Host Response Research Articles

Cost-effectiveness of Procalcitonin (PCT) guidance for antibiotics management of adult sepsis patients in the Egyptian context

BackgroundSepsis, which is described as a life-threatening organ malfunction brought on by an unbalanced host response to infection, continues to be a significant healthcare issue that affects millions of individuals each year. It is well-known that sepsis can affect anyone around the world, but the employed survey results showed that there are significant regional variations in sepsis incidence as well as mortality rates. Although there are no definite estimates for Egypt, the highest rates were in Low-Middle-Income Countries (LMICs).Procalcitonin (PCT) is a host response marker with high specificity for bacterial infections, unlike C-reactive protein (CRP) or white blood cell count (WBC), which represent the traditional methods of detecting inflammation and infection. Its dynamic profile and superior prognostic prediction make it invaluable for assessing response to antibiotic treatment and improving clinical care for sepsis patients.Our main purpose was to evaluate the cost-effectiveness of PCT guidance compared to no PCT guidance in the antibiotic management of adult sepsis patients according to the Egyptian context.MethodsWe developed a decision tree model to compare the PCT-guided antibiotic management duration endpoint versus the conventional laboratory culture-based antibiotic management in adult sepsis patients. We employed the“Delphi technique” to reach a satisfactory consensus regarding the resources attributed to each compared alternative. The primary measure of the study was the additional cost associated with each Quality-Adjusted Life Year (QALY) gained by sepsis survivors over a one-year time horizon.Base-case, deterministic and probabilistic sensitivity analyses were conducted using TreeAge, Software.ResultsBase-case analysis showed no dominance for either alternative and resulted in an Incremental Cost-Effectiveness Ratio (ICER) value of 297,783.57 Egyptian Pounds per Quality Adjusted Life Year (L.E/QALY) in favor of the PCT guidance alternative, Deterministic sensitivity analysis revealed that the highest impact magnitudes on ICER reside with seven input parameters, the top two parameters that had the most significant influence were the costs of ICU stay with and without PCT guidance. The CEAC showed a slightly higher probability in terms of acceptability in favor of the no PCT guidance choice along the WTP scale till reaching equal probabilities at the willingness-to-pay (WTP) value point of 390,000 (state currency) after which the - probability supports the PCT guidance choice. ConclusionsIn the Egyptian context, PCT guidance has no cost-effectiveness domination over no PCT guidance in Antibiotics management for adult sepsis patients. This may be attributed to the high cost of PCT investigation that shall be resolved by standardization of its cost when applying the approach of DRG cost packages.

Understanding host's response to staphylococcal scalded skinsyndrome.

The aim of this review was to summarise the current knowledge on host-related factors that contribute to the development and severity of staphylococcal scalded skin syndrome (SSSS) in children. A comprehensive assessment and analysis of the existing literature on SSSS clinical features, pathogenesis and susceptibility factors. SSSS is a blistering skin disease caused by circulating exfoliative toxins (ETs) of Staphylococcus aureus (S. aureus), almost exclusively affecting infants, young children and immunocompromised individuals. ETs possess serine protease activity and target desmoglein-1 (Dsg-1) in the superficial epidermis. While the role of S. aureus ETs and site of action are well-described, other host factors such as impaired immune responses to ETs, poor renal clearance and genetic factors are crucial for the onset of and/or the severity of SSSS in children. The fate of desmosomal fractions after cleavage by ETs, as well as the role of dermal inflammatory cell infiltrates remain to be elucidated.

Opportunities and Challenges of Application of Cytosorb Therapy in Sepsis Management

