Host Response Research Articles (Page 1)

Paroxetine attenuates sepsis by preserving the expression of the G protein-coupled chemokine receptor CXCR2 on neutrophils.

Decoding host immune response: circRNAs in Klebsiella variicola-infected chicken spleens.

Sepsis is life-threatening inflammatory disease, and its pathogenesis and prognostic factors remain unclear. In addition, the symptoms and signs of sepsis patients lack specificity, which makes the diagnosis, treatment and prognosis evaluation of sepsis extremely difficult. Recently, with the emergence and development of detection technologies, various sepsis-related biomarkers have emerged. Biomarkers could be considered as indicators of either infection or dysregulated host response or response to treatment and/or aid clinicians to prognosticate patient risk. Therefore, searching for reliable biomarkers and evaluating their role in sepsis is envisaged to aid clinical decision-making. This article reviews the advances in research on sepsis biomarkers and their application in the early prediction of organ dysfunction to improve our understanding of current sepsis biomarkers and provide a reference for the application of biomarkers in the clinical diagnosis, treatment, and prognosis of sepsis. Besides, we propose that the combining multiple biomarkers is expected to be a more accurate and comprehensive strategy to evaluate the condition and prognosis of sepsis patients.

Acute respiratory distress syndrome (ARDS) is a life-threatening respiratory failure syndrome, and sepsis is a dysregulated host response to infection. Although sepsis is a major ARDS trigger, the causal relationship at the genetic level remains unestablished. This study assesses the causal effect of sepsis on the risk of ARDS using 2-sample Mendelian randomization (MR). We performed a 2-sample MR analysis using summary statistics from genome-wide association studies. Sepsis-associated single nucleotide polymorphisms (SNPs) were derived from the UK Biobank (11,643 cases; 474,841 controls). ARDS outcome data were obtained from the FinnGen project (165 cases; 216,363 controls). Analyses utilized the "TwoSampleMR" package in R, with primary causal estimation via the inverse-variance-weighted method, supplemented by sensitivity analyses including weighted median regression, MR Egger regression (MR-Egger), and MR pleiotropy residual sum and outlier for horizontal pleiotropy assessment. Quality control encompassed SNP harmonization for allele alignment, exclusion of ambiguous palindromic SNPs, and Bonferroni correction. Inverse-variance-weighted analysis showed no significant causal effect of genetically predicted sepsis on ARDS risk (odds ratio [OR] = 0.514, 95% confidence interval: 0.195-1.359, P = .943). Sensitivity analyses confirmed null associations (MR-Egger test: OR = 0.309, P = .276; weighted median: OR = 0.950, P = .943). No directional pleiotropy was detected (MR-Egger intercept, P = .172; MR pleiotropy residual sum and outlier global test, P = .527). The leave-one-out analysis revealed no significant SNPs. Exploratory analysis identified 5 pleiotropic loci (succinyl-CoA glutarate-CoA transferase, Ras-related protein Rab-38, glutamate ionotropic receptor kainate type subunit 4, adrenoceptor alpha-1 B, and axis inhibition protein 1). This MR study found no genetic evidence supporting a causal relationship between sepsis and ARDS. The identified pleiotropic loci warrant further investigation of shared biological pathways.

