Gram-negative Sepsis Research Articles

Risk Factors for 30-Day Mortality in Neonatal Gram-Negative Bacilli Sepsis.

Multidrug-resistant gram-negative bacilli (MDR-GNB) have emerged globally as a serious threat and with a high case fatality rate (CFR). We performed a case-control study in a Thai neonatal intensive care unit to identify the risk factors for 30-day CFR of GNB sepsis between 1991 and 2017. The CFR was analyzed by Cox's proportional hazards model. For 27 years, the percentage of MDR-GNB from GNB sepsis was 66% (169/257). The medians (interquartile ranges) of gestational age and birth weight of the neonates with GNB sepsis were 33 (29-38) weeks and 1,817 (1,100-2,800) grams, respectively. The 30-day CFRs of the neonates with MDR-GNB and non-MDR-GNB sepsis were 33% (56/169) and 20% (18/88), respectively, (hazard ratio [HR] = 1.74; 95% confidence interval [CI]: 1.03-2.97; p = 0.04). Using Cox's proportional hazards model, nonsurvivors in GNB sepsis were more likely to have septic shock (adjusted HR [aHR] = 6.67; 95% CI: 3.28-13.57; p < 0.001) or no microbiological cure (aHR = 10.65; 95% CI: 4.98-22.76; p < 0.001) than survivors. Neonates suspected of sepsis with septic shock need broad-spectrum empirical antimicrobial therapy until the second successive negative culture, especially in high MDR areas.

Dysregulation of Lipid Metabolism during Gram-Negative Sepsis in Mkp-1 Deficient Mice

Abstract Mitogen-activated protein kinase phosphatase (Mkp)-1 exerts its anti-inflammatory activities during Gramnegative sepsis by deactivating p38 and JNK. We have previously shown that Mkp-1+/+ mice, but not Mkp-1−/− mice, exhibit hypertriglyceridemia and hepatic glycogen depletion during severe sepsis. However, the regulation of hepatic lipid stores and the underlying mechanism of lipid dysregulation during sepsis remains an enigma. To understand the molecular mechanism underlying the sepsis-associated metabolic changes and the role of Mkp-1 in the process, we infected Mkp-1+/+ and Mkp-1−/− mice with Escherichia coli i.v., and assessed the effects of Mkp-1 deficiency on tissue lipid contents. We also examined global gene expression profile by RNA-seq in the livers. We found that in the absence of E. coli infection, Mkp-1 deficiency decreased liver triglyceride levels. Upon E. coli infection, Mkp-1+/+ mice, but not Mkp-1−/− mice, developed hepatocyte ballooning and increased lipid deposition in the livers. E. coli infection caused profound changes in gene expression profile of a large number of proteins that regulate lipid metabolism in wildtype mice, while these changes were substantially disrupted in Mkp-1−/− mice. Interestingly, in Mkp-1+/+ mice E. coli infection resulted in down-regulation of genes that facilitate fatty acid synthesis but upregulation of CD36 and Dgat2, whose protein products mediate fatty acid uptake and triglyceride synthesis, respectively. Taken together, our studies indicate that sepsis leads to a profound change in metabolic gene expression programs and Mkp-1 plays an important role in this process.

Human Adipose-Derived Mesenchymal Stem Cells Modify Lung Immunity and Improve Antibacterial Defense in Pneumosepsis Caused by Klebsiella pneumoniae.