Sepsis is a life-threatening organ dysfunction due to a dysregulated host response to infection. In 2017, an estimated 48·9 million incident cases of sepsis were recorded worldwide, and 11·0 million sepsis-related deaths were reported, representing 19·7% of all global deaths.1 Though overall data related to sepsis is poor but it is also a major health care challenge for resource limited countries. Severe sepsis is a significant & common health problem in ICU patients of Bangladesh2. A continuum of severity from sepsis to septic shock and multi-organ dysfunction syndrome (MODS) exists. MODS is a clinical syndrome characterized by the development of progressive and potentially reversible physiologic dysfunction in 2 or more organs or organ systems that is induced by a variety of acute insults, including sepsis. Sepsis leads to malignant intravascular inflammation, coagulopathy, circulatory derangement, tissue hypoxia, cytotoxicity and apoptosis. As a result, dysfunction of vital organ systems occur. Host response and other factors influenc outcome. Patients with sepsis must be treated with-timely, appropriate antibiotics, intravenousfluids, vasopressor and inotropic support & oxygen therapy.3 Other additional treatments including extracorporeal blood purification techniques (BPT). These techniques include hemofiltration, hemoperfusion, intermittent or continuous high-volume hemofiltration (HVHF), plasmapheresis or adsorption.4 The rationale behind such an approach is to achieve “immune homeostasis” which theoretically reduces the potential damage caused by dysregulation of the host response to infection. Given the pivotal role of cytokine production in sepsis, it follows that removal of these substances, through such BPT, may attenuate the response particularly in the early phase of sepsis.5 Indications include 1) Rhabdomyolysis resulting from Reperfusion syndrome, Trauma, Malignant Hyperthermia. 2) External injuries including Sepsis/Septic shock, Hemorrhagic shock, Trauma, Ruptured aortic aneurysm, Post-Cardiac Arrest Syndrome, Cardio-pulmonary resuscitation, Extensive surgery, Organ transplantation, Cardiosurgical intervention, Severe skin and soft tissue damage, Burns, Necrotizing fasciitis, Post-Cardiotomy Syndrome, Acute Respiratory Distress Syndrome. 3) Diseases: Pancreatitis, Liver insufficiency, Renal insufficiency, Stroke, Myocardial infarction, Cardiogenic shock/Heart failure, Tumor Lysis Syndrome, Hemophagocytosis Syndrome. Liver failure/Hyperbilirubinemia bridging to transplant or to recovery, Life-threatening bleeding under Direct Oral Anticoagulants (DOAC)6. Bangladesh Crit Care J September 2024; 12 (2): 79-80

Differential Expression of Mitogen-Activated Protein Kinase Kinase 3 (MAP2K3) and Interleukin12B (IL12B) in the Bursa of Fabricius of chicken infected with Infectious Bursal Disease Virus

Infectious Bursal Disease (IBD) caused by Infectious Bursal Disease virus (IBDV), poses a significant threat to the poultry industry, causing immunosuppression and economic losses since its discovery in 1957. To understand the host response to IBDV infection, this study examined the modulation of MAP2K3 and IL12B in chickens infected with IBDV. A local IBDV isolate propagated in embryonated chicken eggs was inoculated into 18-day-old chicken. The mRNA transcription levels of MAP2K3 and IL12B in bursal tissue were quantified by real-time quantitative polymerase chain reaction on day two post-infection and compared with those of uninfected, age-matched control birds (sham inoculated). The study revealed increased expression of the MAP2K3 and IL12B genes, indicating their role in inflammatory response during IBDV infection. Thus, the present investigation sheds light on the involvement of MAP2K3 and IL12B in the inflammatory response to IBDV infection in chickens. Keywords: Infectious bursal disease virus, immunosuppression, MAP2K3, IL12B, pro-inflammatory cytokine gene expression

T-cell Clonality in Pleomorphic Dermal Sarcoma in Male Veterans: A Report of 2 Cases and a Review of the Literature.

The standard treatment of choice for pleomorphic dermal sarcoma (PDS), a relatively uncommon soft tissue sarcoma and 1 morphologically similar to atypical fibroxanthoma, is wide local excision with close clinical follow-up. Studies regarding management of advanced/metastatic PDS with immune checkpoint inhibitors are limited as most STSs have historically been viewed as being immunologically inert. Contradicting this belief, in this report, we describe 2 cases of PDS with a robust host response. Histopathology of both cases revealed a dermal neoplasm comprising mitotically active, pleomorphic, spindled-to-ovoid cells, which were immunohistochemically negative for keratinocytic, melanocytic, and smooth muscle markers. An unusual feature in both cases was the presence of a brisk host response. Additional workup of the infiltrating lymphocyte population revealed an abnormal CD4:CD8 ratio in both cases, with the proportion of CD8+ lymphocytes surpassing (case 1) and equaling (case 2) that of the CD4+ T-lymphocyte population. The increased proportion of CD8+ lymphocytes prompted the additional workup of TCR gene rearrangement, which revealed a clonal population of T lymphocytes in both cases. The robust and clonal T-lymphocyte host response in both of our cases suggests that PDS appears to fit the classic model of an inflammatory-type tumor and may be a candidate for checkpoint inhibition. Future work includes additional reports of cases of PDS with an infiltrating clonal T-lymphocyte population and detailing the function and specificity of the infiltrating T lymphocytes to ascertain whether they have the potential to recognize and lyse the tumors they colonize.

