Lethal Sepsis Research Articles

Vegetation Formation in Staphylococcus Aureus Endocarditis Inversely Correlates With RNAIII and sarA Expression in Invasive Clonal Complex 5 Isolates.

Infective endocarditis (IE) is one of the most feared and lethal diseases caused by Staphylococcus aureus. Once established, the infection is fast-progressing and tissue destructive. S. aureus of the clonal complex 5 (CC5) commonly cause IE yet are severely understudied. IE results from bacterial colonization and formation of tissue biofilms (known as vegetations) on injured or inflamed cardiac endothelium. S. aureus IE is promoted by adhesins, coagulases, and superantigens, with the exotoxins and exoenzymes likely contributing to tissue destruction and dissemination. Expression of the large repertoire of virulence factors required for IE and sequelae is controlled by complex regulatory networks. We investigated the temporal expression of the global regulators agr (RNAIII), rot, sarS, sarA, sigB, and mgrA in 8 invasive CC5 isolates and established intrinsic expression patterns associated with IE outcomes. We show that vegetation formation, as tested in the rabbit model of IE, inversely correlates with RNAIII and sarA expression during growth in Todd-Hewitt broth (TH). Large vegetations with severe sequelae arise from strains with high-level expression of colonization factors but slower transition towards expression of the exotoxins. Overall, strains proficient in vegetation formation, a hallmark of IE, exhibit lower expression of RNAIII and sarA. Simultaneous high expression of RNAIII, sarA, sigB, and mgrA is the one phenotype assessed in this study that fails to promote IE. Thus, RNAIII and sarA expression that provides for rheostat control of colonization and virulence genes, rather than an on and off switch, promote both vegetation formation and lethal sepsis.

The interaction between STING and NCOA4 exacerbates lethal sepsis by orchestrating ferroptosis and inflammatory responses in macrophages

The discovery of STING-related innate immunity has recently provided a deep mechanistic understanding of immunopathy. While the detrimental effects of STING during sepsis had been well documented, the exact mechanism by which STING causes lethal sepsis remains obscure. Through single-cell RNA sequence, genetic approaches, and mass spectrometry, we demonstrate that STING promotes sepsis-induced multiple organ injury by inducing macrophage ferroptosis in a cGAS- and interferon-independent manner. Mechanistically, Q237, E316, and S322 in the CBD domain of STING are critical binding sites for the interaction with the coiled-coil domain of NCOA4. Their interaction not only triggers ferritinophagy-mediated ferroptosis, but also maintains the stability of STING dimers leading to enhanced inflammatory response, and reduces the nuclear localization of NCOA4, which impairs the transcription factor coregulator function of NCOA4. Meanwhile, we identified HET0016 by high throughput screening, a selective 20-HETE synthase inhibitor, decreased STING-induced ferroptosis in peripheral blood mononuclear cells from patients with sepsis and mortality in septic mice model. Our findings uncover a novel mechanism by which the interaction between STING and NCOA4 regulates innate immune response and ferroptosis, which can be reversed by HET0016, providing mechanistic and promising targets insights into sepsis.

ARG1 as a promising biomarker for sepsis diagnosis and prognosis: evidence from WGCNA and PPI network

BackgroundSepsis is a life-threatening multi-organ dysfunction caused by the dysregulated host response to infection. Sepsis remains a major global concern with high mortality and morbidity, while management of sepsis patients relies heavily on early recognition and rapid stratification. This study aims to identify the crucial genes and biomarkers for sepsis which could guide clinicians to make rapid diagnosis and prognostication.MethodsPreliminary analysis of multiple global datasets, including 170 samples from patients with sepsis and 110 healthy control samples, revealed common differentially expressed genes (DEGs) in peripheral blood of patients with sepsis. After Gene Oncology (GO) and pathway analysis, the Weighted Gene Correlation Network Analysis (WGCNA) was used to screen for genes most related with clinical diagnosis. Also, the Protein-Protein Interaction Network (PPI Network) was constructed based on the DEGs and the hub genes were found. The results of WGCNA and PPI network were compared and one shared gene was discovered. Then more datasets of 728 experimental samples and 355 control samples were used to prove the diagnostic and prognostic value of this gene. Last, we used real-time PCR to confirm the bioinformatic results.ResultsFour hundred forty-four common differentially expressed genes in the blood of sepsis patients from different ethnicities were identified. Fifteen genes most related with clinical diagnosis were found by WGCNA, and 24 hub genes with most node degrees were identified by PPI network. ARG1 turned out to be the unique overlapped gene. Further analysis using more datasets showed that ARG1 was not only sharply up-regulated in sepsis than in healthy controls, but also significantly high-expressed in septic shock than in non-septic shock, significantly high-expressed in severe or lethal sepsis than in uncomplicated sepsis, and significantly high-expressed in non-responders than in responders upon early treatment. These all demonstrate the performance of ARG1 as a key biomarker. Last, the up-regulation of ARG1 in the blood was confirmed experimentally.ConclusionsWe identified crucial genes that may play significant roles in sepsis by WGCNA and PPI network. ARG1 was the only overlapped gene in both results and could be used to make an accurate diagnosis, discriminate the severity and predict the treatment response of sepsis.

