scholarly journals Therapeutic Efficacy of Lysophosphatidylcholine in Severe Infections Caused by Acinetobacter baumannii

2015 ◽  
Vol 59 (7) ◽  
pp. 3920-3924 ◽  
Author(s):  
Younes Smani ◽  
Juan Domínguez-Herrera ◽  
José Ibáñez-Martínez ◽  
Jerónimo Pachón
Keyword(s):  
Acinetobacter Baumannii ◽  
Therapeutic Efficacy ◽  
Immune Cell ◽  
Early Time ◽  
Experimental Models ◽  
Antimicrobial Treatment ◽  
Enzyme Linked Immunosorbent Assay ◽  
Preemptive Therapy ◽  
Necrosis Factor Alpha ◽  
Content Type

ABSTRACTDue to the significant increase in antimicrobial resistance ofAcinetobacter baumannii, immune system stimulation to block infection progression may be a therapeutic adjuvant to antimicrobial treatment. Lysophosphatidylcholine (LPC), a major component of phospholipids in eukaryotic cells, is involved in immune cell recruitment and modulation. The aim of this study was to show if LPC could be useful for treating infections caused byA. baumannii. A. baumanniiATCC 17978 was used in this study. Levels of serum LPC and levels of the inflammatory cytokines tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), IL-1β, and IL-10 were determined by spectrophotometric assay and enzyme-linked immunosorbent assay (ELISA), respectively, using a murine peritoneal sepsis model in which mice were inoculated with 5.3 log CFU/ml ofA. baumannii. The therapeutic efficacy of LPC againstA. baumanniiin murine peritoneal sepsis and pneumonia models was assessed for 48 h after bacterial infection. At early time points in the murine model of peritoneal sepsis caused byA. baumannii, LPC was depleted and was associated with an increase of inflammatory cytokine release. Preemptive therapy with LPC in murine peritoneal sepsis and pneumonia models markedly enhanced spleen and lung bacterial clearance and reduced the numbers of positive blood cultures and the mouse mortality rates. Moreover, treatment with LPC reduced proinflammatory cytokine production. These data demonstrate that LPC is efficacious as a preemptive treatment in experimental models of peritoneal sepsis and pneumonia caused byA. baumannii.

scholarly journals Efficacy of Lysophosphatidylcholine in Combination with Antimicrobial Agents against Acinetobacter baumannii in Experimental Murine Peritoneal Sepsis and Pneumonia Models

2016 ◽  
Vol 60 (8) ◽  
pp. 4464-4470 ◽  
Author(s):  
R. Parra Millán ◽  
M. E. Jiménez Mejías ◽  
V. Sánchez Encinales ◽  
R. Ayerbe Algaba ◽  
A. Gutiérrez Valencia ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Antimicrobial Agents ◽  
Immune Cell ◽  
Lethal Dose ◽  
Interleukin 10 ◽  
Experimental Models ◽  
Enzyme Linked Immunosorbent Assay ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Tnf Α

ABSTRACTImmune response stimulation to prevent infection progression may be an adjuvant to antimicrobial treatment. Lysophosphatidylcholine (LPC) is an immunomodulator involved in immune cell recruitment and activation. In this study, we aimed to evaluate the efficacy of LPC in combination with colistin, tigecycline, or imipenem in experimental murine models of peritoneal sepsis and pneumonia. We usedAcinetobacter baumanniistrain Ab9, which is susceptible to colistin, tigecycline, and imipenem, and multidrug-resistant strain Ab186, which is susceptible to colistin and resistant to tigecycline and imipenem. Pharmacokinetic and pharmacodynamic parameters for colistin, tigecycline, and imipenem and the 100% minimal lethal dose (MLD100) were determined for both strains. The therapeutic efficacies of LPC, colistin (60 mg/kg of body weight/day), tigecycline (10 mg/kg/day), and imipenem (180 mg/kg/day), alone or in combination, were assessed against Ab9 and Ab186 at the MLD100in murine peritoneal sepsis and pneumonia models. The levels of pro- and anti-inflammatory cytokines, i.e., tumor necrosis factor alpha (TNF-α) and interleukin-10 (IL-10), were determined by enzyme-linked immunosorbent assay (ELISA) for the same experimental models after inoculating mice with the MLD of both strains. LPC in combination with colistin, tigecycline, or imipenem markedly enhanced the bacterial clearance of Ab9 and Ab186 from the spleen and lungs and reduced bacteremia and mouse mortality rates (P< 0.05) compared with those for colistin, tigecycline, and imipenem monotherapies. Moreover, at 4 h post-bacterial infection, Ab9 induced higher TNF-α and lower IL-10 levels than those with Ab186 (4 μg/ml versus 3 μg/ml [P< 0.05] and 2 μg/ml versus 3.4 μg/ml [P< 0.05], respectively). LPC treatment combined with colistin, tigecycline, or imipenem modestly reduced the severity of infection byA. baumanniistrains with different resistance phenotypes compared to LPC monotherapy in both experimental models.