Harnessing the host response for precision infectious disease diagnosis.

SUMMARYDetection of the presence of infection and its etiology must be accurate and timely to facilitate appropriate antimicrobial use. Diagnostic strategies that rely solely on pathogen detection often are insufficient due to poor test characteristics, inability to differentiate colonization from infection, or protracted delay to result. Understanding the human response across different pathogens on a clinical and molecular level can provide more accurate, timely, and useful answers, especially in critical illness and diagnostic uncertainty. Improvements in understanding the human immune response including genomics, protein analysis, gene expression, and cellular morphology have led to rapid innovation of new host response-based diagnostic tests. This review describes the limitations of pathogen-focused technology and the benefits of examining the breadth of immune response to diagnose infection. It then explores biomarkers that have been studied for this purpose and scrutinizes the performance of host-based multianalyte testing. Currently cleared diagnostics and those in late-stage development are described in depth, with a focus on the purpose of testing and its utility for clinicians. Finally, it concludes by examining opportunities for further host response-derived diagnostic innovation.

Host Response Markers of Inflammation and Endothelial Activation Associated with COVID-19 Severity and Mortality: A GeoSentinel Prospective Observational Cohort

Background: The effect of the COVID-19 pandemic on healthcare systems emphasized the need for rapid and effective triage tools to identify patients at risk of severe or fatal infection. Measuring host response markers of inflammation and endothelial activation at clinical presentation may help to inform appropriate triage and care practices in patients with SARS-CoV-2 infection. Methods: We enrolled patients with COVID-19 across five GeoSentinel clinical sites (in Italy, Belgium, Canada, and the United States) from September 2020 to December 2021, and analyzed the association of plasma markers, including soluble urokinase-type plasminogen activator receptor (suPAR), soluble tumor necrosis factor receptor-1 (sTREM-1), interleukin-6 (IL-6), interleukin-8 (IL-8), complement component C5a (C5a), von Willebrand factor (VWF-a2), and interleukin-1 receptor antagonist (IL-1Ra), with 28-day (D28) mortality and 7-day (D7) severity (discharged, hospitalized on ward, or died/admitted to the ICU). Results: Of 193 patients, 8.9% (16 of 180) died by D28. Higher concentrations of suPAR were associated with increased odds of mortality at D28 and severity at D7 in univariable and multivariable regression models. The biomarkers sTREM-1 and IL-1Ra showed bivariate associations with mortality at D28 and severity at D7. IL-6, VWF, C5a, and IL-8 were not as indicative of progression to severe disease or death. Conclusions: Our findings confirm previous studies’ assertions that point-of-care tests for suPAR and sTREM-1 could facilitate the triage of patients with SARS-CoV-2 infection, which may help guide hospital resource allocation.

Synergistic role of Mycobacterium indicus pranii and human beta Defensin-2 as adjunctive therapy against Mycobacterium tuberculosis

Host-directed therapies (HDT) via modulation of specific host responses like inflammation can limit mycobacterial infection. HDTs could be included in current TB therapy as an adjunct to increase bacterial clearance and limit tissue damage to control spread. Individually, Mycobacterium indicus pranii (MIP) and human beta defensin-2 (hBD-2) are promising therapies for tuberculosis (TB). They can directly target the TB bacilli and enhance cell-mediated immune responses, which is limiting with conventional drugs. Therefore, our study investigated the combined application of MIP and hBD-2 to evaluate their efficacy in clearing infections caused by Mycobacterium smegmatis (M.smeg) and Mycobacterium tuberculosis (M.tb) (both avirulent; H37Ra and virulent strain; H37Rv) in THP-1 cells and human monocyte-derived macrophages (MDMs). A strong pro-inflammatory response was observed against the combination of MIP and hBD-2 which also correlated with a significant reduction in the bacterial load. This combination further showed protection against M.tb by enhancing pyroptosis in the infected cells. The study suggests the combined use of these potent immunomodulators, which could be employed as an effective mode of therapy as adjuvants against mycobacterial infections after validation in a suitable animal model.