Efficacy of Candida dubliniensis and Fungal β-Glucans in Inducing Trained Innate Immune Protection Against Inducers of Sepsis

Fungal-bacterial intra-abdominal infections (IAI) can lead to sepsis with significant morbidity and mortality. We have established a murine model of Candida albicans (Ca) and Staphylococcus aureus (Sa) IAI that results in acute lethal sepsis. Prior intraperitoneal or intravenous inoculation with low virulence Candida dubliniensis (Cd) confers high level protection against lethal Ca/Sa IAI and sepsis. Protection via Cd immunization is associated with decreased pro-inflammatory cytokines and mediated by Gr-1+ putative myeloid-derived suppressor cells (MDSCs) representing a novel form of trained innate immunity (TII). The objective of these studies was to determine the extent of Cd-mediated TII against sepsis of broad origin and explore the potential of fungal cell wall components as abiotic immunogen alternatives to induce TII, including zymosan depleted of TLR2 activity (d-zymosan), or purified preparations of β-glucan. Immunized mice were challenged 14 days post-immunization with a lethal array of live or abiotic inducers of sepsis, including Ca/Sa, Ca/Escherichia coli (Ca/Ec), LPS or untreated zymosan. Results showed that live Cd immunization was protective against sepsis induced by Ca/Ec and zymosan, but not LPS. Similar to protection against Ca/Sa, survival was dependent on Gr-1+ cells with no role for macrophages. Among the fungal cell wall compounds as immunogens, immunization with d-zymosan and an alkali-treated form of β-glucan also resulted in significant protection against sepsis induced by Ca/Sa or Ca/Ec, but not LPS sepsis. Again, there was a strong dependence on Gr-1+ cells for protection with one exception, an added role for macrophages in the case of protection induced by alkali-treated β-glucan. Overall, these results demonstrate that immunization with Cd as well as abiotic fungal cell components are capable of Gr-1+ cell-mediated trained innate immune protection against sepsis of broad microbial origin. In addition, abiotic β-glucans represent potential alternatives to live Cd for protection against lethal polymicrobial sepsis.

Methylsulfonylmethane protects against lethal dose MRSA-induced sepsis through promoting M2 macrophage polarization

BackgroundMulti-drug-resistant bacterial infections, which have become a global threat, lack effective treatments. The discoveries of non-antibiotics with different modes of antibacterial action, such as methylsulfonylmethane (MSM), are a promising new treatment for multi-drug-resistant pathogens. MethodsWe constructed a mouse peritonitis infection model to evaluate the effects of MSM against methicillin-resistant Staphylococcus aureus (MRSA) infection. The time-kill kinetics of MSM against MRSA and the effect of MSM on the integrity of bacterial cell membrane were measured. Viability effects of MSM on THP1 cells were performed by CCK-8 cytotoxicity assay. Systematic inflammatory factor levels of mice were detected using ELISA. The immune response of peritoneal macrophages during MRSA-infection was evaluated using RNA sequencing. Gene Ontology function, Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses, and correlation analyses were applied to analysis RNA sequencing data. RT-qPCR, western blotting and flow cytometry were performed to analysis the gene and protein expression levels of macrophages. ResultsIn in vitro experiments, MSM did not show significant killing effects on the growth of MRSA directly and did not destroy bacterial membrane integrity. MSM also displayed no significant effects on the proliferative capacity of THP1 cells. However, MSM treatment protected mice against a lethal dose MRSA-infection and decreased systemic inflammation. MSM upregulated metabolic pathway in peritoneal macrophages, especial glycolysis, during MRSA infection. MSM increased the expression of M2 markers (such as Arg1), promoted phosphorylation of STAT3 (which regulates M2 polarization), and decreased the expression of M1 markers in peritoneal macrophages. Additionally, MSM treatment increased the expression of H3K18 lactylation specific target genes, including Arg1. GNE-140, the LDHA-specific inhibitor of glycolysis, blocked the MSM-induced Arg1 expression in this disease model. ConclusionsMSM protects against MRSA infection through immunomodulation. MSM promotes the expression of Arg1 by lactate-H3K18la pathway to control macrophage to M2 polarization; it firstly provides therapeutic potential for drug-resistant infections and sepsis.

