Sepsis, defined as life-threatening organ dysfunction due to a dysregulated host response to infection, is recognised by the World Health Organization as a global health priority. Each year, 5000 of the 18 000 adults with sepsis treated in Australian intensive care units die, with survivors suffering long-term physical, cognitive and psychological dysfunction, which is poorly recognised and frequently untreated. There are currently no effective pharmacological treatments for sepsis, making early recognition, resuscitation and immediate treatment with appropriate antibiotics the key to reducing the burden of resulting disease. The majority of sepsis, around 70–80%, is community acquired making emergency departments and primary care key targets to improve recognition and early management. Case fatality rates for sepsis are decreasing in many countries with the reduction attributed to national or regional screening and quality improvement programmes focused on early identification and immediate treatment. The optimum approach to treating established sepsis has been informed by high-quality, multicentre investigator initiated randomised trials with much of the valuable data coming from National Health and Medical Research Council-funded trials run from Australia. While early recognition and improved management of the acute episode are important steps in reducing death and disability from sepsis, a substantial reduction in the burden of sepsis-related disease requires action across the entire healthcare system. In this narrative review, we provide a summary of current knowledge on epidemiology of sepsis and septic shock and recommendations on the optimum approach to the management of these conditions in adults.

Sepsis and septic shock: current approaches to management.

OBJECTIVES Checkpoint inhibitors have been proposed for sepsis following reports of increased checkpoint molecule expression in septic patients. To determine whether clinical studies investigating checkpoint molecule expression provide strong evidence supporting trials of checkpoint inhibitors for sepsis. DATA SOURCES PubMed, EMBASE, Scopus, Web of Science, inception through October 2019. STUDY SELECTION Studies comparing checkpoint molecule expression in septic patients versus healthy controls or critically ill nonseptic patients or in sepsis nonsurvivors versus survivors. DATA EXTRACTION Two investigators extracted data and evaluated study quality. DATA SYNTHESIS Thirty-six studies were retrieved. Across 26 studies, compared with healthy controls, septic patients had significantly (p ≤ 0.05) increased CD4+ lymphocyte programmed death-1 and monocyte programmed death-ligand-1 expression in most studies. Other checkpoint molecule expressions were variable and studied less frequently. Across 11 studies, compared with critically ill nonseptic, septic patients had significantly increased checkpoint molecule expression in three or fewer studies. Septic patients had higher severity of illness scores, comorbidities, and mortality in three studies providing analysis. Across 12 studies, compared with septic survivors, nonsurvivors had significantly increased expression of any checkpoint molecule on any cell type in five or fewer studies. Of all 36 studies, none adjusted for nonseptic covariates reported to increase checkpoint molecule expression. CONCLUSIONS Although sepsis may increase some checkpoint molecule expression compared with healthy controls, the data are limited and inconsistent. Further, data from the more informative patient comparisons are potentially confounded by severity of illness. These clinical checkpoint molecule expression studies do not yet provide a strong rationale for trials of checkpoint inhibitor therapy for sepsis.

Inhibitory Immune Checkpoint Molecule Expression in Clinical Sepsis Studies: A Systematic Review.

Sepsis is described as a life-threatening organ dysfunction and a heterogeneous syndrome that is a leading cause of morbidity and mortality in intensive care settings. Severe sepsis could incite an uncontrollable surge of inflammatory cytokines, and the host immune system's immunosuppression could respond to counter excessive inflammatory responses, characterized by the accumulated anti-inflammatory cytokines, impaired function of immune cells, over-proliferation of myeloid-derived suppressor cells and regulatory T cells, depletion of immune effector cells by different means of death, etc. In this review, we delve into the underlying pathological mechanisms of sepsis, emphasizing both the hyperinflammatory phase and the associated immunosuppression. We offer an in-depth exploration of the critical mechanisms underlying sepsis, spanning from individual immune cells to a holistic organ perspective, and further down to the epigenetic and metabolic reprogramming. Furthermore, we outline the strengths of artificial intelligence in analyzing extensive datasets pertaining to septic patients, showcasing how classifiers trained on various clinical data sources can identify distinct sepsis phenotypes and thus to guide personalized therapy strategies for the management of sepsis. Additionally, we provide a comprehensive summary of recent, reliable biomarkers for hyperinflammatory and immunosuppressive states, facilitating more precise and expedited diagnosis of sepsis. 

The potential immunological mechanisms of sepsis

OBJECTIVE
The present study aimed to investigate the protective action and mechanism of songorine on sepsis-induced acute lung injury (ALI).