Clinical Utility of Recently FDA Approved IntelliSep test (Sepsis biomarker) for early Diagnosis of Sepsis: Comparison with other Biomarkers and von Willebrand Factor/ADAMTS13 Ration

Abstract Background Sepsis, a relatively common presentation in emergency departments, is a life-threatening disease. Recently, IntelliSep test by Cytovale (San Francisco, CA) received FDA approval as sepsis biomarker. We investigated clinical utility of this test using 44 patients (19 disease group and 25 non-disease group). Materials and Methods IntelliSep assesses cellular host response via deformability cytometry of leukocyte biophysical properties and intended for use in conjunction with clinical assessments and laboratory findings for early detection of sepsis. Test results are available within 10 minutes. Results consists of IntelliSep Band 1 (low risk, score: 0.1-4.9) to Band 3 (high risk, score: 6.3-10; total scale: 0.1-10). We measured IntelliSep score in 44 patients using EDTA blood. Left over plasma was used for measuring both plasma von Willebrand factor (vWF) antigen and ADAMTS13 antigen by ELISA assays. Monocyte distribution width (MDW) were obtained during routine CBC analysis using Beckman hematology analyzer. Lactate and high sensitivity troponin I were measured using Beckman analyzer. Results The median IntelliSep score was two-fold higher in the disease group (mean score 7.1, SD: 1.5, median: 7.4) compared to non-disease group (mean score 4.0, SD: 1.4, Median: 3.7) indicating that this new test can identify patients with high risk of developing sepsis and also rule out low risk patients (p<0.01 by both Mann-Whitney U test two tailed and t-test two tailed). The median MDW was also 34.8 % higher in the disease group (mean:25.6, SD: 5.0, Median: 24.4) compared to non-disease group (mean: 18.9, SD: 2.4, Median: 18.1) and difference was also statistically significant (p < 0.01 by both Mann-Whitney U test and t-test, two tailed). However, correlation between IntelliSep scores and MDW was only modest (overall, r= 0.66). Both lactate and procalcitonin concentrations were significantly higher in the disease group compared to the non-disease group. Interestingly, high-sensitivity troponin I concentrations were also significantly higher in the disease group. In addition, we observed significantly higher plasma vWF antigen in the disease group compared to the non-disease group (mean: 67.4 ug/mL in disease group vs 34.1 ug/mL in the non-disease group. However, in some patients in the disease group plasma vWF values were 6.8-fold higher than normal. In addition, vWF/ADAMTS13 ratio was also significantly elevated in the disease group compared to non-disease group. Discussion New IntelliSep test is useful in early prediction of sepsis in patients admitted to emergency department and may be superior to MDW and lactate for early diagnosis. Significant increase in plasma vWF in these patients indicate that vWF may also be a surrogate marker for endotheliopathy in sepsis. Lack of correlation between plasma VWF and Intellisep results indicates that these two markers probably measure different pathways for sepsis (endothelial activation vs neutrophil activation).

Tenacibaculum maritimum can boost inflammation in Dicentrarchus labrax upon peritoneal injection but cannot trigger tenacibaculosis disease.

