Host Response Research Articles

Genotype-driven sensitivity of mice to tick-borne encephalitis virus correlates with differential host responses in peripheral macrophages and brain

BackgroundTick-borne encephalitis (TBE) is the most common tick-borne viral infection in Eurasia. Outcomes range from asymptomatic infection to fatal encephalitis, with host genetics likely playing a role. BALB/c mice have intermediate susceptibility to TBE virus (TBEV) and STS mice are highly resistant, whereas the recombinant congenic strain CcS-11, which carries 12.5% of the STS genome on the BALB/c background, is more susceptible than BALB/c mice. In the present study, we employed these genetically distinct mouse models to investigate the host response to TBEV infection in both peripheral macrophages, one of the initial target cell populations, and the brain, the terminal target organ of the virus.MethodsTBEV growth and the production of key cytokines and chemokines were measured and compared in macrophages derived from BALB/c, CcS-11, and STS mice. In addition, brains from these TBEV-infected mouse strains underwent in-depth transcriptomic analysis.ResultsVirus production in BALB/c and CcS-11 macrophages exhibited similar kinetics 24 and 48 h post-infection (hpi), but CcS-11 macrophages yielded significantly higher titers 72 hpi. Macrophages from both sensitive strains demonstrated elevated chemokine and proinflammatory cytokine production upon infection, whereas the resistant strain, STS, showed no cytokine/chemokine activation. Transcriptomic analysis of brain tissue demonstrated that the genetic background of the mouse strains dictated their transcriptional response to infection. The resistant strain exhibited a more robust cell-mediated immune response, whereas both sensitive strains showed a less effective cell-mediated response but increased cytokine signaling and signs of demyelination, with loss of oligodendrocytes.ConclusionsOur findings suggest that variations in susceptibility linked to host genetic background correspond with distinct host responses, both in the periphery upon virus entry into the organism and in the brain, the target organ of the virus. These results provide insights into the influence of host genetics on the clinical trajectory of TBE.

The circulating plasma microRNA signature in human visceral leishmaniasis.

Visceral leishmaniasis (VL) is a vector-borne disease caused by the obligate intracellular protozoan Leishmania donovani in India. VL can be complicated by post-kala-azar dermal leishmaniasis (PKDL), a macular or nodular rash that develops in 10%-20% of patients after treatment of VL in India. Patients with PKDL are infectious to sand flies, promoting further transmission of the parasite. MicroRNAs (miRNAs) are 18-25 nt, non-coding RNAs that simultaneously regulate the expression of several or many target transcripts. This study was based on the hypothesis that the host response to L. donovani is modified by distinct sets of miRNAs in VL or PKDL and that these might differ from healthy controls. We investigated this hypothesis using a NanoString panel to profile the miRNAs expressed in the plasma of patients with VL or PKDL diagnosed at a hospital in Bihar, India. We compared these to plasma microRNAs of healthy control individuals from the same endemic villages. miRNAs hsa-miR-223-3p, hsa-miR-191-5p, hsa-miR-23a-3p, and hsa-1285-5p were significantly higher in the plasma samples from patients with VL compared to either PKDL or endemic controls. Prediction programs highlighted potential mRNA targeted by these miRNAs, among which we verified the down-modulation of several transcripts belonging to the NFκB and NLRP3 inflammasome pathways in circulating leukocytes of VL patients. By contrast, miRNA patterns in subjects with PKDL were similar to control subjects, possibly suggesting that the pathogenic immune response during PKDL is primarily localized in the skin.IMPORTANCEInfection of humans with the protozoan Leishmania donovani can be asymptomatic or it can cause fatal visceral leishmaniasis (VL), sometimes followed by the cutaneous complication PKDL. Parasites are spread through sand fly bites in endemic regions, and parasites in post-kala-azar dermal leishmaniasis (PKDL) skin lesions are a source of prolonged parasite transmission to sand flies, compromising disease eradication efforts. Since microRNAs can simultaneously modify the expression of multiple genes, we examined microRNAs in the blood that might be partial determinants of pathogenic responses leading to VL or PKDL. Our studies revealed several miRNAs expressed that are elevated in the plasma of patients with VL, which suppress some of the inflammatory responses that promote parasite killing. However, miRNA profiles were very similar between PKDL patients and controls, raising the possibility that major factors that lead to prolonged retention of parasites in the skin during PKDL are not systemic but are localized in the skin.