scholarly journals Efficacy of Lysophosphatidylcholine as Direct Treatment in Combination with Colistin against Acinetobacter baumannii in Murine Severe Infections Models

Antibiotics ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 194
Author(s):  
Andrea Miró-Canturri ◽  
Rafael Ayerbe-Algaba ◽  
Manuel Enrique Jiménez-Mejías ◽  
Jerónimo Pachón ◽  
Younes Smani
Keyword(s):  
Acinetobacter Baumannii ◽  
Multidrug Resistant ◽  
Experimental Models ◽  
Antimicrobial Treatment ◽  
Clinical Settings ◽  
Monotherapy Group ◽  
Bacterial Concentration ◽  
Sepsis Model ◽  
Severe Infections ◽  
Stimulation Of

The stimulation of the immune response to prevent the progression of an infection may be an adjuvant to antimicrobial treatment. Here, we aimed to evaluate the efficacy of lysophosphatidylcholine (LPC) treatment in combination with colistin in murine experimental models of severe infections by Acinetobacter baumannii. We used the A. baumannii Ab9 strain, susceptible to colistin and most of the antibiotics used in clinical settings, and the A. baumannii Ab186 strain, susceptible to colistin but presenting a multidrug-resistant (MDR) pattern. The therapeutic efficacies of one and two LPC doses (25 mg/kg/d) and colistin (20 mg/kg/8 h), alone or in combination, were assessed against Ab9 and Ab186 in murine peritoneal sepsis and pneumonia models. One and two LPC doses combined with colistin and colistin monotherapy enhanced Ab9 and Ab186 clearance from spleen, lungs and blood and reduced mice mortality compared with those of the non-treated mice group in both experimental models. Moreover, one and two LPC doses reduced the bacterial concentration in tissues and blood in both models and increased mice survival in the peritoneal sepsis model for both strains compared with those of the colistin monotherapy group. LPC used as an adjuvant of colistin treatment may be helpful to reduce the severity and the resolution of the MDR A. baumannii infection.

scholarly journals Toll-Like Receptors Participate in Macrophage Activation and Intracellular Control of Leishmania (Viannia) panamensis

2011 ◽  
Vol 79 (7) ◽  
pp. 2871-2879 ◽  
Author(s):  
Carolina Gallego ◽  
Douglas Golenbock ◽  
Maria Adelaida Gomez ◽  
Nancy Gore Saravia
Keyword(s):  
Macrophage Activation ◽  
Early Time ◽  
Parasitic Infections ◽  
Toll Like Receptors ◽  
Necrosis Factor Alpha ◽  
Systematic Screening ◽  
Content Type ◽  
Murine Bone Marrow ◽  
Host Cell Response ◽  
Tnf Α