METHODS
The sepsis-induced ALI mouse and cell models were established by lipopolysaccharide (LPS) induction. Lung injury was assayed by hematoxylin and eosin staining, lung injury score, and lung wet-to-dry (W/D) weight ratio. Apoptosis in lung tissues was evaluated by TUNEL assay, and the expression of apoptosis-related markers (Bcl2, Bax, and caspase-3) was measured by western blotting. Levels of pro-inflammatory factors and oxidative stress markers in the bronchoalveolar lavage fluid (BALF) of mice were measured by ELISA and RT-qPCR. The expression of PI3K/AKT/NRF2 pathway-related proteins was analyzed by western blotting.


RESULTS
Songorine treatment at 40 mg/kg mitigated sepsis-induced ALI, characterized by improved histopathology, lung injury score, and lung W/D weight ratio (p < 0.05). Moreover, songorine markedly attenuated sepsis-induced apoptosis in lung tissues; this was evidenced by an increase in Bcl2 levels and a decrease in Bax and caspase-3 levels (p < 0.01). Also, songorine reduced levels of proinflammatory cytokines (TNF-α, IL-6, IL-1β and MPO) and oxidative stress regulators (SOD and GSH) in the BALF of LPS-induced sepsis mice and RAW264.7 cells (p < 0.05). In addition, songorine upregulated the PI3K/AKT/NRF2 pathway-related proteins in LPS-induced sepsis mice and RAW264.7 cells (p < 0.05). Furthermore, LY294002 (a PI3K inhibitor) treatment reversed the protective effect of songorine on sepsis-induced ALI.


CONCLUSION
Songorine inhibits oxidative stress-related inflammation in sepsis-induced ALI via the activation of the PI3K/AKT/NRF2 signaling pathway.

Songorine inhibits oxidative stress-related inflammation through PI3K/AKT/NRF2 signaling pathway to alleviate lipopolysaccharide-induced septic acute lung injury.

As an immune marker, serum soluble programmed cell death ligand-1 (sPD-L1) is significantly increased in sepsis and is predictive of mortality. We investigated the prognostic value of sPD-L1 in postseptic immunosuppression and progression to chronic critical illness (CCI).Adults with sepsis in intensive care units (ICUs) for the first time were screened and assigned to either a chronic critical illness (CCI) group (ICU stay ≥14 days with persistent organ dysfunction) or a rapid recovery (RAP) group based on clinical outcome. Data regarding basic admission information and clinical parameters were collected and compared across the two groups. Serum sPD-L1 levels were detected by enzyme-linked immunosorbent assay at admission and on the 7th day (D7). Logistic regression analysis was used to determine the factors affecting septic patients' lymphocytopenia diagnosis on day 7 and CCI progression during hospitalization. The receiver operating characteristic (ROC) curve and DeLong test were used to assess variable predictive power.During the study period, a total of 166 septic patients were admitted to the intensive care unit, and 91 septic patients were enrolled after screening. Compared to those in healthy individuals, the sPD-L1 levels in septic patients were significantly higher and positively correlated with traditional inflammatory markers and disease severity scores (P < 0.05). In a multivariate regression analysis, sPD-L1 alone predicted lymphocytopenia on day 7 (P < 0.05). In the sepsis cohort, 59 patients (64.8%) experienced RAP, and 32 patients (35.2%) developed CCI. Compared to the RAP group, the patients in the CCI group had a higher mean age, greater severity of disease, and higher mortality (P < 0.05). D7-sPD-L1 remained higher in the CCI group, and the area under the curve (AUC) that predicted the occurrence of CCI was equivalent to the APACHE II score, with AUCs of 0.782 and 0.708, respectively.The severity of infection and immunosuppression in sepsis may be linked to serum sPD-L1. D7-sPD-L1 is valuable in predicting the progression of CCI in patients. 

Predictive value of soluble programmed cell death ligand-1 in the progression of septic patients to chronic critical illness in the intensive care unit: A prospective observational clinical study