Sepsis, a life-threatening condition resulting from a dysregulated host response to infection, is associated with high mortality and remains a major global health burden. Sepsis is characterized by an imbalance between oxidative stress and inflammation, leading to disruption of thiol-disulfide homeostasis, hematological abnormalities, cytokine dysregulation, and widespread tissue injury. An experimental sepsis model was established in thirty-two male Balb-C mice using lipopolysaccharide administration. Animals were randomized into four groups: control, vitamin E, sepsis, and sepsis plus vitamin E. Serum oxidative stress markers, thiol-disulfide parameters, and inflammatory mediators, including C-reactive protein, interleukin-40, and tumor necrosis factor-alpha, were measured. Hematological indices of systemic inflammation were evaluated (Neutrophil-to-Lymphocyte Ratio, Platelet-to-Lymphocyte Ratio), and lung, liver, and kidney tissues were examined histologically using a semi-quantitative scoring system. Lipopolysaccharide-induced sepsis caused marked disruption of thiol-disulfide balance, characterized by reduced native and total thiol levels, elevated disulfide levels, increased cytokine release, and severe histopathological injury. Vitamin E supplementation restored thiol-disulfide homeostasis, decreased oxidative stress, and attenuated systemic inflammation. In the sepsis plus vitamin E group, serum thiol levels increased significantly, while disulfide levels declined. Interleukin-40 showed a 24.2% reduction and tumor necrosis factor-alpha a 9.8% reduction compared with untreated septic animals. Histopathological analyses confirmed reduced inflammatory cell infiltration, vascular congestion, and tissue degeneration, particularly in the lungs. Vitamin E demonstrated significant protective effects against sepsis-induced oxidative and inflammatory injury by preserving thiol-disulfide homeostasis and reducing cytokine production. The more pronounced effect on interleukin-40 compared with tumor necrosis factor-alpha suggests selective modulation of inflammatory pathways and highlights interleukin-40 as a potential biomarker and therapeutic target. These findings support vitamin E as a promising adjunctive therapy in sepsis, although further studies are required to define optimal dosing strategies and assess clinical applicability.

Sepsis constitutes a profoundly heterogeneous and dynamic clinical syndrome, precipitated by a maladaptive host response to infection in which the immune system’s regulatory balance is fundamentally disrupted. The intricate interplay between proinflammatory and anti-inflammatory pathways, ordinarily responsible for maintaining immune homeostasis, becomes pathologically skewed. Within this altered immunological landscape, cytokines serve as pivotal mediators, orchestrating a cascade of cellular events that may culminate in a rapid transition from systemic hyperinflammation to a state of immune exhaustion or suppression. This review offers a critical synthesis of the current scientific literature on the immunopathogenesis of sepsis, with a particular emphasis on the molecular and cellular mechanisms governing cytokine regulation. Special attention is directed toward elucidating the contribution of these mediators to the onset and progression of multiorgan dysfunction syndrome (MODS), a central and often fatal complication of severe sepsis. Through an integrative examination of the principal immune signaling networks and pathophysiological processes involved in sepsis, this review provides a cohesive theoretical framework positioning immune dysregulation as the fundamental axis of clinical deterioration. Such an approach underscores the imperative for a deeper insight into the immunological architecture of sepsis, thereby laying the groundwork for the rational design of targeted, mechanism-based therapeutic strategies.

Sepsis is a life-threatening syndrome characterized by dysregulated host responses to infection, leading to severe organ dysfunction and a high mortality rate. Reducing the incidence of sepsis is of paramount importance. Given that sepsis-associated drugs largely fail in clinical trials, in this project, we devised and validated a novel long-acting C5a-blocking cyclic peptide drug (Cp1) via phage screening technology to block the upstream “bottleneck molecule” C5a-mediated amplification cascade of the inflammatory response. In the early stage of infection, we utilized the efficient neutralization of Cp1 against C5a to effectively curb the “waterfall effect” of inflammatory factors and mitigate the progression to dysregulated systemic inflammation, thereby providing effective prevention and therapeutic intervention for sepsis. First, in vitro and in vivo studies collectively demonstrated the optimal binding affinity and blocking selectivity of Cp1. The excellent plasma stability of Cp1 further endows it with antibody-like systemic circulation. In the CLP-induced sepsis model, Cp1 significantly suppressed the expression of inflammatory factors and chemokines in both plasma and peritoneal lavage fluid (PLF). Additionally, Cp1 potently inhibited innate immune injury. Ultimately, after a single administration of Cp1, the CLP-induced septic mice presented a significant reduction in bacterial burden, evident amelioration of organ dysfunction, and notable prolongation of survival time. Overall, the novel cyclic peptide drug Cp1 developed in this study is a highly promising and cost-competitive therapeutic option for sepsis prophylaxis and therapy.