Despite being a bacterial pathogen with devastating consequences, Tenacibaculum maritimum's pathogenesis is not fully understood. The aim of the present study was to elucidate if different inoculation routes (intraperitoneal - i.p - injection and bath challenge - known to induce mortality) can induce tenacibaculosis (i.e., using the same T. maritimum inoculum), as well as evaluate the short-term immune response of European sea bass (D. labrax). Additionally, the host response against i.p. injection of extracellular products (ECPs) was also studied. Fish were i.p. challenged with 5.5 × 105 CFU mL-1 of T. maritimum cells with or without ECPs (BECPs and BWO, respectively), ECPs alone or marine broth (mock). Another group of fish was bath-challenged with 5.5 × 105 CFU mL-1 to confirm the virulence of the bacterial inoculum. Undisturbed specimens were used as controls. The severity of both challenges was determined by following percentage survival. Blood, liver and head-kidney samples were collected at 0, 3, 6, 24 and 48h post-challenge for assessing immune parameters, oxidative stress and gene expression. Total and differential peritoneal cell counts were performed. The presence of viable bacteria in the blood and peritoneal cavity was studied. Symptoms of tenacibaculosis, such as skin/fin abrasions, were only observed in the bath-challenged fish, where 0% survival was recorded, whereas 100% survival was observed after i.p. injection of the same bacterial inoculum. An increase in total leukocyte numbers in the peritoneal cavity was observed 3h post-injection of BECPs when compared to the other treatments. Blood total leukocytes, lymphocytes, and thrombocyte numbers dropped after the challenge, mainly in fish challenged with BECPs. At 48h post-challenge, bactericidal activity in the plasma increased in fish injected with bacteria (with and without ECPs). The same tendency was seen for some of the oxidative stress parameters. The increased expression of il1β, il6, il8, and hamp1 in fish challenged with ECPs and BECPs suggests a more exacerbated pro-inflammatory response in the head-kidney against these inocula. The infection trial and the observed immune responses showed that the infection route is a determinant factor regarding T. maritimum-induced pathogenesis in European sea bass.

Identification and Targeting of Regulators of SARS-CoV-2-Host interactions in the Airway Epithelium.

Although the impact of SARS-CoV-2 in the lung has been extensively studied, the molecular regulators and targets of the host-cell programs hijacked by the virus in distinct human airway epithelial cell populations remain poorly understood. This is in part ascribed to the use of non-primary cell systems, overreliance on single-cell gene expression profiling that not ultimately reflect protein activity and bias toward the downstream effects rather than their mechanistic determinants. Here we address these issues by network-based analysis of single cell transcriptomic profiles of pathophysiologically relevant human adult basal, ciliated and secretory cells to identify master regulator (MR) protein modules controlling their SARS-CoV-2-mediated reprogramming. This uncovered chromatin remodeling, endosomal sorting, ubiquitin pathway as well as proviral factors identified by CRISPR analyses as components of the host response collectively or selectively activated in these cells. Large-scale perturbation assays, using a clinically-relevant drug library, identified 11 drugs able to invert the entire MR signature activated by SARS-CoV-2 in these cell types. Leveraging MR analysis and perturbational profiles of human primary cells, represents a novel mechanism-based approach and resource that can be directly generalized to interrogate signatures of other airway conditions for drug prioritization.

Neonatal overfeeding attenuates microgliosis and hippocampal damage in an infant rat model of pneumococcal meningitis.

Pneumococcal meningitis (PM) triggers apoptotic neuronal and progenitor cell death in the hippocampal dentate gyrus (DG), resulting in subsequent cognitive impairment. Microglia play a crucial role in PM-induced hippocampal damage. While the lasting effects of neonatal nutrition on health are well documented, the influence of early-life overfeeding on the host response to neuroinfections remains uncertain. This study aimed to examine whether neonatal overfeeding affects the outcome of PM in the hippocampus (HC). Overfeeding was induced by adjusting litter size immediately after birth. On the eleventh day of life, rats were intracisternally injected with Streptococcus pneumoniae or saline, followed by euthanasia after 24 hours for brain dissection. Histological analysis evaluated apoptosis in the DG and the extent of inflammatory infiltrate in the hippocampal fissure, while microgliosis was assessed by immunohistochemistry. The hippocampal transcriptome was analyzed using RNAseq, and the mRNA levels of specific inflammatory biomarkers were evaluated via RT-qPCR. Overfed rats exhibited 40.5% greater body mass compared to their normal-fed counterparts. Intriguingly, PM-induced apoptosis in the DG was 50% lower in overfed rats. This effect was accompanied by significant alterations in the hippocampal transcriptional profile, particularly the lack of activation of the Programmed cell death pathway in overfed infected animals. RT-qPCR analysis of Aif1 and examination of Iba1-immunostained cells revealed mild microgliosis in the HC of infected-overfed animals. This reduced microglial reaction may be attributed to the diminished activation of interferon signaling pathways, as disclosed by the transcriptome analysis, potentially preventing microglial priming. Additionally, evidence of reduced neuroinflammation in overfed rats with PM was observed through the milder activation of pathways associated with Toll-like receptors, interleukins, and chemokine signaling. Furthermore, overfed animals exhibited increased transcription of proinflammatory Il6 and anti-inflammatory Il10 genes, with the latter showing higher expression even in the absence of PM, suggesting a priming effect of overfeeding on hippocampal immune cells. This study sheds light on the complex interplay between early-life overfeeding, immune response, and neuroprotection in infant rats with PM. The findings demonstrate the neuroprotective impact of early-life overfeeding in the context of PM, linked to the modulation of microglial function.