Immunotherapy targeting the programmed cell death protein-1 (PD-1)–programmed cell death ligand-1 (PDL-1) axis in sepsis is poised for clinical trials, although optimal inclusion criteria and predictors of response are not well characterized. We evaluated the kinetics of soluble (s)PD-1 and sPD-L1 in 30 septic intensive care unit (ICU) patients and 30 nonseptic ICU patients (Table 1). sPD-1 and sPD-L1 were significantly elevated among the septic cohort compared with the nonseptic ICU patients at enrollment (17.7 pg/ml vs. 4.5 pg/ml, p = 0.002; and 29.9 pg/ml vs. 11.3 pg/ml, p = 0.02; respectively) and were associated with sepsis (Fig. 1). Higher sPD-L1 on day 3 was associated with mortality among septic patients (16.7 pg/ml vs. 3.0 pg/ml, p = 0.054) and also in the total ICU cohort (14.9 pg/ ml vs. 2.7 pg/ml, p = 0.026). Soluble PD-L1 regressed on interleukin (IL)-6 and interferon (IFN)γ levels were significantly associated in the total ICU cohort and septic patients, possibly pointing to upstream triggers for post-transcriptional modifications. Tumor necrosis factor (TNF)α regressed on sPD-1 and sPD-L1 was significant in all populations including septic survivors, revealing possible downstream effects of sPD-1 and sPD-L1. Initial sPD-1 levels correlated with a drop in lymphocyte count to < 1 × 10/L (area under the receiver operating characteristic (ROC) curve 0.72, p = 0.006) and to < 0.6 × 10/L (area under the ROC curve 0.68, p = 0.02). sPD-L1 also correlated with lymphocyte count drop to < 1 × 10/L during the hospital stay. The correlation between the two immune checkpoint molecules, sPD-1 and sPD-L1, was also significant on enrollment, and at days 1 and 3 (p < 0.001, p < 0.001, p = 0.004, respectively; Fig. 2). sPD-1 and sPD-L1 are easily sampled, making them advantageous biomarkers in sepsis. A recent study demonstrated elevated sPD-1 among patients with infected pancreatitis [1]. sPD-1 may serve as an indicator of severity of sepsis among emergency room patients [2]. Lange et al. [3] reported that sPD-1 levels did not differ significantly between septic and nonseptic critically ill patients and had no association with outcome among septic patients. Our results may stem from sampling a different population to Lange and colleagues. Our controls, while critically ill, had lower severity of illness and mortality. Additionally, we excluded patients with immunocompromise, malignancy, and organ transplantation due to possible iatrogenic skewing of sPD-1 and sPD-L1. Approximately half of the control group in Lange et al. developed infections; thus, observations comparing sepsis versus nonseptic groups were limited to initial measurement only. sPD-1 and sPD-L1 are point-of-care tests that might eventually guide personalized medicine in sepsis. These soluble immune checkpoints can risk-stratify patients for immunotherapy in sepsis and may potentially serve as targets themselves.

/pdf/soluble-programmed-cell-death-protein-1-and-programmed-cell-7s61h1e2dv.pdf

Soluble programmed cell death protein-1 and programmed cell death ligand-1 in sepsis.

Background Alzheimer's disease (AD) is a neurodegenerative disorder and the major cause of senile dementia. The Reelin pathway has been involved in both learning and AD pathogenesis. However, the specific Reelin-related gene signature during the pathological process remains unknown. Methods Reelin-related gene (CDK5R1) expression was analyzed using the GEO datasets. The relevant genes of CDK5R1 were identified using differential expression analysis and weighted gene correlation network analysis (WGCNA) based on the GSE43850 dataset. ConsensusClusterPlus analysis was applied to identify subtypes (C1 and C2) of AD. The CIBERSORT algorithm was used to assess the immune cell infiltration between the two AD subtypes. Results CDK5R1 was downregulated in AD. 244 differentially expressed CDK5R1-related genes (DECRGs) between the two subgroups were mainly enriched in GABAergic synapse, neuroactive ligand-receptor interaction, synapse organization, neurotransmitter transport, etc. Furthermore, the GSVA results indicated that immune-related pathways were significantly enriched in the C1 subgroup. Interestingly, 10 Reelin pathway-related genes (CRK, DAB2IP, LRP8, RELN, STAT5A, CDK5, CDK5R1, DAB1, FYN, and SH3KBP1) were abnormally expressed between the two subgroups. The proportion of T cell gamma delta, monocytes, macrophage M2, and dendritic cells activated decreased from C1 to C2, while the proportion of plasma cells, T cell follicular helper, and NK cells activated increased. Conclusion Two CDK5R1-related subtypes of AD were identified, helping us to better understand the role of CDK5R1 in the pathological process of AD.