Glycyrrhizin attenuates caspase-11-dependent immune responses and coagulopathy by targeting high mobility group box 1

Caspase-11, a cytosolic endotoxin (lipopolysaccharide: LPS) receptor, mediates pyroptosis, coagulopathy and lethality in endoxemia and bacterial sepsis. The activation of caspase-11 requires high mobility group box 1 (HMGB1)-mediated translocation of LPS from the extracellular space to the cytosol. Here we show that HMGB1-dependent cytosolic delivery of LPS was blocked by glycyrrhizin, a medication to treat liver diseases. Glycyrrhizin competitively bound HMGB1 and thereby inhibiting the physical interaction between HMGB1 and LPS. Treatment of glycyrrhizin significantly attenuated caspase-11-dependent immune responses, coagulopathy, organ injury and lethality in endotoxemia and experimental sepsis. Together, our data suggest that pharmacological inhibition of the cytosolic delivery of LPS by glycyrrhizin might be a potential therapeutic strategy to treat sepsis, which is a leading cause of death in hospitals worldwide.

HS1 deficiency protects against sepsis by attenuating neutrophil-inflicted lung damage

Sepsis remains an important health problem worldwide due to inefficient treatments often resulting in multi-organ failure. Neutrophil recruitment is critical during sepsis. While neutrophils are required to combat invading bacteria, excessive neutrophil recruitment contributes to tissue damage due to their arsenal of molecular weapons that do not distinguish between host and pathogen. Thus, neutrophil recruitment needs to be fine-tuned to ensure bacterial killing, while avoiding neutrophil-inflicted tissue damage. We recently showed that the actin-binding protein HS1 promotes neutrophil extravasation; and hypothesized that HS1 is also a critical regulator of sepsis progression. We evaluated the role of HS1 in a model of lethal sepsis induced by cecal-ligation and puncture. We found that septic HS1-deficient mice had a better survival rate compared to WT mice due to absence of lung damage. Lungs of septic HS1-deficient mice showed less inflammation, fibrosis, and vascular congestion. Importantly, systemic CLP-induced neutrophil recruitment was attenuated in the lungs, the peritoneum and the cremaster in the absence of HS1. Lungs of HS1-deficient mice produced significantly more interleukin-10. Compared to WT neutrophils, those HS1-deficient neutrophils that reached the lungs had increased surface levels of Gr-1, ICAM-1, and L-selectin. Interestingly, HS1-deficient neutrophils had similar F-actin content and phagocytic activity, but they failed to polymerize actin and deform in response to CXCL-1 likely explaining the reduced systemic neutrophil recruitment in HS1-deficient mice. Our data show that HS1 deficiency protects against sepsis by attenuating neutrophil recruitment to amounts sufficient to combat bacterial infection, but insufficient to induce tissue damage.

Transitional premonocytes emerge in the periphery for host defense against bacterial infections.

Circulating Ly6Chi monocytes often undergo cellular death upon exhaustion of their antibacterial effector functions, which limits their capacity for subsequent macrophage differentiation. This shrouds the understanding on how the host replaces the tissue-resident macrophage niche effectively during bacterial invasion to avert infection morbidity. Here, we show that proliferating transitional premonocytes (TpMos), an immediate precursor of mature Ly6Chi monocytes (MatMos), were mobilized into the periphery in response to acute bacterial infection and sepsis. TpMos were less susceptible to apoptosis and served as the main source of macrophage replenishment when MatMos were vulnerable toward bacteria-induced cellular death. Furthermore, TpMo and its derived macrophages contributed to host defense by balancing the proinflammatory cytokine response of MatMos. Consequently, adoptive transfer of TpMos improved the survival outcome of lethal sepsis. Our findings hence highlight a protective role for TpMos during bacterial infections and their contribution toward monocyte-derived macrophage heterogeneity in distinct disease outcomes.