Survival of Patients with Solid Tumours and Sepsis Admitted to Intensive Care in a Tertiary Oncology Centre: A Retrospective Analysis.

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Patients with cancer are at risk of developing sepsis and requiring intensive care unit (ICU) admission. We aimed to assess survival of patients with a solid tumour admitted to ICU as an emergency with sepsis, and to identify predictors of 90-day survival at admission. We conducted a retrospective cohort survival analysis. We identified adults with a solid tumour admitted to ICU with sepsis between 01/01/2011 and 31/12/2020 at a tertiary oncology centre with two hospitals (London and Surrey, UK). We defined sepsis using the Sepsis-3 definition. The primary outcome was 90-day survival. We used the parametric accelerated failure time model for multivariate analysis to generate acceleration factors (AF). 625 patients were identified and the 90-day survival rate was 59.5%(353/593).Multivariate analysis identified the presence of localized (AF 0.13, 95% CI 0.06-0.25) or regionalized disease (AF 0.21, 95% CI 0.12-0.36) compared to distant metastatic disease, unplanned surgery on the day of admission (AF 0.15, 95% CI 0.07-0.31), lactate (AF 1.25 95% CI 1.15-1.35), Sequential Organ Failure Assessment Score (AF 1.19, 95% CI 1.12-1.27), previous radiotherapy (AF 1.89, 95% CI 1.14-3.125), previous systemic anti-cancer treatment (excluding hormonal therapy) (AF 1.49, 95% CI 0.93-2.38), bacteraemia (AF 0.47, 95% CI 0.27-0.81) and serum albumin (AF 0.94, 95% CI 0.91-0.98) as independent predictors of 90-day survival. This study of solid tumour patients admitted to ICU is one of the largest providing survival data to inform clinicians and patients. This data provides information on factors that should be considered when deliberating the possible outcome of ICU admission for a patient with solid malignancy and sepsis and highlights that the presence of cancer itself should not limit ICU admission for sepsis.

The role of N6-methyladenosine (m6A) mRNA modifications in herpesvirus infections.

Herpesviruses, a family of large enveloped DNA viruses, establish persistent infections in a wide range of hosts. This characteristic requires an intricate network of interactions with their hosts and host cells. In recent years, the interplay between herpesviruses and the epitranscriptome-chemical modifications in transcripts that may affect mRNA biology and fate-has emerged as a novel aspect of herpesvirus-host interactions. In particular, herpesviruses display different mechanisms to modulate and usurp the most abundant mRNA modification, N6-methyladenosine or m6A. Some herpesviruses interfere with m6A methylation of transcripts, while others enhance or take advantage of m6A methylation of viral and/or cellular transcripts. In many cases, herpesviruses appear to modulate the m6A methylation process to suppress the antiviral host response. This review highlights the strategies used by members of the different herpesvirus subfamilies to manipulate host m6A mediators and how these contribute to virus replication and the antiviral host response. Research aimed at deciphering the interaction of herpesviruses with the m6A epitranscriptome not only may lead to new avenues in the design of antiviral and immunomodulatory strategies, but also provides new insights in the regulation and the role of m6A transcript methylation in general.

Comprehensive guide for epigenetics and transcriptomics data quality control.

Host response to environmental exposures such as pathogens and chemicals can include modifications to the epigenome and transcriptome. Improved signature discovery, including the identification of the agent and timing of exposure, has been enabled by advancements in assaying techniques to detect RNA expression, DNA base modifications, histone modifications, and chromatin accessibility. The interrogation of the epigenome and transcriptome cascade requires analyzing disparate datasets from multiple assay types, often at single-cell resolution, derived from the same biospecimen. However, there remains a paucity of rigorous quality control standards of those datasets that reflect quality assurance of the underlying assay. This guide outlines a comprehensive suite of metrics that can be used to ensure quality from 11 different epigenetics and transcriptomics assays. Recommended mitigative actions to address failed metrics are provided. The workflow presented aims to improve benchwork protocols and dataset quality to enable accurate discovery of exposure signatures.