/pdf/identification-of-two-cdk5r1-related-subtypes-and-2hup65l3.pdf

Identification of Two CDK5R1-Related Subtypes and Characterization of Immune Infiltrates in Alzheimer's Disease Based on an Integrated Bioinformatics Analysis

Introduction Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a commonly occurring sequelae of traumatic injury resulting from indirect insults like hypovolemic shock and/or extrapulmonary sepsis. The high lethality rate associated with these pathologies outlines the importance of clarifying the “priming” effects seen in the post-shock lung microenvironment, which are understood to bring about a dysregulated or overt immune response when triggered by a secondary systemic infectious/septic challenge culminating in ALI. In this pilot project, we test the hypothesis that application of a single cell multiomics approach can elucidate novel phenotype specific pathways potentially contributing to shock-induced ALI/ARDS. Methods Hypovolemic shock was induced in C57BL/6 (wild-type), PD-1, PD-L1, or VISTA gene deficient male mice, 8–12 weeks old. Wild-type sham surgeries function as negative controls. A total of 24-h post-shock rodents were sacrificed, their lungs harvested and sectioned, with pools prepared from 2 mice per background, and flash frozen on liquid nitrogen. N = 2 biological replicates (representing 4 mice total) were achieved for all treatment groups across genetic backgrounds. Samples were received by the Boas Center for Genomics and Human Genetics, where single cell multiomics libraries were prepared for RNA/ATAC sequencing. The analysis pipeline Cell Ranger ARC was implemented to attain feature linkage assessments across genes of interest. Results Sham (pre-shock) results suggest high chromatin accessibility around calcitonin receptor like receptor (CALCRL) across cellular phenotypes with 17 and 18 feature links, exhibiting positive correlation with gene expression between biological replicates. Similarity between both sample chromatin profiles/linkage arcs is evident. Post-shock wild-type accessibility is starkly reduced across replicates where the number of feature links drops to 1 and 3, again presenting similar replicate profiles. Samples from shocked gene deficient backgrounds displayed high accessibility and similar profiles to the pre-shock lung microenvironment. Conclusion High pre-shock availability of DNA segments and their positive correlation with CALCRL gene expression suggests an apparent regulatory capacity on transcription. Post-shock gene deficient chromatin profiles presented similar results to that of pre-shock wild-type samples, suggesting an influence on CALCRL accessibility. Key changes illustrated in the pre-ALI context of shock may allow for additional resolution of “priming” and “cellular pre-activation/pre-disposition” processes within the lung microenvironment.

/pdf/application-of-single-cell-multiomics-points-to-changes-in-3h5gb6hk.pdf

Application of single cell multiomics points to changes in chromatin accessibility near calcitonin receptor like receptor and a possible role for adrenomedullin in the post-shock lung

Objectives Tigecycline is recognized as one of the last-line antibiotics to treat serious bacterial infection caused by carbapenem-resistant Klebsiella pneumoniae (CRKP). The plasmid-borne gene tet(X4) mediates high resistance to tigecycline. However, the prevalence and genetic context of tet(X4) in K. pneumoniae from various sources are not fully understood. Here, we investigated the prevalence of tet(X4)-positive K. pneumoniae and characterized the genetic context of tet(X4)-bearing plasmids in K. pneumoniae isolates. Methods Polymerase chain reaction (PCR) was used to detect the tet(X4) gene. The transferability of the tet(X4)-carrying plasmids was tested by conjugation assays. The Galleria mellonella infection model was used to test virulence of tet(X4)-positive strains. Whole-genome sequencing and genome-wide analysis were performed to identify the antimicrobial resistance and the virulence genes, and to clarify the genetic characteristics of the tet(X4)-positive isolates. Results Among 921 samples, we identified two tet(X4)-positive K. pneumoniae strains collected from nasal swabs of two pigs (0.22%, 2/921). The two tet(X4)-positive isolates exhibited high minimum inhibitory concentrations to tigecycline (32–256 mg/L) and tetracycline (256 mg/L). The plasmids carrying the tet(X4) gene can transfer from the donor strain K. pneumoniae to the recipient strain Escherichia coli J53. Genetic analysis of the complete sequence of two tet(X4)-carrying plasmids pTKPN_3-186k-tetX4 and pTKPN_8-216k-tetX4 disclosed that the tet(X4) gene was flanked by delta ISCR2 and IS1R, which may mediate the transmission of the tet(X4) gene. Conclusion The prevalence of tet(X4)-positive K. pneumoniae among different sources was low. ISCR2 and IS1R may contribute to the horizontal transfer of tet(X4) gene. Effective measures should be taken to prevent the transmission of tet(X4)-producing K. pneumoniae in humans or animals.

Characterization of two multidrug-resistant Klebsiella pneumoniae harboring tigecycline-resistant gene tet(X4) in China

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Soluble programmed cell death protein-1 and programmed cell death ligand-1 in sepsis.

Identification of Two CDK5R1-Related Subtypes and Characterization of Immune Infiltrates in Alzheimer's Disease Based on an Integrated Bioinformatics Analysis

Application of single cell multiomics points to changes in chromatin accessibility near calcitonin receptor like receptor and a possible role for adrenomedullin in the post-shock lung

Characterization of two multidrug-resistant Klebsiella pneumoniae harboring tigecycline-resistant gene tet(X4) in China