Granulocyte colony-stimulating factor protects against arthritogenic alphavirus pathogenesis in a type I IFN-dependent manner.

Arthritogenic alphaviruses cause disease characterized by fever, rash, and incapacitating joint pain. Alphavirus infection stimulates robust inflammatory responses in infected hosts, leading to the upregulation of several cytokines, including granulocyte colony-stimulating factor (G-CSF). G-CSF is secreted by endothelial cells, fibroblasts, macrophages, and monocytes and binds to colony stimulating factor 3 receptor (CSF3R, also known as G-CSFR) on the surface of myeloid cells. G-CSFR signaling initiates proliferation, differentiation, and maturation of myeloid cells, especially neutrophils. Importantly, G-CSF has been found at high levels in both the acute and chronic phases of chikungunya disease; however, the role of G-CSF in arthritogenic alphavirus disease remains unexplored. Here, we sought to test the effect of G-CSF on chikungunya virus (CHIKV) and Mayaro virus (MAYV) infection using G-CSFR-deficient mice (G-CSFR-/-). We observed sustained weight loss in G-CSFR-/- mice following viand MAYV infection compared to wild-type mice. Furthermore, G-CSFR-/- mice had a significantly higher percentage of inflammatory monocytes and reduction in neutrophils throughout infection. The difference in weight loss in G-CSFR-/- mice induced by alphavirus infection was corrected by blocking type I IFN signaling. In summary, these studies show that type I IFN signaling contributes to G-CSFR mediated control of arthritogenic alphavirus disease.

Surviving Sepsis Campaign guideline update:problems and progress

Sepsis is a clinical syndrome, the core of which is the disorder of the host's response to infection. Sepsis progresses to septic shock, which can lead to increased mortality, so early identification and standardized management are particularly important. Over the past 30 years, the definition of septic shock has gradually changed, with efforts to improve the identification and screening of early septic shock, and to emphasize the importance of organ dysfunction in patients with septic shock. The birth of the rescue systemic infection movement has played an important role in the management of septic shock patients. Although the cluster management of septic shock patients has reduced the overall mortality of septic shock patients, the management still faces many challenges. How to provide personalized treatment to patients, especially some controversial treatments, is still a major area for us to consider and explore.

Differential transcriptomic host responses in the early phase of viral and bacterial infections in human lung tissue explants ex vivo