Inhibitory functions of cornuside on TGFBIp-mediated septic responses.

Transforming growth factor β-induced protein (TGFBIp), as an extracellular matrix protein, is expressed TGF-β in some types of cells. Experimental sepsis is mediated by expressed and released TGFBIp in primary human umbilical vein endothelial cells (HUVECs). Cornuside (CNS) is a bisiridoid glucoside compound found in the fruit of Cornus officinalis SIEB. et ZUCC. Based on the known functions of CNS, such as the immunomodulatory and anti-inflammatory activities, we tested whether TGFBIp-mediated septic responses were suppressed by CNS in human endothelial cells and mice and investigated the underlying anti-septic mechanisms of CNS. Data showed that the secretion of TGFBIp by lipopolysaccharide (LPS) and severe septic responses by TGFBIp were effectively inhibited by CNS. And, TGFBIp-mediated sepsis lethality and pulmonary injury were reduced by CNS. Therefore, the suppression of TGFBIp-mediated septic responses by CNS suggested that CNS may be used as a potential therapeutic agent for several vascular inflammatory diseases, with the inhibition of the TGFBIp signaling pathway as the mechanism of action.Graphical abstract

Design, synthesis, and in-silico studies of pyrazolylpyridine analogues: A futuristic antibacterial contender against coagulase positive superbug-MRSA

In the coagulation cascade during host infection by MRSA, staphylococci are blocked within a fibrin clot mesh, and very hard to clear these pathogens by host tissues and also enable the pathogen to cause lethal sepsis. To overcome this complication, this work aimed at synthesis of pyrazolylpyridine analogs as potential anti-superbug agents and using a simple synthetic protocol. The synthesized pyrazolylpyridine analogs were characterized using spectroscopic techniques like FTIR, NMR, and mass spectroscopy. All synthesized pyrazolylpyridine analogs were evaluated for the in-vitro antibacterial activity. The antibacterial activity was further confirmed with cellular content leakage and measurement of potassium efflux. The anti-biofilm activity was studied qualitatively and quantitatively with crystal violet dye technique. The compounds binding ability with 1NU7 and 1MWT proteins were tested using molecular docking and further analogs were exposed to dynamic simulations. The synthesized compounds were also inspected for their ADMET analysis. It was observed that 4(a g) series showed a potential antibacterial activity compared to 3(a g) analogs to standard drug vancomycin. The MIC value of 4e was found to 30±0.4 µg/mL and also showed an excellent anti-biofilm activity. The revealed data was strongly correlated with molecular docking studies on staphylocoagulase enzyme (PDB: 1NU7) and Penicillin-binding protein 2a (PBP2a) (PDB: 1MWT) with a good docking score, and glide score with high binding energy. By dynamic simulation it was obtained that 4d exhibit stable interaction with staph-coagulase enzyme up to 20 ns with PBP2a protein, and compound 4e exhibited stable interaction at both active and allosteric site. The potent pyrazolylpyridine was designed and synthesized to treat infectious agent MRSA. Among the analogs synthesized, compound 4e showed antibacterial activity validated by insilico studies. In this study, experimental results show significant anti-coagulase, anti-biofilm and antimicrobial activity against MRSA by synthesised compound 4e. This leads to the compound 4e can serve as a potent drug against MRSA in upcoming days.

Protective Role of an Initial Low-Dose Septic Challenge against Lethal Sepsis in Neonatal Mice: A Pilot Study.

Neonatal sepsis is characterized by systemic bacterial invasion followed by a massive inflammatory response. At present, no therapeutic strategy has been found that significantly reduces the mortality of neonatal sepsis. We aimed to investigate the protective role of an initial low-dose septic challenge for the prevention of subsequent lethal sepsis in a mouse model. A stock cecal slurry (CS) solution was prepared from adult ceca. The LD83 (1.5 mg CS/g) was used for all animals. An initial challenge of normal saline (NS) or 0.5 mg CS/g (non-lethal dose) was administered at four days of age, then 1.5 mg CS/g was administered intraperitoneally at seven days of age (72 h post-initial challenge), and survival was monitored. Initial exposure to NS (n = 10) resulted in 90% mortality following exposure to the LD83 CS dose in contrast to an initial exposure to CS (n = 16), which significantly decreased mortality to 6% (p < 0.0001), reduced blood bacterial counts, attenuated inflammatory responses, and suppressed lipid mediators. Initial exposure to a non-lethal CS dose prior to exposure to a lethal CS dose significantly reduces sepsis mortality, a protective effect that might be mediated by modulating abnormal systemic inflammatory responses.