Adult mesenchymal stem cells exert immunomodulatory effects that might improve the host response during sepsis. Knowledge on the effect of adipose‐derived mesenchymal stem cells (ASCs) in sepsis is limited. Klebsiella (K.) pneumoniae is a common cause of gram‐negative pneumonia and sepsis. This study sought to determine the effect of human ASCs on the host response during pneumosepsis in mice. Mice were infected with K. pneumoniae via the airways to induce a gradually evolving infection in the lung culminating pneumosepsis. One or 6 hours after infection, mice were infused intravenously with ASCs or vehicle, and euthanized after 16 hours or 48 hours, respectively. The effects of freshly cultured and cryopreserved ASCs were compared, the latter formulation being more clinically relevant. Intravenously administered ASCs were visualized in lung tissue by immunostaining at 1 and 3 hours, but not at 15 hours after infusion. Although early after infection, ASCs did not or only modestly influence bacterial loads, they reduced bacterial burdens in lungs and distant organs at 48 hours. ASCs reduced the lung levels of pro‐inflammatory cytokines and attenuated lung pathology, but did not influence distant organ injury. ASCs strongly modified the lung transcriptome in uninfected mice and especially mice with pneumosepsis. Cryopreserved and cultured ASCs induced largely similar effects on the lung transcriptome. These data indicate that human ASCs induce profound immune modulatory effects in the lungs, resulting in reduced bacterial burdens and lung inflammation during pneumosepsis caused by a common human pathogen, suggesting that ASCs may be an adjunctive therapeutic in this condition. stem cells translational medicine 2019;8:785&796

Association of the early absolute CD64-expressing neutrophil count and sepsis outcome.

To evaluate the early absolute CD64/CD15/CD45 neutrophil count as a marker of prognosis of sepsis outcome the absolute CD64/CD15/CD45 count was measured by flow cytometry in 65 patients with confirmed or suspected Gram-negative sepsis and organ dysfunction. Serum interleukin(IL)-8 and interferon-gamma (IFNγ) were measured by an enzyme immunoassay. An absolute count lower than 2500cells/mm3 could early discriminate non-survivors with sensitivity 82.9% (OR 3.46, 95%CIs 1.10-10.95, p 0.042). After forward step-wise Cox- regression analysis, it was found that acute coagulopathy, acute renal injury, and an early absolute CD64/CD15/CD45 count lower than 2500/mm3 were independently associated with unfavorable outcome. The OR for death among patients with an absolute CD64/CD15/CD45 neutrophil count greater than 2500/mm3 and circulating IL-8 greater than 95pg/ml was 0.44; this was significantly increased to 7.44 among patients with an absolute CD64/CD15/CD45 neutrophil count lower than 2500/mm3 (p 0.045 by the Breslow-Day's test; p 0.046 by the Tarone's test). An absolute CD64/CD15/CD45 count below 2500/mm3 can be a useful prognosticator of sepsis outcome and a probable indicator of sepsis immunosuppression.

Inhibition of HMGB1/RAGE-mediated endocytosis by HMGB1 antagonist box A, anti-HMGB1 antibodies, and cholinergic agonists suppresses inflammation

BackgroundExtracellular high mobility group box 1 protein (HMGB1) serves a central role in inflammation as a transporter protein, which binds other immune-activating molecules that are endocytosed via the receptor for advanced glycation end-products (RAGE). These pro-inflammatory complexes are targeted to the endolysosomal compartment, where HMGB1 permeabilizes the lysosomes. This enables HMGB1-partner molecules to avoid degradation, to leak into the cytosol, and to reach cognate immune-activating sensors. Lipopolysaccharide (LPS) requires this pathway to generate pyroptosis by accessing its key cytosolic receptors, murine caspase 11, or the human caspases 4 and 5. This lytic, pro-inflammatory cell death plays a fundamental pathogenic role in gram-negative sepsis. The aim of the study was to identify molecules inhibiting HMGB1 or HMGB1/LPS cellular internalization.MethodsEndocytosis was studied in cultured macrophages using Alexa Fluor-labeled HMGB1 or complexes of HMGB1 and Alexa Fluor-labeled LPS in the presence of an anti-HMGB1 monoclonal antibody (mAb), recombinant HMGB1 box A protein, acetylcholine, the nicotinic acetylcholine receptor subtype alpha 7 (α7 nAChR) agonist GTS-21, or a dynamin-specific inhibitor of endocytosis. Images were obtained by fluorescence microscopy and quantified by the ImageJ processing program (NIH). Data were analyzed using student’s t test or one-way ANOVA followed by the least significant difference or Tukey’s tests.ResultsAnti-HMGB1 mAb, recombinant HMGB1 antagonist box A protein, acetylcholine, GTS-21, and the dynamin-specific inhibitor of endocytosis inhibited internalization of HMGB1 or HMGB1-LPS complexes in cultured macrophages. These agents prevented macrophage activation in response to HMGB1 and/or HMGB1-LPS complexes.ConclusionThese results demonstrate that therapies based on HMGB1 antagonists and the cholinergic anti-inflammatory pathway share a previously unrecognized molecular mechanism of substantial clinical relevance.

