Transcriptional profiles of pulmonary innate immune responses to isogenic antibiotic‐susceptible and multidrug‐resistant <i>Pseudomonas aeruginosa</i>

Tam, Vincent H.; Pérez, Cynthia; Ledesma, Kimberly R.; Lewis, Russell E.

doi:10.1111/1348-0421.12581

Cited by 7 publications

(6 citation statements)

References 11 publications

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“…An earlier study [37] correlated the cytokine levels and bacterial clearance during an intraperitoneal infection in mice with MDR and sensitive isolates, along with reference strains of P. aeruginosa, and found that MDR strains induced a greater immune response that was able to effectively clear the infective bacteria at 12 h post-infection (p.i.). This suggested the presence of a fitness trade-off that compromises the pathogenic potentials and virulence of MDR isolates [38]. A previous study analyzing different mechanisms of antibiotic resistance that occur in clinical isolates of P. aeruginosa, causing severe bloodstream infections, concluded that acquisition of resistance did not lead to decreased fitness [39], and this correlated well with observations of enhanced survival of MDR-PA in infected cells that were made in our study too.…”

Section: Discussionsupporting

confidence: 90%

Multidrug-Resistant Pseudomonas aeruginosa Evokes Differential Inflammatory Responses in Human Microglial and Retinal Pigment Epithelial Cells

et al. 2020

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Increasing incidences of multidrug-resistant (MDR) pathogens causing endophthalmitis threaten our ability to treat this condition, and the modulation of inflammatory responses by MDR bacteria is not known. In this study, using human microglia and retinal pigment epithelial (RPE) cells, we compare the inflammatory responses of sensitive (S-PA) and multidrug-resistant (MDR-PA) clinical isolates of Pseudomonas aeruginosa. Infected cells were subjected to qPCR analysis, enzyme-linked immunosorbent assay (ELISA), and immunostaining to assess the expression of inflammatory mediators. Both microglia and RPE cells, challenged with S-PA and MDR-PA, induced a time-dependent expression of inflammatory cytokines. Significant differences were observed in expression levels of Toll-like receptors (TLR) TLR4, TLR5, and TLR9 in microglia cells challenged with MDR-PA vs. S-PA. Similarly, mRNA levels of interleukin (IL)-6, tumor necrosis factor (TNF)-α, Interferon (IFN)-γ, and matrix metalloproteinase (MMP)-9 were also higher in MDR-PA-infected cells. At protein levels, upregulation was observed for IL-10 (p = 0.004), IL-8 (p = 0.0006), IL-1β (p = 0.02), and Granulocyte-macrophage colony-stimulating factor (GM-CSF) (p = 0.0006) in cells infected MDR-PA versus S-PA in both microglia and RPE cells; however, the response was delayed in RPE cells. Heatmap and STRING analysis highlighted the existence of a cross-talk between the inflammatory and cytokine-mediated signaling pathways. Our study highlights a differential inflammatory response evoked by MDR vs. sensitive pathogens in retinal cells during endophthalmitis.

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Section: Discussionsupporting

confidence: 90%

Multidrug-Resistant Pseudomonas aeruginosa Evokes Differential Inflammatory Responses in Human Microglial and Retinal Pigment Epithelial Cells

et al. 2020

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“…For example, ICU patients infected with extensively drug-resistant (XDR) P. aeruginosa presented elevated amounts of IL-10 in blood, as compared to patients infected with non-MDR P. aeruginosa ( Gomez-Zorrilla et al, 2017b ). Same result was obtained in a mouse model of P. aeruginosa pneumonia ( Tam et al, 2018 ). Consistently, patients infected with MDR M. tuberculosis presented higher amounts of IL-10 in the serum, as compared to patients infected with non-MDR M. tuberculosis ( Pinheiro et al, 2013 ).…”

Section: Mdr and Non-mdr Bacteria Induce Differential Il-10 Productiosupporting

confidence: 72%

Expanding the Current Knowledge About the Role of Interleukin-10 to Major Concerning Bacteria