BackgroundThe first 24 h of infection represent a critical time window in interactions between pathogens and host tissue. However, it is not possible to study such early events in human lung during natural infection due to lack of clinical access to tissue this early in infection. We, therefore, applied RNA sequencing to ex vivo cultured human lung tissue explants (HLTE) from patients with emphysema to study global changes in small noncoding RNA, mRNA, and long noncoding RNA (lncRNA, lincRNA) populations during the first 24 h of infection with influenza A virus (IAV), Mycobacterium bovis Bacille Calmette-Guerin (BCG), and Pseudomonas aeruginosa.ResultsPseudomonas aeruginosa caused the strongest expression changes and was the only pathogen that notably affected expression of microRNA and PIWI-associated RNA. The major classes of long RNAs (> 100 nt) were represented similarly among the RNAs that were differentially expressed upon infection with the three pathogens (mRNA 77–82%; lncRNA 15–17%; pseudogenes 4–5%), but lnc-DDX60-1, RP11-202G18.1, and lnc-THOC3-2 were part of an RNA signature (additionally containing SNX10 and SLC8A1) specifically associated with IAV infection. IAV infection induced brisk interferon responses, CCL8 being the most strongly upregulated mRNA. Single-cell RNA sequencing identified airway epithelial cells and macrophages as the predominant IAV host cells, but inflammatory responses were also detected in cell types expressing few or no IAV transcripts. Combined analysis of bulk and single-cell RNAseq data identified a set of 6 mRNAs (IFI6, IFI44L, IRF7, ISG15, MX1, MX2) as the core transcriptomic response to IAV infection. The two bacterial pathogens induced qualitatively very similar changes in mRNA expression and predicted signaling pathways, but the magnitude of change was greater in P. aeruginosa infection. Upregulation of GJB2, VNN1, DUSP4, SerpinB7, and IL10, and downregulation of PKMYT1, S100A4, GGTA1P, and SLC22A31 were most strongly associated with bacterial infection.ConclusionsHuman lung tissue mounted substantially different transcriptomic responses to infection by IAV than by BCG and P. aeruginosa, whereas responses to these two divergent bacterial pathogens were surprisingly similar. This HLTE model should prove useful for RNA-directed pathogenesis research and tissue biomarker discovery during the early phase of infections, both at the tissue and single-cell level.

Can virus infection induce sepsis?

Sepsis is a clinical syndrome caused by a dysregulated host response to infection that can lead to multiple organ dysfunction syndrome and death. Severe viral infections can also induce sepsis, which is essentially similar to bacterial sepsis in physiological mechanism and management strategies, but slightly different in detail. Anti-microbial treatment and restoration of immune homeostasis are key to breaking the vicious circle of sepsis. Therefore, it is important to develop more accurate and convenient measures for pathogen detection and research into targeted anti-microbial agents, as well as to explore ways of evaluating the dynamic immune status of host and individualized immunotherapies based on immune status.

Immune Dysregulation in the Oral Cavity during Early SARS-CoV-2 Infection.

Tissue-specific immune responses are critical determinants of health-maintaining homeostasis and disease-related dysbiosis. In the context of COVID-19, oral immune responses reflect local host-pathogen dynamics near the site of infection and serve as important "windows to the body," reflecting systemic responses to the invading SARS-CoV-2 virus. This study leveraged multiplex technology to characterize the salivary SARS-CoV-2-specific immunological landscape (37 cytokines/chemokines and 11 antibodies) during early infection. Cytokine/immune profiling was performed on unstimulated cleared whole saliva collected from 227 adult SARS-CoV-2+ participants and 37 controls. Statistical analysis and modeling revealed significant differential abundance of 25 cytokines (16 downregulated, 9 upregulated). Pathway analysis demonstrated early SARS-CoV-2 infection is associated with local suppression of oral type I/III interferon and blunted natural killer-/T-cell responses, reflecting a potential novel immune-evasion strategy enabling infection. This virus-associated immune suppression occurred concomitantly with significant upregulation of proinflammatory pathways including marked increases in the acute phase proteins pentraxin-3 and chitinase-3-like-1. Irrespective of SARS-CoV-2 infection, prior vaccination was associated with increased total α-SARS-CoV-2-spike (trimer), -S1 protein, -RBD, and -nucleocapsid salivary antibodies, highlighting the importance of COVID-19 vaccination in eliciting mucosal responses. Altogether, our findings highlight saliva as a stable and accessible biofluid for monitoring host responses to SARS-CoV-2 over time and suggest that oral-mucosal immune dysregulation is a hallmark of early SARS-CoV-2 infection, with possible implications for viral evasion mechanisms.

Mycobacterium tuberculosis Suppresses Inflammatory Responses in Host through Its Cholesterol Metabolites.