Abstract P004: Mapping the tumor-sentinel node immune migratome demonstrates a key role for CCR7+ dendritic cells in the successful response to immunoradiotherapy

Abstract Immune checkpoint inhibition has demonstrated no benefit when combined with chemoradiotherapy for locally advanced HNSCC, raising the possibility that standard therapies compromise the response to immunotherapy. To address this hypothesis, we previously demonstrated that ablating tumor draining lymphatics abolishes the response to immune-oncology therapy. Specifically, we defined that the response to immunotherapy is coordinated by interferon type-I signaling through the cDC1 population in tumor-draining lymph nodes. These findings support the premise that successful tumor responses to immuno-oncology therapies is predicated upon intact and functional, locoregional anatomy. Accordingly, we hypothesize that lymphatic-preserving, tumor-directed immune oncology therapy will promote antitumor immunity by enhancing surveillance along the tumor-immune-lymphatic axis. To explore this, we employ a novel mouse reporter model that allows precise spatiotemporal labeling of immune effector cells. Combined with sentinel lymph node mapping, our reporter model enables selective labeling of immune effectors within the tumor microenvironment and subsequent tracking and characterization of these cells as they migrate to the sentinel lymph node. This approach led us to define the “cancer immune migratome” - the repertoire of immune cells actively migrating from tumors to lymph nodes during an antitumor response. For precise cellular identification, we employed CITE-sequencing, which integrates single-cell RNA expression with surface protein markers, allowing us to comprehensively define the characteristics of migrating immune cells. This work represents the first characterization of immune cell populations migrating from the tumor to the sentinel lymph node, revealing the diversity and dynamics of these populations in antitumor immunity. We then develop a tumor-directed, lymphatic-sparing radiotherapy model to modulate the tumor immune microenvironment without inducing tumor regression. Sequential administration of tumor-directed radiotherapy followed by PD-1 checkpoint inhibition achieves complete and durable responses. Analysis of the cancer immune migratome during immunoradiotherapy revealed a crucial role for an activated population of CCR7+ dendritic cells. These migratory dendritic cells are reprogrammed, via rational sequencing of radiation and immunotherapy, from their canonical role in immune tolerance to actively drive antitumor immunity. This reprogramming enhances T cell priming, clonotypic expansion, and, ultimately, the successful tumor response to immunoradiotherapy. Disruption of sentinel lymphatic channels or selective blockade of CCR7+ DC entry into the SLN abrogates the response to immunoradiotherapy. Overall, this work supports rationally sequencing immune-sensitizing, lymphatic-preserving, tumor-directed radiotherapy followed by immune checkpoint inhibition to optimize tumor response. Our findings support a therapeutic strategy that enhances host response to immunotherapy by directing activated dendritic cells to sentinel lymph nodes. Citation Format: Robert Saddawi-Konefka, Riyam Al Msari, Shiqi Tang, Lauren M. Clubb, Santiago Fassardi, Riley Jones, Farhoud Faraji, Shiruyeh Schokrpur, Bryan S. Yung, Michael M. Allevato, Shawn M. Jensen, Bernard A. Fox, Richard Bell, J. Silvio Gutkind, Andrew Sharabi, Joseph A. Califano. Mapping the tumor-sentinel node immune migratome demonstrates a key role for CCR7+ dendritic cells in the successful response to immunoradiotherapy. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr P004

Plasma EphA2 level is a superior biomarker to Del-1 for sepsis diagnosis and prognosis