Introduction: Acute necrotizing encephalopathy (ANE) is a rare but severe neurological condition, typically triggered by viral infections, including influenza. It is characterized by a dysregulated immune-inflammatory host response, leading to rapid neurological deterioration, including encephalopathy and multifocal brain lesions. Diagnosis and treatment are challenging, and the condition is associated with high morbidity and mortality. Case description: We report the case of a 48-year-old immunocompetent male who presented twice to the emergency department with fever and rapidly progressing altered consciousness, followed by generalized seizures. Neuroimaging revealed characteristic bilateral thalamic lesions and diffuse cerebral haemorrhage. Rapid diagnostic testing confirmed influenza A virus infection, leading to the diagnosis of influenza-associated acute necrotizing encephalopathy. Despite the initiation of antiviral therapy with oseltamivir, along with high-dose intravenous corticosteroids and immunoglobulins, the patient passed away due to severe neurological complications. Discussion: Adult-onset ANE is exceptionally rare, particularly in Western populations, and is associated with a fulminant clinical course. Common features include altered mental status and seizures, often progressing to severe outcomes despite treatment. Given its non-specific prodromal symptoms and rapid neurological decline, early recognition and prompt neuroimaging are essential for diagnosis and management. Increased awareness of this condition among clinicians may facilitate earlier intervention and potentially improve outcomes. Conclusion: The present case report highlights the fatal outcome of ANE as a rare complication of Influenza A infection in an immunocompetent adult.

Sepsis is a life-threatening condition characterized by organ dysfunction resulting from a maladaptive host response to infection and remains a leading cause of mortality in critically ill patients. Organ dysfunction frequently occurs as a sepsis complication, exacerbating systemic inflammation and contributing to increased mortality. Current treatment modalities for sepsis-induced organ dysfunction (SIOD) are limited to infection control, organ function support, and anti-inflammatory interventions. However, their effectiveness is limited. Mesenchymal stem cells (MSCs) possess immunomodulatory and regenerative properties and offer a promising therapeutic approach for addressing SIOD syndrome through diverse mechanisms. This review elucidates the pathophysiological basis of SIOD, investigates the potential mechanisms and therapeutic applications of MSCs in the management of SIOD, and outlines existing challenges to underpin future MSC-based strategies for sepsis-induced organ injury treatment.

Background Helminth infections are widespread in resource-limited settings, and modulate host immune responses, with potential implications for viral coinfections. Intestinal helminths can alter susceptibility to respiratory viruses, but the mechanisms influencing SARS-CoV-2 infection outcomes remain poorly understood. Methods Using the Syrian hamster model, we investigated the impact of prior infection with the human hookworm Ancylostoma ceylanicum on host responses to SARS-CoV-2. Tissue-specific transcriptional responses were compared among four groups: naive, hookworm-only, SARS-CoV-2-only, and coinfected with both pathogens, 3 and 6 days post-viral infection. Viral titers and weight loss were assessed, and RNA-seq transcriptome profiles from lung and intestinal tissues were interrogated to identify differentially expressed genes and cellular pathways. Results Prior hookworm infection did not significantly alter viral titers or weight loss compared to SARS-CoV-2 infection alone, but distinct transcriptional signatures compared were identified compared to either single infection. Coinfection uniquely differentially regulated hematopoiesis and B cell-associated genes (e.g., ATF5 , IGHM , JCHAIN ) in the lungs, and immune and stress response pathways and inflammation-associated genes (e.g. FOLR2 , PLA2GF , FABP3 ) in the intestine. Genes and pathways differentially regulated by SARS-CoV-2 alone, but with attenuated transcriptional responses in the lungs of coinfected hamsters were observed, including the loss of upregulation of toll-like receptor signaling and previously proposed host biomarkers for COVID-19 severity ( CHI3L1 , HMOX1 ), Long COVID ( FCG4 / FCGR3A and FST ) and mortality ( FST ). In the intestine, hookworm-associated suppression of type I interferon-related genes ( TAP1 , IRF7 ) was reversed with SARS-CoV-2 coinfection, highlighting pathogen-specific modulation of innate antiviral signaling. Genes and pathways consistently differentially regulated by with SARS-CoV-2 were consistent with expectations, and many hemoglobin pathways were differentially regulated with hookworm in the intestine. CIBERSORT analysis was estimated relative leukocyte abundances in each sample cohort. Conclusion Our findings demonstrate that A. ceylanicum infection reshapes host transcriptional responses to SARS-CoV-2 in a tissue-specific manner, enhancing B cell immunity in the lung while driving intestinal inflammation. Hookworm-induced immune modulation attenuated key SARS-CoV-2-responsive genes and pathways, suggesting potential mechanisms for reduced disease severity observed in helminth-endemic regions. These findings establish a molecular framework to better understand helminth, SARS-CoV-2 and host immune interactions, with relevance for other respiratory viral infections.