Elucidating the effect of antibiotics on Pal's release from Escherichia coli

The clinical condition of sepsis often results from a systemic bacterial infection, followed by an over‐exuberant immune response, which leads to widespread inflammation. Severe sepsis can result in organ failure or death. Past studies have proposed a role for bacterial Peptidoglycan‐Associated Lipoprotein (Pal) in the pathogenesis of Gram‐negative sepsis. In this study, we confirmed the ability of Escherichia coli (E. coli) to release Pal under certain conditions, and we employed both in vitro and in vivo (mouse) studies and protein detection methods to determine the effect of antibiotics on Pal's release from E. coli. Results from our studies suggest that antibiotics that target peptidoglycan may enhance Pal's release more so than other antibiotics.Support or Funding InformationRochester Institute of TechnologyThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Neutrophil-to-lymphocyte ratio in patients with gram-negative sepsis admitted to intensive care unit.

Several studies have investigated the role of Neutrophil to Lymphocyte Ratio (N/L ratio) in the early diagnosis of infection, which had different results. We assessed this ratio in early diagnosis of Gram-negative sepsis admitted to ICU. This cross sectional study was approved by ethics committee of Urmia University of Medical Sciences and conducted during 2015. All patients with gram negative sepsis admitted to general intensive care unit (GICU) were enrolled. Demographic characteristics, APACHE II score, duration of mechanical ventilation and ICU length of stay, average neutrophil, lymphocyte count, and their ratio on the first, second and third day of hospitalization, and mortality were recorded. P < 0.05 was significant. One hundred and thirty nine patients were studied during one year with mean age 68.29 ±17. 4 years. 136 patients received mechanical ventilation with mean 13.85 ±2.07 days. The mean white blood cells count on the first day of hospitalization was 11776.04±5789.60,and on the second and third days was 12446±2101.16 and 13241.01 ± 7077.17, respectively. The ratio of neutrophil to lymphocyte on the day of hospitalization was 11.38±1.02. This ratio on the second and third days was 11.98±0.99 and 12.94±1.3, respectively. Furthermore, 46.8% of patients died. According to the T-test, significant difference was seen between two groups in term of APACHEII score, count of neutrophil, WBC and N/L ratio on the second and third days (p < 0.05). Blood cell analysis and N/L ratio can be used as a predictor for severity of gram negative sepsis along with other diagnostic procedures.

Bradykinin receptor deficiency or antagonism do not impact the host response during gram-negative pneumonia-derived sepsis

BackgroundKinins are short peptides with a wide range of proinflammatory properties that are generated from kininogens in the so-called kallikrein-kinin system. Kinins exert their biological activities through stimulation of two distinct receptor subtypes, the kinin or bradykinin B1 and B2 receptors (B1R, B2R). Acute challenge models have implicated B1R and B2R in the pathogenesis of sepsis. However, their role in the host response during sepsis originating from the lung is not known.ResultsTo determine the role of B1R and B2R in pneumonia-derived sepsis, B1R/B2R-deficient mice and wild-type mice treated with the B1R antagonist R-715 or the B2R antagonist HOE-140 were studied after infection with the common gram-negative pathogen Klebsiella pneumoniae via the airways. Neither B1R/B2R deficiency nor B1R or B2R inhibition influenced bacterial growth at the primary site of infection or dissemination to distant body sites. In addition, B1R/B2R deficiency or inhibition did not impact local or systemic inflammatory responses during Klebsiella induced pneumosepsis.ConclusionsThese data argue against an important role for kinins in the host response to pneumonia-derived sepsis caused by a clinically relevant pathogen.