1065. Efficacy of Cefiderocol in Experimental Stenotrophomonas maltophilia Pneumonia in Persistently Neutropenic Rabbits

Background Stenotrophomonas maltophilia causes lethal pneumonia, bacteremia, and sepsis in immunocompromised patients. As a standard of care, trimethoprim-sulfamethoxazole (T/S) is considered to be the first-line therapy for Stenotrophomonas pneumonia. Cefiderocol (CFDC) is a new parenteral siderophore cephalosporin that is transported through the outer cell membrane as a siderophore mimic that then inhibits Gram-negative cell wall biosynthesis. CFDC has potent activity in vitro against S. maltophilia; however, little is known about its in vivo activity against Stenotrophomonas pneumonia in immunocompromised hosts. We therefore studied CFDC in comparison to TS in the persistently neutropenic rabbit model of Stenotrophomonas pneumonia. This rabbit model, in contrast to conventional murine models, reflects the human pattern of infection more accurately over time.MethodsWe initially studied the plasma pharmacokinetics of CFDC in non-infected and infected animals. Stenotrophomonas pneumonia was established by direct endotracheal inoculation of S. maltophilia 1×1010 CFUs for tracheobronchial colonization that evolved into bronchopneumonia. Experimental groups consisted of CFDC, T/S, and untreated controls (UC). Rabbits received CFDC at 120 mg/kg IV Q8h and T/S at 5 mg/kg IV Q12h. Profound persistent neutropenia was maintained with cytosine arabinoside. Treatment was continued for 10 days.ResultsThere were no significant differences between non-infected and infected rabbits in CFDC pharmacokinetics. Rabbits treated with CFDC and T/S demonstrated significant decreases of residual pulmonary and BAL bacterial burden vs UC (p≤0.001). CFDC achieved full clearance of S. maltophilia from lung tissue and BAL. This antibacterial activity coincided with significant reduction of lung weights (marker of organism-mediated pulmonary injury) in the CFDC group vs T/S and UC (p< 0.01). Survival was prolonged in the CFDC treatment group with 87% survival in comparison to that of T/S (25%) and UC (0%) (p< 0.01). Table 1. Efficacy of Cefiderocol in Experimental Stenotrophomonas maltophilia Pneumonia in Persistency Neutropenic Rabbits ConclusionCefiderocol is highly active in treatment of experimental S. maltophilia pneumonia in persistently neutropenic rabbits, thus laying the foundation for future clinical investigations against this lethal infection. Disclosures Naoki Ishibashi, MD, Shionogi, Inc. (Employee) Benjamin Georgiades, n/a, Shionogi, Inc. (Consultant) Roger Echols, MD, Shionogi (Consultant) Robert A. Bonomo, MD, entasis (Research Grant or Support)Merck (Grant/Research Support)NIH (Grant/Research Support)VA Merit Award (Grant/Research Support)VenatoRx (Grant/Research Support) Yoshinori Yamano, PhD, Shionogi (Employee) Thomas J. Walsh, MD, PhD (hon), Scynexis (Consultant, Grant/Research Support)Shionogi (Consultant, Grant/Research Support)

Sestrin2 protects against lethal sepsis by suppressing the pyroptosis of dendritic cells

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Sestrin2 (SESN2), a highly evolutionarily conserved protein, is critically involved in the cellular response to various stresses and has been confirmed to maintain the homeostasis of the internal environment. However, the potential effects of SESN2 in regulating dendritic cells (DCs) pyroptosis in the context of sepsis and the related mechanisms are poorly characterized. In this study, we found that SESN2 was capable of decreasing gasdermin D (GSDMD)-dependent pyroptosis of splenic DCs by inhibiting endoplasmic reticulum (ER) stress (ERS)-related nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3)-mediated ASC pyroptosome formation and caspase-1 (CASP-1) activation. Furthermore, SESN2 deficiency induced NLRP3/ASC/CASP-1-dependent pyroptosis and the production of proinflammatory cytokines by exacerbating the PERK–ATF4–CHOP signaling pathway, resulting in an increase in the mortality of septic mice, which was reversed by inhibiting ERS. These findings suggest that SESN2 appears to be essential for inhibiting NLRP3 inflammasome hyperactivation, reducing CASP-1-dependent pyroptosis, and improving sepsis outcomes through stabilization of the ER. The present study might have important implications for exploration of novel potential therapeutic targets for the treatment of sepsis complications.