Traumatic injury induces a complex host response, comprising endothelial damage, and simultaneous pro- and anti-inflammatory responses. These may contribute to complications seen in some patients days or weeks later. Although there is ever-increasing evidence showing that resuscitation with blood products improves survival, their impact on the host response remains unclear. A terminally anaesthetised Large White pig model of traumatic haemorrhagic shock (THS) and prolonged care evaluated different resuscitation fluids (saline, fresh frozen plasma (FFP), packed red blood cells and FFP (1:1), or fresh whole blood (n = 9 per group)). Serial blood samples were collected for ELISA, haematology and flow cytometry, and post-mortem tissue samples collected for RT-qPCR and immunohistochemistry. THS significantly increased circulating markers of endothelial activation (angiopoietin-2 and vWF antigen; both p < 0.001) and glycocalyx shedding (hyaluronic acid; p < 0.001). THS also elicited a robust inflammatory response, with significant elevations in circulating interleukin-6 and HMGB-1 (both: p < 0.001), neutrophilia (p <0.001), lymphopenia (p < 0.001) and increased inflammatory gene expression across a number of tissues. Compared to saline, resuscitation with blood products reduced hyaluronic acid (p < 0.001) but not angiopoeitin-2 or vWF antigen (both p > 0.05). The effect of blood products on peripheral cytokine concentrations or immune cell populations was minimal, nor did they significantly alter tissue inflammatory gene expression, neutrophil or lymphocyte number compared to saline-treated animals. These data suggest resuscitation with blood products can protect the endothelial glycocalyx, but they have little impact on the acute (< 8 hour) host response(s) to THS and prolonged care compared to animals treated with saline.

Trypanosoma cruzi produces a long-lasting and diverse antibody response in infected hosts. Recently, with the advent of high-density peptide microarrays, millions of peptides from the complete proteomes of two T. cruzi strains were subjected to extensive immune profiling revealing thousands of discrete antibody-binding peaks and antigenic regions in proteins, from infected human hosts across diverse human populations. Furthermore, hundreds of the identified epitopes were subjected to redundant site-specific mutagenesis to reveal residues important for antibody-binding in these epitopes. This chapter provides software and tools to analyze peptide microarray data in this context and also guiding examples to allow users to re-analyze data in their own ways.

Stenotrophomonas muris was first discovered as a potential human pathogen. Since it shares 99.72% similarity of the 16S rRNA to Stenotrophomonas maltophilia, conventional diagnostic methods usually classify it as S. maltophilia clinically. However, the two human pathogens should be distinguished. The reason is that they have different virulence and different drug susceptibilities, which result in different administrations of drugs to treat their infections. To better distinguish these two pathogens and treat infections of S. muris, we investigated the virulence genes, the host response of S. muris infections, and susceptibility of S. muris to different drugs. The results we show in this paper will guide researchers to identify virulence genes, diagnostic biomarkers, and targets to develop treatment strategies for S. muris infections.

Despite recent advances in preventative options, respiratory syncytial virus (RSV) infection is still a major cause of hospitalizations of young children and older adults, with no specific treatment available. The aryl hydrocarbon receptor (AHR) is a transcription factor originally identified as the mediator of the toxic effects of environmental pollutants but later shown to be also activated by dietary and endogenous ligands. AHR is involved in various physiological and pathophysiological processes, including host response to infections. Many clinically relevant viruses have been shown to induce AHR activation as a strategy to evade antiviral immunity and promote replication, including the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It is currently not known whether RSV infection affects the AHR pathway. In this study, we investigated the effects of RSV infection on the AHR signaling pathway by using in vitro and in vivo experimental models. We found that RSV infection led to inhibition of the AHR-dependent gene transcription in human airway epithelial cells and in lungs of mice. Human lung epithelial cells lacking AHR showed upregulation of genes related to inflammatory response and airway remodeling, as well as increased production of pro-inflammatory mediators in response to RSV infection. In contrast, administration of the dietary AHR ligand indole-3-carbinol (I3C) to mice led to beneficial effects on RSV-associated disease, including anti-inflammatory and antiviral activity. Collectively, our results suggest that the AHR has a protective role during RSV infection and therefore its modulation can be explored as a novel therapeutic target for RSV-induced disease.