Development of a novel short 12-meric papiliocin-derived peptide that is effective against Gram-negative sepsis

The development of novel peptide antibiotics with potent activity against multidrug-resistant Gram-negative bacteria and anti-septic activity is urgently needed. In this study, we designed short, 12-meric antimicrobial peptides by substituting amino acids from the N-terminal 12 residues of the papiliocin (Pap12-1) peptide to alter cationicity and amphipathicity and improve antibacterial activity and bacterial membrane interactions. Pap12-6, with an amphipathic α-helical structure and Trp12 at the C-terminus, showed broad-spectrum antibacterial activity, especially against multidrug-resistant Gram-negative bacteria. Dye leakage, membrane depolarization, and electron microscopy data proved that Pap12-6 kills bacteria by permeabilizing the bacterial membrane. Additionally, Pap12-6 significantly reduced the secretion of NO, TNF-α, and IL-6 and secreted alkaline phosphatase reporter gene activity confirmed that Pap12-6 shows anti-inflammatory activity via a TLR4-mediated NF-κB signaling pathway. In a mouse sepsis model, Pap12-6 significantly improved survival, reduced bacterial growth in organs, and reduced LPS and inflammatory cytokine levels in the serum and organs. Pap12-6 showed minimal cytotoxicity towards mammalian cells and controlled liver and kidney damage, proving its high bacterial selectivity. Our results suggest that Pap12-6 is a promising peptide antibiotic for the therapeutic treatment of Gram-negative sepsis via dual bactericidal and immunomodulatory effects on the host.

Novel Chitohexaose Analog Protects Young and Aged mice from CLP Induced Polymicrobial Sepsis

In Gram-negative bacterial sepsis, production of excess pro-inflammatory cytokines results in hyperinflammation and tissue injury. Anti-inflammatory cytokines such as IL-10 inhibit inflammation and enhance tissue healing. Here, we report a novel approach to treat septicemia associated with intra-abdominal infection in a murine model by delicately balancing pro- and anti-inflammatory cytokines. A novel oligosaccharide compound AVR-25 selectively binds to the TLR4 protein (IC50 = 0.15 µM) in human peripheral blood monocytes and stimulates IL-10 production. Following the cecal ligation and puncture (CLP) procedure, intravenous dosing of AVR-25 (10 mg/kg, 6–12 h post-CLP) alone and in combination with antibiotic imipenem protected both young adult (10–12 week old) and aged (16–18 month old) mice against polymicrobial infection, organ dysfunction, and death. Proinflammatory cytokines (TNF-α, MIP-1, i-NOS) were decreased significantly and restoration of tissue damage was observed in all organs. A decrease in serum C-reactive protein (CRP) and bacterial colony forming unit (CFU) confirmed improved bacterial clearance. Together, these findings demonstrate the therapeutic ability of AVR-25 to mitigate the storm of inflammation and minimize tissue injury with high potential for adjunctive therapy in intra-abdominal sepsis.

Increased TLR4 Expression Aggravates Sepsis by Promoting IFN-γ Expression in CD38-/- Mice.