ABSTRACTToll-like receptors (TLRs) play a central role in macrophage activation and control of parasitic infections. Their contribution to the outcome ofLeishmaniainfection is just beginning to be deciphered. We examined the interaction ofLeishmania panamensiswith TLRs in the activation of host macrophages.L. panamensisinfection resulted in upregulation of TLR1, TLR2, TLR3, and TLR4 expression and induced tumor necrosis factor alpha (TNF-α) secretion by human primary macrophages at comparable levels and kinetics to those of specific TLR ligands. The TLR dependence of the host cell response was substantiated by the absence of TNF-α production in MyD88/TRIF−/−murine bone marrow-derived macrophages and mouse macrophage cell lines in response to promastigotes and amastigotes. Systematic screening of TLR-deficient macrophages revealed that TNF-α production was completely abrogated in TLR4−/−macrophages, consistent with the increased intracellular parasite survival at early time points of infection. TNF-α secretion was significantly reduced in macrophages lacking endosomal TLRs but was unaltered by a lack of TLR2 or MD-2. Together, these findings support the participation of TLR4 and endosomal TLRs in the activation of host macrophages byL. panamensisand in the early control of infection.

scholarly journals The Carbohydrate Lectin Receptor Dectin-1 Mediates the Immune Response to Exserohilum rostratum

2016 ◽  
Vol 85 (3) ◽  
Author(s):  
Jennifer L. Reedy ◽  
Paige E. Negoro ◽  
Marianela Feliu ◽  
Allison K. Lord ◽  
Nida S. Khan ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Cell ◽  
Wide Spectrum ◽  
Granulomatous Inflammation ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Macrophage Response ◽  
Lectin Receptor ◽  
Exserohilum Rostratum

ABSTRACT Dematiaceous molds are found ubiquitously in the environment and cause a wide spectrum of human disease, including infections associated with high rates of mortality. Despite this, the mechanism of the innate immune response has been less well studied, although it is key in the clearance of fungal pathogens. Here, we focus on Exserohilum rostratum, a dematiaceous mold that caused 753 infections during a multistate outbreak due to injection of contaminated methylprednisolone. We show that macrophages are incapable of phagocytosing Exserohilum. Despite a lack of phagocytosis, macrophage production of tumor necrosis factor alpha is triggered by hyphae but not spores and depends upon Dectin-1, a C-type lectin receptor. Dectin-1 is specifically recruited to the macrophage-hyphal interface but not the macrophage-spore interface due to differences in carbohydrate antigen expression between these two fungal forms. Corticosteroid and antifungal therapy perturb this response, resulting in decreased cytokine production. In vivo soft tissue infection in wild-type mice demonstrated that Exserohilum provokes robust neutrophilic and granulomatous inflammation capable of thwarting fungal growth. However, coadministration of methylprednisolone acetate results in robust hyphal tissue invasion and a significant reduction in immune cell recruitment. Our results suggest that Dectin-1 is crucial for macrophage recognition and the macrophage response to Exserohilum and that corticosteroids potently attenuate the immune response to this pathogen.

scholarly journals Inducing Humoral and Cellular Responses to Multiple Sporozoite and Liver-Stage Malaria Antigens Using Exogenous Plasmid DNA

2013 ◽  
Vol 81 (10) ◽  
pp. 3709-3720 ◽  
Author(s):  
B. Ferraro ◽  
K. T. Talbott ◽  
A. Balakrishnan ◽  
N. Cisper ◽  
M. P. Morrow ◽  
...  
Keyword(s):  
Dna Sequences ◽  
Elispot Assay ◽  
Intracellular Cytokine Staining ◽  
Interleukin 2 ◽  
Cellular Responses ◽  
Enzyme Linked Immunosorbent Assay ◽  
Necrosis Factor Alpha ◽  
Liver Stage ◽  
Content Type ◽  
Ifn Γ