The adaptive immune response is integral to controlling infections. Both T-cell receptors (TCRs) and immunoglobulin G (IgG) recognize antigens via hypervariable regions in their binding sites, referred to as complementarity determining regions (CDRs), of which CDR3 is one of the best characterized. CDR3 sequence diversity is generated by rearrangement of the respective TCR and IgG variable (V), joining (J), and diversity (D) gene segments during cell maturation, which can produce a highly diverse repertoire of TCR or IgG clonotypes. The diversity of clonotypes produced, as well as the expansion of some and/or their replacement by others, illustrates host responses to infection and its efficacy. It may also reflect changes induced by vaccination or treatment, guiding their optimization. Here, we present a method for the analysis of the TCR and IgG immune repertoire from bulk RNA-sequencing data of peripheral blood mononuclear cells (PBMCs) from Rhesus macaques, with a focus on CDR3 sequences in the context of Trypanosoma cruzi infection, a protozoan parasite causing chronic disease.

Background Sepsis, a life-threatening condition caused by a dysregulated host response to infection, remains a major cause of mortality worldwide. Identifying reliable biomarkers for prognosis and treatment is urgently needed. This study investigates the role of the Apoptosis Inhibitor of Macrophages (AIM), also known as CD5L, as a potential prognostic biomarker and therapeutic target in sepsis. Methods We measured free and total AIM concentrations in 90 septic patients enrolled in SepsisDataNet.NRW cohort (German Clinical Trial Registry No. DRKS00018871; http://www.sepsisdatanet.nrw ). Blood samples were collected on days 1, 4, and 8, and AIM levels were quantified using ELISA. Kaplan-Meier analysis and Cox regression were performed to assess the association between AIM levels and 30-day survival. Western blot analysis was performed to detect AIM in human serum IgM and in the IgM-enriched intravenous immunoglobulin IVIG preparation Pentaglobin ® . Results High total AIM concentrations (&amp;gt;85 ng/ml) were significantly associated with improved 30-day survival on day 1 (HR: 3.131, 95% CI: 1.629-6.019, p = 0.009), 4 (HR: 2.525, 95% CI: 1.198-5.322, p = 0.0042), and day 8 (HR: 2.317, 95% CI: 0.8565-6.266, p = 0.0457). Free AIM showed a significant association with survival only on day 8 (HR: 2.374, 95% CI: 0.8721-6.461, p = 0.0393). Conclusion Total AIM concentration is a significant predictor of a 30-day survival in sepsis, supporting its potential use as a prognostic biomarker. Our findings also suggest that AIM may serve as a valuable prognostic biomarker and a potential target for immune-modulating therapies, including IgM-enriched intravenous immunoglobulins (IVIGs).