Gram-negative bacterial sepsis accounts for up to 50% worldwide sepsis that causes hospital mortality. Acute kidney injury (AKI), a common complication of Gram-negative bacterial sepsis, is caused by Toll-like receptor 4 (TLR4) activation. Lipopolysaccharide (LPS) is an endotoxin in Gram-negative bacteria and is recognized specifically by TLR4, which initiates innate immune response. Also, TLR4 signaling pathway activation is essential in response to LPS infection. CD38 is one of the well-known regulators of innate immunity, whose dysregulation contributes to sepsis. Many studies have proven that an attenuated Gram-positive bacterium induces sepsis in a CD38-blocking model. However, the pathogenesis of Gram-negative bacteria-induced sepsis in a CD38−/− mouse model remains unclear. The aim of this study is to investigate whether kidney injury is still attenuated in a LPS-induced CD38−/− sepsis model and identify the potential mechanism. We assess the severity of kidney injury related to proinflammatory cytokine expressions (IFN-γ, TNF-α, IL-1β, and IL-6) in WT and CD38−/− mice. Our results showed more aggravated kidney damage in CD38−/− mice than in WT mice, accompanied with an increase of proinflammatory cytokine expression. In addition, compared with CD38−/−TLR4mut mice, we found an increase of TLR4 expression and mRNA expression of these cytokines in the kidney of CD38−/− mice, although only increased IFN-γ level was detected in the serum. Taken together, these results demonstrated that an increased TLR4 expression in CD38−/− mice could contribute to the aggravation of AKI through boosting of the production of IFN-γ.

Strongyloides Hyperinfection Syndrome in an Immunosuppressed Patient

Strongyloides stercoralis is an intestinal nematode which is endemic in tropical and subtropical countries. The global prevalence of Strongyloides is unknown. Strongyloidiasis is found more frequently in the socioeconomically disadvantaged, in institutionalized populations, and in rural areas. The spectrum of disease varies. It may cause asymptomatic infection, mild eosinophilia or hyperinfection syndrome in the most severe form. Here we reported a case of Strongyloides hyperinfection syndrome in an immunosuppressed patient. This patient is a 54-year-old man with myasthenia gravis on long term azathioprine and prednisolone. He presented with fever associated with diarrhoea and was in septic shock. His blood culture was positive for Klebsiella pneumoniae. Strongyloides stercoralis larvae were detected in his sputum and stool sample. He was diagnosed to have Strongyloides hyperinfection and was treated with subcutaneous ivermectin. He recovered well. Our case demonstrated the association of Strongyloides hyperinfection with superimposed gram-negative sepsis as a consequence of prolonged immunosuppression. A high index of suspicion is needed in approaching patient with risk factors of hyperinfection syndrome.

LPS removal reduces CD80-mediated albuminuria in critically ill patients with Gram-negative sepsis.

LPS-induced sepsis is a leading cause of acute kidney injury (AKI) in critically ill patients. LPS may induce CD80 expression in podocytes with subsequent onset of proteinuria, a risk factor for progressive chronic kidney disease (CKD) frequently observed after AKI. This study aimed to investigate the therapeutic efficacy of LPS removal in decreasing albuminuria through the reduction of podocyte CD80 expression. Between January 2015 and December 2017, 70 consecutive patients with Gram-negative sepsis-induced AKI were randomized to either have coupled plasma filtration and adsorption (CPFA) added to the standard care ( n = 35) or not ( n = 35). To elucidate the possible relationship between LPS-induced renal damage, proteinuria, and CD80 expression in Gram sepsis, a swine model of LPS-induced AKI was set up. Three hours after LPS infusion, animals were treated or not with CPFA for 6 h. Treatment with CPFA significantly reduced serum cytokines, C-reactive protein, procalcitonin, and endotoxin levels in patients with Gram-negative sepsis-induced AKI. CPFA significantly lowered also proteinuria and CD80 urinary excretion. In the swine model of LPS-induced AKI, CD80 glomerular expression, which was undetectable in control pigs, was markedly increased at the podocyte level in LPS-exposed animals. CPFA significantly reduced LPS-induced proteinuria and podocyte CD80 expression in septic pigs. Our data indicate that LPS induces albuminuria via podocyte expression of CD80 and suggest a possible role of timely LPS removal in preventing the maladaptive repair of the podocytes and the consequent increased risk of CKD in sepsis-induced AKI.

Comparison of Antithrombin III and Pentoxifylline Treatments in Gram Negative Sepsis Patients Developing Disseminated Intravascular Coagulation.