ABSTRACTA vaccine candidate that elicits humoral and cellular responses to multiple sporozoite and liver-stage antigens may be able to confer protection againstPlasmodium falciparummalaria; however, a technology for formulating and delivering such a vaccine has remained elusive. Here, we report the preclinical assessment of an optimized DNA vaccine approach that targets fourP. falciparumantigens: circumsporozoite protein (CSP), liver stage antigen 1 (LSA1), thrombospondin-related anonymous protein (TRAP), and cell-traversal protein for ookinetes and sporozoites (CelTOS). Synthetic DNA sequences were designed for each antigen with modifications to improve expression and were delivered usingin vivoelectroporation (EP). Immunogenicity was evaluated in mice and nonhuman primates (NHPs) and assessed by enzyme-linked immunosorbent assay (ELISA), gamma interferon (IFN-γ) enzyme-linked immunosorbent spot (ELISpot) assay, and flow cytometry. In mice, DNA with EP delivery induced antigen-specific IFN-γ production, as measured by ELISpot assay and IgG seroconversion against all antigens. Sustained production of IFN-γ, interleukin-2, and tumor necrosis factor alpha was elicited in both the CD4+and CD8+T cell compartments. Furthermore, hepatic CD8+lymphocytes produced LSA1-specific IFN-γ. The immune responses conferred to mice by this approach translated to the NHP model, which showed cellular responses by ELISpot assay and intracellular cytokine staining. Notably, antigen-specific CD8+granzyme B+T cells were observed in NHPs. Collectively, the data demonstrate that delivery of gene sequences by DNA/EP encoding malaria parasite antigens is immunogenic in animal models and can harness both the humoral and cellular arms of the immune system.

scholarly journals Colonic Immunopathogenesis of Clostridium difficile Infections

2014 ◽  
Vol 21 (4) ◽  
pp. 509-517 ◽  
Author(s):  
Charles Darkoh ◽  
Bradley P. Turnwald ◽  
Hoonmo L. Koo ◽  
Kevin W. Garey ◽  
Zhi-Dong Jiang ◽  
...  
Keyword(s):  
Clostridium Difficile ◽  
Immunological Response ◽  
Effector Memory ◽  
Enzyme Linked Immunosorbent Assay ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Monocyte Chemoattractant Protein 1 ◽  
Effector Memory T Cells ◽  
Th1 And Th2 Cytokines ◽  
Factor Alpha

ABSTRACTThere are major gaps in our understanding of the immunopathogenesis ofClostridium difficileinfections (CDIs). In this study, 36 different biomarkers were examined in the stools of CDI and non-CDI patients using the Proteome Profiler human cytokine array assay and quantitative enzyme-linked immunosorbent assay. Diarrheal stools from patients with CDI (CDI-positive diarrheal stools) showed higher relative amounts of the following inflammatory markers than the diarrheal stools from CDI-negative patients (CDI-negative diarrheal stools): C5a, CD40L, granulocyte colony-stimulating factor, I-309, interleukin-13 (IL-13), IL-16, IL-27, monocyte chemoattractant protein 1, tumor necrosis factor alpha, and IL-8. IL-8 and IL-23 were present in a larger number of CDI-positive diarrheal stools than CDI-negative diarrheal stools. Th1 and Th2 cytokines were not significantly different between the CDI-positive and CDI-negative diarrheal stools. Lactoferrin and calprotectin concentrations were also higher in the CDI-positive diarrheal stools. Our results demonstrate that CDI elicits a proinflammatory host response, and we report for the first time that IL-23 is a major marker in CDI-positive diarrheal stools. IL-23 may explain the lack of a robust immunological response exhibited by a proportion of CDI patients and may relate to recurrence; the IL-23 levels induced during CDI in these patients may be inadequate to sustain the cellular immunity conferred by this cytokine in promoting the induction and proliferation of effector memory T cells.

scholarly journals Efficacy of lysophosphatidylcholine as direct treatment in combination with colistin against Acinetobacter baumannii in murine severe infections models

2020 ◽  
Author(s):  
A Miró-Canturri ◽  
R Ayerbe-Algaba ◽  
ME Jiménez-Mejías ◽  
J Pachón ◽  
Y Smani
Keyword(s):  
Acinetobacter Baumannii ◽  
Experimental Models ◽  
Antimicrobial Treatment ◽  
Clinical Settings ◽  
Bacterial Clearance ◽  
Bacterial Concentration ◽  
Direct Treatment ◽  
Sepsis Model ◽  
Severe Infections ◽  
Stimulation Of