et al. 2018

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Interleukin-10 (IL-10) is one of the most important anti-inflammatory cytokine produced during bacterial infection. Two related phenomena explain the importance of IL-10 production in this context: first, the wide range of cells able to produce this cytokine and second, the wide effects that it causes on target cells. In a previous report we described opposing roles of IL-10 production during bacterial infection. Overall, during infections caused by intracellular bacteria or by pathogens that modulate the inflammatory response, IL-10 production facilitates bacterial persistence and dissemination within the host. Whereas during infections caused by extracellular or highly inflammatory bacteria, IL-10 production reduces host tissue damage and facilitates host survival. Given that these data were obtained using antibiotic susceptible bacteria, the potential application of these studies to multi-drug resistant (MDR) bacteria needs to be evaluated. MDR bacteria can become by 2050 a major death cause worldwide, not only for its ability to resist antimicrobial therapy but also because the virulence of these strains is different as compared to antibiotic susceptible strains. Therefore, it is important to understand the interaction of MDR-bacteria with the immune system during infection. This review discusses the current data about the role of IL-10 during infections caused by major circulating antibiotic resistant bacteria. We conclude that the production of IL-10 improves host survival during infections caused by extracellular or highly inflammatory bacteria, however, it is detrimental during infections caused by intracellular bacteria or bacterial pathogens that modulate the inflammatory response. Importantly, during MDR-bacterial infections a differential IL-10 production has been described, compared to non-MDR bacteria, which might be due to virulence factors specific of MDR bacteria that modulate production of IL-10. This knowledge is important for the development of new therapies against infections caused by these bacteria, where antibiotics effectiveness is dramatically decreasing.

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“…Studies have shown an elevated amount of IL-10 in MDR P. aeruginosa –induced sepsis as compared with non-MDR P. aeruginosa infection in sepsis patients, as well as in a mouse model of P. aeruginosa pneumonia. 3 , 26 It has also been suggested that IL-10 in response to Mycobacterium tuberculosis infection, may downregulate the immune response and limit tissue injury, but overexpression of these cytokines may have a negative impact on the capacity to control infection. 27 Some studies have also shown that, in patients with human immunodeficiency virus infection 28 , 29 and other experimental infections, 30 – 32 high levels of IL-6 correlated with susceptibility to the pathogen and the disease severity of associated diseases.…”

Section: Discussionmentioning

confidence: 99%

Multidrug-ResistantPseudomonas aeruginosaTriggers Differential Inflammatory Response in Patients With Endophthalmitis

Naik

Singh

Rudraprasad

et al. 2021

Trans. Vis. Sci. Tech.

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Purpose Infections with multidrug-resistant Pseudomonas aeruginosa (MDR-PA) lead to poor clinical outcomes in endophthalmitis patients, and its interactions with the host immune system remain largely unknown. The current study aimed to determine the association of MDR-PA infection with the cytokine expression profile in patients with endophthalmitis. Methods Vitreous of 12 patients with culture-proven MDR-PA along with 12 samples from antibiotic-susceptible P. aeruginosa (S-PA) and 20 non-infectious controls were included in the study. Expression patterns of IL-6, IL-10, IL-1α, IL-1β, IFN-γ, TNF-α, IL-8, and GM-CSF in the vitreous were analyzed by multiplex immunoassay and correlated with the clinical severity. We also assessed the phosphorylation level of different immune pathway molecules. Results In the MDR-PA group, significantly ( P < 0.05) increased expression of IL-6, IL-8, IL-10, IL-1β, and TNF-α was observed in comparison with the S-PA group. The increased inflammatory mediators in MDR-PA correlated with the disease severity. Additionally, the increased expression of inflammatory mediators was positively correlated to the activation levels of Akt, STAT3, JNK, p70 S6 kinase, and NF-кB ( P < 0.05) in the MDR-PA group. Conclusions The current study shows the differential host immune response and phosphorylation levels of signaling molecules in MDR-PA endophthalmitis, thereby linking antibiotic resistance with distinct immune regulation. Translational Relevance This study provides evidence for the use of inflammatory mediator levels of IL-6, IL-8, IL-10, IL-1β, and TNF-α as potential diagnostic biomarkers of MDR endophthalmitis warranting prompt administration of immune modulators to avoid irreversible damage to the retina and vision loss.

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Transcriptional profiles of pulmonary innate immune responses to isogenic antibiotic‐susceptible and multidrug‐resistant Pseudomonas aeruginosa

Cited by 7 publications

References 11 publications

Multidrug-Resistant Pseudomonas aeruginosa Evokes Differential Inflammatory Responses in Human Microglial and Retinal Pigment Epithelial Cells

Multidrug-Resistant Pseudomonas aeruginosa Evokes Differential Inflammatory Responses in Human Microglial and Retinal Pigment Epithelial Cells

Expanding the Current Knowledge About the Role of Interleukin-10 to Major Concerning Bacteria

Multidrug-ResistantPseudomonas aeruginosaTriggers Differential Inflammatory Response in Patients With Endophthalmitis

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