Indoprofen exerts a potent therapeutic effect against sepsis by alleviating high mobility group box 1-mediated inflammatory responses

Indoprofen is a non-steroidal anti-inflammatory drug, and has provided insights into treatment of spinal muscular atrophies; however, the treatment effect of indoprofen on sepsis and the precise underlying mechanism remain to be elucidated. This study was carried out to examine the inhibitory effect of indoprofen on high mobility group box 1 (HMGB1)-mediated inflammatory responses in vivo and in vitro. Intraperitoneal injection of indoprofen (20 or 40 mg/kg) at 8 h post-sepsis markedly improved the survival of BALB/c mice and ameliorated multiple-organ injury by blocking the inflammatory responses. In addition, indoprofen partially reduced the HMGB1 level in the serum and in the lung, as well as ameliorated pulmonary edema. Mechanistically, indoprofen potently inhibited the release of HMGB1 following stimulation by lipopolysaccharide (LPS) or polyinosinic:polycytidylic acid (poly I:C), and suppressed recombinant human HMGB1(rhHMGB1)-induced inflammatory responses. It was also found that indoprofen has both cyclooxygenase 2-dependent and -independent inhibitory effects on the proinflammatory effect of HMGB1 in THP-1 cells. Further, the drug reduced rhHMGB1-induced cell surface levels of toll-like receptor 2, toll-like receptor 4, and receptor of advanced glycation end-products in a concentration-dependent manner. Collectively, these data demonstrated that the anti-inflammatory effect of indoprofen in sepsis was associated with HMGB1-mediated inflammatory responses, thus offering a favorable mechanistic basis to support the therapeutic potential of indoprofen for the treatment of lethal sepsis or other inflammatory diseases.

Trained Innate Immunity Induced by Vaccination with Low-Virulence Candida Species Mediates Protection against Several Forms of Fungal Sepsis via Ly6G+ Gr-1+ Leukocytes.

ABSTRACTWe recently discovered a novel form of trained innate immunity (TII) induced by low-virulence Candida species (i.e., Candida dubliniensis) that protects against lethal fungal/bacterial infection. Mice vaccinated by intraperitoneal (i.p.) inoculation are protected against lethal sepsis following Candida albicans/Staphylococcus aureus (Ca/Sa) intra-abdominal infection (IAI) or Ca bloodstream infection (BSI). The protection against IAI is mediated by long-lived Gr-1+ leukocytes as putative myeloid-derived suppressor cells (MDSCs) and not by prototypical trained macrophages. This study aimed to determine if a similar TII mechanism (Gr-1+ cell-mediated suppression of sepsis) is protective against BSI and whether this TII can also be induced following intravenous (i.v.) vaccination. For this, mice were vaccinated with low-virulence Candida strains (i.p. or i.v.), followed by lethal challenge (Ca/Sa i.p. or Ca i.v.) 14 days later, and observed for sepsis (hypothermia, sepsis scoring, and serum cytokines), organ fungal burden, and mortality. Similar parameters were monitored following depletion of macrophages or Gr-1+ leukocytes during lethal challenge. The results showed that mice vaccinated i.p. or i.v. were protected against lethal Ca/Sa IAI or Ca BSI. In all cases, protection was mediated by Ly6G+ Gr-1+ putative granulocytic MDSCs (G-MDSCs), with no role for macrophages, and correlated with reduced sepsis parameters. Protection also correlated with reduced fungal burden in spleen and brain but not liver or kidney. These results suggest that Ly6G+ G-MDSC-mediated TII is induced by either the i.p. and i.v. route of inoculation and protects against IAI or BSI forms of systemic candidiasis, with survival correlating with amelioration of sepsis and reduced organ-specific fungal burden.