ABSTRACTObjectivesThe stimulation of the immune response to prevent the progression of the infection may be an adjuvant to antimicrobial treatment. Previously, we showed that preemptive treatment with lysophosphatidylcholine (LPC) in combination with colistin improved the therapeutic efficacy of colistin against MDR Acinetobacter baumannii. In this study, we aimed to evaluate the efficacy of direct treatment with LPC in combination with colistin in murine experimental models of severe infections by A. baumannii.MethodsWe used A. baumannii strain Ab9, which is susceptible to colistin and most of the antibiotics used in clinical settings, and A. baumannii strain Ab186, which is susceptible to colistin but presents a MDR pattern. The therapeutic efficacies of one and two doses of LPC (25 mg/kg/d) and colistin (20 mg/kg/8h), alone or in combination, were assessed against Ab9 and Ab186 in murine peritoneal sepsis and pneumonia models.ResultsOne and two doses of LPC in combination with colistin and colistin monotherapy enhanced bacterial clearance of Ab9 and Ab186 from spleen, lungs and blood and reduced mortality rates compared with those of the non-treated mice group in both experimental models (P<0.05). Moreover, one and two doses of LPC reduced the bacterial concentration in tissues and blood in both models, and increased mice survival in peritoneal sepsis model for both strains compared with those of colistin monotherapy group.ConclusionsLPC used as an adjuvant of colistin treatment may be helpful to reduce the severity and the resolution of the infection by MDR A. baumannii.

scholarly journals Salmonella enterica Induces Joint Inflammation and Expression of Interleukin-17 in Draining Lymph Nodes Early after Onset of Enterocolitis in Mice

2012 ◽  
Vol 80 (6) ◽  
pp. 2231-2239 ◽  
Author(s):  
Mariángeles Noto Llana ◽  
Sebastián Hernán Sarnacki ◽  
María Victoria Vázquez ◽  
Alejandra Sonia Gartner ◽  
Mónica Nancy Giacomodonato ◽  
...  
Keyword(s):  
Lymph Nodes ◽  
Salmonella Enterica ◽  
Fold Increase ◽  
Joint Inflammation ◽  
Enzyme Linked Immunosorbent Assay ◽  
Interleukin 17 ◽  
Mesenteric Lymph Nodes ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Tnf Α

ABSTRACTIn developing countries, one-third of reactive arthritis (ReA) cases are associated withSalmonellaenterocolitis; nevertheless, there is no animal model for studying this pathology. Here we induced a self-limitingSalmonella entericaserovar Enteritidis enterocolitis in mice to analyze the onset of ReA. BALB/c mice received orally 20 μg of streptomycin 24 h before intragastric inoculation of a low dose (3 × 103to 4 × 103CFU) ofS. Enteritidis. In response toSalmonellainfection, a 30-fold increase in the expression of interleukin-17 (IL-17), measured by quantitative PCR, was observed in mesenteric lymph nodes 5 days postinfection. At this time synovitis was already evident, and concomitantly, a significant increase in joint tumor necrosis factor alpha (TNF-α) was detected by enzyme-linked immunosorbent assay (ELISA). The early development of joint lesions was accompanied by an increased expression of IL-17 in inguinal and popliteal lymph nodes. Infection with 107CFU of an isogenic ΔinvGmutant bearing a defective type III secretion system ofSalmonellaencoded in the pathogenicity island 1 apparatus (TTSS-1) induced enterocolitis histologically similar to that triggered by the wild-type strain. Interestingly, despite the higher infective dose used, the mutant did not trigger intestinal IL-17. Moreover, no synovitis was observed in mice suffering ΔinvGenterocolitis. Neutralization of IL-17 in mice infected withS. Enteritidis prevented both synovitis and the increment of TNF-α in the joints, suggesting that IL-17 participates in the generation ofSalmonella-induced ReA through the induction of TNF-α in the joints.

scholarly journals Cooperativity between Stenotrophomonas maltophilia and Pseudomonas aeruginosa during Polymicrobial Airway Infections

