. While identifying and treating infections early is paramount to improving patient outcomes, more and more data demonstrate limited courses of antibiotics improve outcomes. Prolonged (10-14 day) courses of antibiotics have remained the standard of care for pneumonia due to gram-negative bacilli (GNR). We aimed to review our GNR VAPs to assess risk factors for recurrent GNR infections.MethodsWe reviewed trauma patients who developed VAP from 02/2019 through 05/2022. Demographics, injury characteristics, and outcomes were reviewed with a focus on pneumonia details including the cultured pathogen(s), antibiotic(s) used, treatment duration, and presence of recurrent infections. We then compared single episode VAPs to multiple episode VAPs among patients infected by GNRs.ResultsEleven of the fifty trauma patients admitted to the ICU suffered a VAP caused by a GNR. Of these eleven patients, six experienced a recurrent infection, four of which were caused by Pseudomonas aeruginosa and two of which were caused by Enterobacter aerogenes. Among the patients who received ten days of antibiotic treatment, half suffered a recurrence. Although, there was no difference in the microbiology or antibiotic duration between the recurrences and single episodes.ConclusionDespite prolonged use of antibiotics, we found that the risk of recurrent or persistent infections was high among patients with VAP due to GNB. Further study is needed to determine optimal treatment to minimize the risk of these recurrences.Key messageVentilator-associated pneumonia due to gram-negative bacilli is a rare but high morbidity complication in intensive care units. Despite prolonged duration of therapy, these infections still appear to account for many recurrent infections and further study into optimal therapy is warranted.

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Central role of toll-like receptor 4 signaling and host defense in experimental pneumonia caused by Gram-negative bacteria.

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Central role of toll-like receptor 4 signaling and host defense in experimental pneumonia caused by Gram-negative bacteria.

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