Lethality by neonatal sepsis, risk factors and microbiological characteristics

Neonatal sepsis is one of the leading causes of death in this population and is related to gestational and perinatal factors as well as factors inherent in the newborn. To associate perinatal, neonatal, and microbiological factors to sepsis mortality. Retrospective ca se-control study of hospitalized newborns with confirmed neonatal sepsis through blood cultures, from 2013 to 2019. Cases were defined as those patients with confirmed sepsis that presented a fa tal outcome and controls as those newborns with confirmed sepsis without a fatal outcome. Cases and controls were compared regarding maternal, perinatal, neonatal, and microbiological factors for quantitative variables in order to identify the trend and concentration of the variables studied. Eleven cases were identified and three controls were randomly assigned to each case, stra tified by gestational age groups. The median birth weight and gestational age were 1,004 grams and 28 weeks, respectively. Escherichia coli was identified in 21% of the patients, Candida parapsilosis in 16%, and Staphylococcus aureus in 14%. There was a statistically significant association between sepsis lethality and vaginal delivery (P = 0.023), infection before 7 days of life (P = 0.025), and Can dida parapsilosis infection (P = 0.049). The multivariate analysis determined a statistically significant association between neonatal sepsis lethality and vaginal delivery and microbiological identification of Candida parapsilosis. Neonatal sepsis lethality was more frequent in the group of extremely preterm infants, newborns withhistory of vaginal delivery, early microbiological isolation, and t infection with Candida parapsilosis.

Targeting multiple mediators of sepsis using multifunctional tannic acid-Zn2+-gentamicin nanoparticles

Targeting multiple mediators of sepsis using multifunctional tannic acid-Zn2+-gentamicin nanoparticles

Glucocorticoid resistance and hyperlactatemia: A tag team to worsen sepsis

Glucocorticoid resistance often dims glucocorticoid's therapeutic efficacy in sepsis. However, the mechanism is incompletely understood. In this issue, Vandewalle etal. (2021) demonstrate that glucocorticoid resistance leads to hyperlactatemia and that this combination facilitates lethal sepsis. This insight gives important clarity to the pathophysiology of sepsis, while further suggesting therapeutic avenues for its treatment.

Gasdermin D inhibition prevents multiple organ dysfunction during sepsis by blocking NET formation

AbstractMultiple organ dysfunction is the most severe outcome of sepsis progression and is highly correlated with a worse prognosis. Excessive neutrophil extracellular traps (NETs) are critical players in the development of organ failure during sepsis. Therefore, interventions targeting NET release would likely effectively prevent NET-based organ injury associated with this disease. Herein, we demonstrate that the pore-forming protein gasdermin D (GSDMD) is active in neutrophils from septic humans and mice and plays a crucial role in NET release. Inhibition of GSDMD with disulfiram or genic deletion abrogated NET formation, reducing multiple organ dysfunction and sepsis lethality. Mechanistically, we demonstrate that during sepsis, activation of the caspase-11/GSDMD pathway controls NET release by neutrophils during sepsis. In summary, our findings uncover a novel therapeutic use for disulfiram and suggest that GSDMD is a therapeutic target to improve sepsis treatment.

AB569, a Novel, Topical Bactericidal Gel Formulation, Kills Pseudomonas aeruginosa and Promotes Wound Healing in a Murine Model of Burn Wound Infection.

ABSTRACTCutaneous thermal injuries from burns/explosives are a major cause of morbidity and mortality and represent a monumental burden on our current health care system. Injury severity is predominantly due to potentially lethal sepsis caused by multidrug-resistant (MDR) bacteria such as Pseudomonas aeruginosa (MDR-PA). Thus, there is a critical need to develop novel and effective antimicrobials for the (i) prevention, (ii) treatment, and (iii) healing of such wounds that are complicated by MDR-P. aeruginosa and other bacterial infections. AB569 is a novel bactericidal tandem consisting of acidified NaNO2 (A-NO2–) and Na2-EDTA. Here, we first show that AB569 acts synergistically to kill all human burn wound strains of P. aeruginosa in vitro. This was found to be due, in part, to the generation of A-NO2–-mediated nitric oxide (NO) formation coupled with the metal chelating properties of Na2-EDTA. Using a murine scald burn wound model of P. aeruginosa infection, an AB569-Solosite gel formulation eradicated all bacteria. Futher, we also demonstrate enhanced AB569-mediated wound healing by not only accelerating wound contraction, but also by reducing levels of the proinflammatory cytokines interleukin-6 (IL-6) and IL-1β while increasing the levels of anti-inflammatory cytokine, IL-10, and granulocyte-colony-stimulating factor (G-CSF). We also observed better epidermal restoration in AB569-treated wounds. Taken together, we conclude that this study provides solid foundational evidence that AB569 can be used topically to treat highly problematic dermal insults, including wound, burn, blast, and likely, diabetic infections in civilian and military populations, and help relieve the economical burden that MDR organisms have on the global health care system.