2020 ◽  
Vol 88 (4) ◽  
Author(s):  
Melissa S. McDaniel ◽  
Trenton Schoeb ◽  
W. Edward Swords
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Clinical Significance ◽  
Stenotrophomonas Maltophilia ◽  
Immune Cell ◽  
Respiratory Infections ◽  
Bacterial Load ◽  
Polymicrobial Infection ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Airway Infections

ABSTRACT Stenotrophomonas maltophilia is a Gram-negative bacterium found ubiquitously in the environment that has historically been regarded as nonpathogenic. S. maltophilia is increasingly observed in patient sputa in cystic fibrosis (CF), and while existing epidemiology indicates that patients with S. maltophilia have poorer diagnoses, its clinical significance remains unclear. Moreover, as multidrug resistance is common among S. maltophilia isolates, treatment options for these infections may be limited. Here, we investigated the pathogenicity of S. maltophilia alone and during polymicrobial infection with Pseudomonas aeruginosa. Colonization, persistence, and virulence of S. maltophilia were assessed in experimental respiratory infections of mice. The results of this study indicate that S. maltophilia transiently colonizes the lung accompanied by significant weight loss and immune cell infiltration and the expression of early inflammatory markers, including interleukin 6 (IL-6), IL-1α, and tumor necrosis factor alpha (TNF-α). Importantly, polymicrobial infection with P. aeruginosa elicited significantly higher S. maltophilia counts in bronchoalveolar lavages and lung tissue homogenates. This increase in bacterial load was directly correlated with the density of the P. aeruginosa population and required viable P. aeruginosa bacteria. Microscopic analysis of biofilms formed in vitro revealed that S. maltophilia formed well-integrated biofilms with P. aeruginosa, and these organisms colocalize in the lung during dual-species infection. Based on these results, we conclude that active cellular processes by P. aeruginosa afford a significant benefit to S. maltophilia during polymicrobial infections. Furthermore, these results indicate that S. maltophilia may have clinical significance in respiratory infections.

scholarly journals Loss of Mitochondrial Protein Fus1 Augments Host Resistance to Acinetobacter baumannii Infection

2013 ◽  
Vol 81 (12) ◽  
pp. 4461-4469 ◽  
Author(s):  
M. Indriati Hood ◽  
Roman Uzhachenko ◽  
Kelli Boyd ◽  
Eric P. Skaar ◽  
Alla V. Ivanova
Keyword(s):  
Immune Response ◽  
Acinetobacter Baumannii ◽  
Immune Cell ◽  
Mitochondrial Protein ◽  
Mammalian Target Of Rapamycin ◽  
Sterile Inflammation ◽  
Interleukin 17 ◽  
Content Type ◽  
Rapid Clearance ◽  
Species Production

ABSTRACTFus1 is a tumor suppressor protein with recently described immunoregulatory functions. Although its role in sterile inflammation is being elucidated, its role in regulating immune responses to infectious agents has not been examined. We used here a murine model ofAcinetobacter baumanniipneumonia to identify the role of Fus1 in antibacterial host defenses. We found that the loss of Fus1 in mice results in significantly increased resistance toA. baumanniipneumonia. We observed earlier and more robust recruitment of neutrophils and macrophages to the lungs of infected Fus1−/−mice, with a concomitant increase in phagocytosis of invading bacteria and more rapid clearance. Such a prompt and enhanced immune response to bacterial infection in Fus1−/−mice stems from early activation of proinflammatory pathways (NF-κB and phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin [mTOR]), most likely due to significantly increased mitochondrial membrane potential and mitochondrial reactive oxygen species production. Significant early upregulation of interleukin-17 (IL-17) in Fus1−/−immune cells was also observed, together with significant downregulation of IL-10. Depletion of neutrophils eliminates the enhanced antibacterial defenses of the Fus1−/−mice, suggesting that ultimately it is the enhanced immune cell recruitment that mediates the increased resistance of Fus1−/−mice toA. baumanniipneumonia. Taken together, our data define the novel role for Fus1 in the immune response toA. baumanniipneumonia and highlight new avenues for immune modulating therapeutic targets for this treatment-resistant nosocomial pathogen.

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