Objective:The aim of this study was to evaluate the effects of antithrombin III (AT III) and pentoxifylline treatments on the gram negative septic patients with disseminated intravascular coagulation (DIC).Method:For six days after plasma AT III activity dropped lower than 80% in Gram-patients who developed DIC were treated with AT III (90-120 IU/kg/day in 6 hours) or pentoxifylline (1.5 mg/kg/h in 6 hours) Fibrinogen, FDP, D-dimer, complete blood count, AT III activity, and DIC scores were calculated and recorded.Results:The coagulation tests, AT III activity and FDP started to improve from the second day of treatment with both treatments (p<0.05). D-Dimer started to decrease on the second day of treatment with pentoxifylline (p<0.001) and fourth day of AT III treatment (p<0.05). Fibrinogen levels decreased on the second day of pentoxifylline treatment (p<0.05) and on the last day of AT III treatment (p<0.001). DIC scores started to decrease on the last day of treatment with AT III treatment (p<0.001) and on the third day of treatment with pentoxifylline (p<0.05).Conclusion:Both ATIII and pentoxifylline treatments had positive effects on fibrinogen, FDP, D-Dimer, AT III activity and DIC scores in patients with Gram-negative sepsis who developed DIC.

Quantitation of Total and Free Thiol β2-Glycoprotein I Levels for Diagnostic and Prognostic Purposes in the Antiphospholipid Syndrome.

β2-Glycoprotein I is the major autoantigen in the antiphospholipid syndrome (APS), a prothrombotic disorder characterized by the occurrence of either venous or arterial thrombosis. In women it is also associated with an increased risk of obstetric complications such as recurrent miscarriages. We have identified that the plasma protein β2-glycoprotein I in healthy individuals exists in an optimal ratio between two distinct forms, an oxidized and free thiol, reduced form. This ratio is disrupted in pathophysiological conditions associated with increased oxidative stress such as the APS, but also in the setting of age-related macular degeneration and gram-negative sepsis. We have developed assays that quantify plasma/serum levels of total and free thiol β2-glycoprotein I which can potentially be used for risk stratification and prognostic purposes in the early stages of the aforementioned conditions.

Influence of the Donor of Hydrogen Sulfide GYY4137 on the Activation of Human Neutrophils by E. coli Lipopolysaccharides

Lipopolysaccharides (LPS), components of the cell wall of gram-negative bacteria, activate neutrophils that trigger pathological processes, including gram-negative sepsis. LPS inhibit spontaneous apoptosis of neutrophils that leads to inflammation. In this work we tested the action of H2S donor (GYY4137) on the activation of human neutrophils by E. coli LPS. We estimated the changes in redox status (ROS level, intracellularglutathione, NO), apoptosis and mitochondrial potential of neutrophils under the LPS action in the presence and absence of GYY4137. GYY4137 reduces the ROS level, slightly reduces GSH, does not influence the NO level and has no apoptogenic effect. LPS induce the increasing of ROS level and inhibit spontaneous apoptosis of neutrophils. We found that GYY4137 prevents the growth of ROS caused by LPS and leads to a reduction of LPS-induced inhibition of neutrophil apoptosis. Thus the mechanism of GYY4137 protection against inflammation, triggered by bacterial infection, is concerned with the neutralization of LPS effect on neutrophils.

Platelet-Dense Granules Worsen Pre-Infection Thrombocytopenia during Gram-Negative Pneumonia-Derived Sepsis