Cholesterol is a key carbon source for Mycobacterium tuberculosis (Mtb) survival and persistence within macrophages. However, little is known about the role of cholesterol metabolism by Mtb in host-Mtb interplay. Here, we report the immune suppression mediated by Mtb's cholesterol metabolites. Conducting the cholesterol metabolic profiling and loss-of-function experiments, we show that the cholesterol oxidation products catalyzed by a thiolase FadA5 from Mtb H37Ra, 4-androstenedione (AD), and its derivant 1,4-androstenedione (ADD) inhibit the expression of pro-inflammatory cytokines and thus promote bacterial survival in bone marrow-derived macrophages (BMDMs). Our time-resolved fluorescence resonance energy transfer (TR-FRET)-based screening further identifies the nuclear receptor LXRα as the target of ADD. Activation of LXRα via ADD impedes the nuclear factor-κB (NF-κB) and mitogen-activated protein kinases (MAPK) signaling and reduces cholesterol accumulation in lipid rafts upon TLR4 simulation, thereby compromising the inflammatory responses. Our findings provide the evidence that Mtb could suppress the host immunity through its cholesterol metabolic enzyme and products, which are potential targets for screening novel anti-tuberculosis (TB) agents.

Efficacy of Eugenol Loaded Chitosan Nanoparticles on Sepsis Induced Liver Injury in Rats

Background: Sepsis is a life-threatening condition responsible for high morbidity and mortality rates around the world and is characterized by a dysregulated host response to infection, resulting in multiple organ dysfunctions. Eugenol is a phenolic aromatic compound derived from clove oil. It has anti-inflammatory, antioxidant, antibacterial, antiviral, antifungal, and anticancer characteristics, which have led to its extensive use in diverse fields, including cosmetology, medicine, and pharmacology. The ongoing study aimed to evaluate the efficacy of eugenol-loaded chitosan nanoparticles (EC-NPs) on sepsis-induced liver damage using the cecal ligation and puncture (CLP) model. Methods: Thirty male albino rats were randomly divided into five groups: Sham, sepsis, and septic rats treated with chitosan, eugenol, or EC-NPs. Results: EC-NPs showed excellent antibacterial, antioxidant, and anti-inflammatory effects in vitro. EC-NP administration significantly improved liver function, as indicated by the decreased liver enzyme activities and C-reactive protein (CRP) level, as well as the increase of albumin content. Moreover, EC-NPs caused an increase in glutathione-reduced and antioxidant enzyme activities, as well as a reduction of malondialdehyde and nitric oxide formation. In addition, the EC-NP treatment reduced the DNA damage in septic rats; also, the EC-NP treatment repaired, to some extent, the abnormal architecture of the hepatic tissues of septic rats. Furthermore, the immunohistochemical examination showed a marked decrease in inflammation through the reduction of TNF-α and IL-1β expression. Conclusion: In conclusion, EC-NPs attenuated liver injury in sepsis through its antiinflammatory, anti-bacterial, and anti-oxidant activities and protection of DNA.

Presepsin Does Not Predict Risk of Death in Sepsis Patients Admitted to the Intensive Care Unit: A Prospective Single-Center Study.

Background: Sepsis is defined as life-threatening organ dysfunction caused by an abnormal host response to infection. The study aimed to evaluate the utility of presepsin (P-SEP) in predicting the risk of death in patients with sepsis at the time of intensive care unit (ICU) admission. Methods: Adult patients were included in the study if they met SEPSIS-3 criteria at ICU admission. Demographic and clinical data were collected. The following inflammatory parameters were determined: C-reactive protein (CRP), procalcitonin (PCT), interleukin-6 (IL-6), and presepsin (P-SEP). Material was collected for microbiological testing depending on the suspected source of infection. The primary endpoint was patient death before ICU discharge. The secondary endpoint was a positive microbiological test result. Results: Eighty-six patients were included in the study. Thirty patients (35%) died before discharge from the ICU. There was no difference in P-SEP, CRP, PCT, and IL-6 values between patients who survived and those who died (p > 0.05 for all). P-SEP, CRP, PCT, and IL-6 were determined at ICU admission and did not accurately predict the risk of death in ROC curve analysis (p > 0.05 for all). Confirmation of the location of the focus of bacterial infection by microbiological testing was obtained in 43 (49%) patients. P-SEP, PCT, CRP, and IL-6 were significantly higher in patients with positive microbiological findings. Conclusions: In patients with suspected sepsis admitted to the Intensive Care Unit, presepsin does not accurately predict the risk of in-hospital death, but it can predict a positive microbiological culture.