BackgroundSepsis is a life-threatening condition characterized by organ dysfunction resulting from dysregulated host response to infections. Approximately 48.9 million people worldwide are diagnosed with sepsis annually, leading to 11 million deaths and representing 19.7% of all global deaths. No specific, effective treatments for sepsis, which has a poor prognosis, are available.ObjectiveThe study aimed to systematically explore the association between genetically predicted modifiable risk factors and sepsis.MethodsUnivariable 2-sample Mendelian randomization (MR) analysis was performed to explore the association between 30 modifiable risk factors (12 lifestyle, 3 educational and psychological, and 15 metabolic factors) and sepsis. Heterogeneity was evaluated using the Cochran Q analysis. Sensitivity analyses were conducted using the MR-Egger regression intercept tests and leave-one-out analyses. Additionally, multivariable MR analyses were performed to adjust for genetic associations between the instruments and obesity.ResultsGenetically predicted smoking (odds ratio [OR] 1.20, 95% CI 1.06‐1.36; P=.005), a higher number of cigarettes smoked daily (OR 1.70, 95% CI 1.29‐2.23; P<.001), a higher overall health rating (OR 2.19, 95% CI 1.61‐2.98; P<.001), BMI (OR 1.50, 95% CI 1.38‐1.63; P<.001), waist circumference (OR 1.70, 95% CI 1.53‐1.89; P<.001), whole body fat mass (OR 1.50, 95% CI 1.37‐1.64; P<.001), trunk fat mass (OR 1.48, 95% CI 1.36‐1.62; P<.001), arm fat mass (OR 1.57, 95% CI 1.43‐1.71; P<.001), and leg fat mass (OR 1.69, 95% CI 1.51‐1.90; P<.001) were associated with increased sepsis risk. However, light physical activity (OR 0.26, 95% CI 0.08‐0.83; P=.03), higher education attainment (OR 0.52, 95% CI 0.40‐0.67; P<.001), and high-density lipoprotein cholesterol (OR 0.91, 95% CI 0.84‐0.98; P=.02) exhibited protective effects against sepsis. Using a multivariate analysis of obesity traits, the waist circumference (OR 2.16, 95% CI 1.18‐3.96; P=.01) was an independent risk factor of sepsis.ConclusionsOur study demonstrated that genetic predictors of lifestyle (smoking and physical activity), educational level, and metabolic factors (waist circumference and high-density lipoprotein cholesterol) exhibited a causal association with sepsis risk. Future research should further investigate the underlying mechanisms of these associations to inform more effective preventive strategies against sepsis.

Sepsis is a syndrome caused by a dysregulated host response to pathogens, representing the leading cause of death from infection. Various murine models of sepsis have shown a time-dependent response based on the time of induction. Mice stimulated with high doses of bacterial lipopolysaccharide (LPS) at the end of the day exhibit a higher mortality rate (~80%) compared with those inoculated in the middle of the night (~30%). In this work, we assessed the differences in serum proteins of septic mice during the day and night. Through this proteomic study, we found significant variations in metabolic pathways, including glucose metabolism, which were associated with a better prognosis. Therefore, we studied the glucose response to LPS during the day and night. In this context, we found an early peak of LPS-induced glucose exclusively at the time of worse prognosis. We also observed a hypoglycemic response to LPS, which was independent of the time of sepsis induction. Finally, we performed a set of metabolic manipulations to study how hyperglycemia influences sepsis severity in mice. We observed that suppressing the glucose peak during the day, through metformin administration, reduced sepsis severity. In contrast, nocturnal glucose administration with LPS was rapidly metabolized and also decreased sepsis severity. In conclusion, sepsis severity may be influenced by the metabolic state at the time of the stimulus. Metabolic rhythms could lead to differences in early glucose management, affecting the outcome of this pathology.

The brain monitors changes in the gut microbiome to maintain health, but the impact of specific bacterial alterations, as well as the underlying mechanisms, remains largely unclear. Here, we discovered an unexpected neuronal regulation of iron metabolism, mediating the neuronal surveillance of gut bacterial activity in C. elegans. Specifically, through a genome-wide screen, we identified 29 E. coli genes, mainly linked to metabolism regulation, whose inactivation could increase dopamine and serotonin biosynthesis in C. elegans head neurons. These neurons respond to the lack of respiratory chain genes in E. coli in the gut by perceiving intestinal mitochondrial impairment resulting from bacterial-induced reduction in host labile iron levels. Such neuronal responses subsequently promote intestinal ferritin-1 expression to counteract bacterially induced labile iron reduction, thus maintaining mitochondrial function. Our findings reveal how alterations in bacterial metabolism can elevate dopamine and serotonin levels in the host brain, demonstrating that the nervous system not only senses microbiome-caused changes in the gut but also feeds back to revert them.

Multiplexed MALDI fingerprints for rapid detection of spontaneous bacterial peritonitis.