Platelet-dense (δ) granules are important for platelet function. Platelets contribute to host defense and vascular integrity during pneumonia and sepsis, and δ granule products, including adenosine diphosphate (ADP), can influence inflammatory responses. We therefore aimed to study the role of platelet δ granules in the host response during sepsis. Hermansky-Pudlak syndrome (Hps)3coa mice (with reduced δ granule content), mice treated with the platelet ADP receptor inhibitor clopidogrel, and appropriate control mice were infected with the human sepsis pathogen Klebsiella pneumoniae via the airways to induce pneumonia and sepsis. In order to override potential redundancy in platelet functions, we also studied Hps3coa and control mice with moderate antibody-induced thrombocytopenia (10%) prior to infection. We found that sepsis-induced thrombocytopenia tended to be less severe in Hps3coa mice, and was significantly ameliorated in Hps3coa mice with low pre-infection platelet counts. Bacterial growth was similar in Hps3coa and control mice in the presence of normal platelet counts prior to infection, but lower in the lungs of Hps3coa mice with low pre-infection platelet counts. Hps3coa mice had unaltered lung pathology and distant organ injury during pneumosepsis, irrespective of pre-infection platelet counts; lung bleeding did not differ between Hps3coa and control mice. Clopidogrel did not influence any host response parameter. These data suggest that platelet δ granules can play a detrimental role in pneumosepsis by aggravating thrombocytopenia and impairing local antibacterial defense, but that these unfavorable effects only become apparent in the presence of low platelet counts.

Dysregulation of Lipid Metabolism in Mkp-1 Deficient Mice during Gram-Negative Sepsis.

Mitogen-activated protein kinase phosphatase (Mkp)-1 exerts its anti-inflammatory activities during Gram-negative sepsis by deactivating p38 and c-Jun N-terminal kinase (JNK). We have previously shown that Mkp-1+/+ mice, but not Mkp-1−/− mice, exhibit hypertriglyceridemia during severe sepsis. However, the regulation of hepatic lipid stores and the underlying mechanism of lipid dysregulation during sepsis remains an enigma. To understand the molecular mechanism underlying the sepsis-associated metabolic changes and the role of Mkp-1 in the process, we infected Mkp-1+/+ and Mkp-1−/− mice with Escherichia coli i.v., and assessed the effects of Mkp-1 deficiency on tissue lipid contents. We also examined the global gene expression profile in the livers via RNA-seq. We found that in the absence of E. coli infection, Mkp-1 deficiency decreased liver triglyceride levels. Upon E. coli infection, Mkp-1+/+ mice, but not Mkp-1−/− mice, developed hepatocyte ballooning and increased lipid deposition in the livers. E. coli infection caused profound changes in the gene expression profile of a large number of proteins that regulate lipid metabolism in wildtype mice, while these changes were substantially disrupted in Mkp-1−/− mice. Interestingly, in Mkp-1+/+ mice E. coli infection resulted in downregulation of genes that facilitate fatty acid synthesis but upregulation of Cd36 and Dgat2, whose protein products mediate fatty acid uptake and triglyceride synthesis, respectively. Taken together, our studies indicate that sepsis leads to a substantial change in triglyceride metabolic gene expression programs and Mkp-1 plays an important role in this process.

Bacterial sepsis triggers an antiviral response that causes translation shutdown.

In response to viral pathogens, the host upregulates antiviral genes that suppress translation of viral mRNAs. However, induction of such antiviral responses may not be exclusive to viruses, as the pathways lie at the intersection of broad inflammatory networks that can also be induced by bacterial pathogens. Using a model of Gram-negative sepsis, we show that propagation of kidney damage initiated by a bacterial origin ultimately involves antiviral responses that result in host translation shutdown. We determined that activation of the eukaryotic translation initiation factor 2-α kinase 2/eukaryotic translation initiation factor 2α (Eif2ak2/Eif2α) axis is the key mediator of translation initiation block in late-phase sepsis. Reversal of this axis mitigated kidney injury. Furthermore, temporal profiling of the kidney translatome revealed that multiple genes involved in formation of the initiation complex were translationally altered during bacterial sepsis. Collectively, our findings imply that translation shutdown is indifferent to the specific initiating pathogen and is an important determinant of tissue injury in sepsis.

Venetoclax in Combination with FLAG-IDA Chemotherapy (FLAG-V-I) for Fit, Relapsed/Refractory AML Patients: Interim Results of a Phase 1b/2 Dose Escalation and Expansion Study

Venetoclax in Combination with FLAG-IDA Chemotherapy (FLAG-V-I) for Fit, Relapsed/Refractory AML Patients: Interim Results of a Phase 1b/2 Dose Escalation and Expansion Study