BackgroundSepsis, characterized by a dysregulated host response to infection, often leads to organ dysfunction, and vascular endothelial dysfunction plays a central role. The erythropoietin-producing hepatocellular carcinoma (Eph)A2 receptor is associated with increased vascular permeability; however, the developmental endothelial locus-1 (Del-1), has contrasting effects on endothelial function. Hence, we examined their potential as biomarkers of sepsis.MethodsIn total, 117 participants, including 20 healthy controls, 21 patients with systemic inflammatory response syndrome (SIRS), and 76 patients with sepsis, were enrolled in this study. Sepsis severity was assessed using the Acute Physiology and Chronic Health Evaluation (APACHE) II and the Sequential Organ Failure Assessment (SOFA) scores.ResultsThe Median plasma EphA2 levels increased progressively from healthy controls to SIRS and sepsis cases (154.29, 293.52, and 554.24 pg/mL; all p < 0.05). The median plasma Del-1 levels were highest in healthy controls, lowest in SIRS, and intermediate level in sepsis (101.27, 16.88, and 36.9 pg/mL; all p < 0.001). The levels of both biomarkers were higher in 28-day non-survivors than in survivors, in patients with sepsis (EphA2:898.09 vs. 475.88 pg/mL, p < 0.001; Del-1:46.09 vs. 32.68 pg/mL, p = 0.193); however, only EphA2 was statistically significant. The area under the curve for the EphA2 was 0.74 in the receiver operating characteristic curve analysis for predicting 28-day mortality, whereas APACHE II, SOFA, and Del-1 showed values of 0.762, 0.614, and 0.595, respectively. Kaplan–Meier analysis using these cutoffs revealed that survival was significantly higher in the group with both low EphA2 and Del-1 levels compared to the group with high levels of both markers (p < 0.001).ConclusionPlasma EphA2 levels consistently increased with sepsis severity, suggesting its biomarker value for sepsis diagnosis and prognosis. In contrast, plasma Del-1 response was variable, indicating its limited prognostic utility.

Visualizing Tomato Spotted Wilt Virus Protein Localization: Cross-Kingdom Comparisons of Protein-Protein Interactions.

Tomato spotted wilt virus (TSWV) is an orthotospovirus that infects both plants and insect vectors, and understanding its protein localization and interactions is crucial for unraveling the infection cycle and host-virus interactions. We investigated and compared the localization of TSWV proteins. The localization between plant and insect cells was overall consistent, indicating a similar mechanism is utilized by the virus in both types of cells. However, a change in localization over time was associated with the viral proteins that did not contain signal peptides and transmembrane domains such as N, NSs, and NSm, which only occurred in the plant cells and not in the insect cells. We also tested the localization of the proteins during an active plant infection using free red fluorescent protein (RFP) as a marker to highlight the nucleus and cytoplasm. Voids in the cytoplasm were shown only during infection, and N, NSs, NSm, and to a lesser extent GN and GC were surrounding these areas, suggesting it may be a site of replication or morphogenesis. Furthermore, we tested the interactions of viral proteins using both bimolecular fluorescence complementation (BiFC) and membrane-based yeast two-hybrid (MbY2H) assays. These revealed self-interactions of NSm, N, GN, GC, and NSs. We also identified interactions between different TSWV proteins, indicating their possible roles, such as between NSs and GC and N and GC, which may be necessary during the replication and assembly processes, respectively. This research expands our knowledge of TSWV infection and elaborates on the intricate relationships between viral proteins, cellular dynamics, and host responses. [Formula: see text] Copyright © 2025 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

Major clinical outcomes of the endodontic infections and gut microbiota axis: a systematic review

Introduction: Endodontic therapy aims to shape, clean, and disinfect the root canal, and is performed by removing all pulp tissue or necrotic remains and microorganisms present in the root canal system. The gut microbiota or specific microbial metabolites not only locally influence the host's inflammatory responses, nutritional intake, or intestinal barrier function, but are also related to the immune and metabolic systems. In addition to antimicrobial activity, calcium hydroxide has properties such as dissolution of organic remnants, anti-inflammatory action, inhibition of inflammatory resorptions, and physical barrier function. Objective: To present the main considerations and clinical outcomes of the relationship between gut microbiota and endodontic infections and highlight endodontic treatment with calcium hydroxide, showing the mechanisms of antibacterial action. Methods: The PRISMA Platform systematic review rules were followed. The search was conducted from September to October 2024 in the Scopus, PubMed, Science Direct, Scielo, and Google Scholar databases. The quality of the studies was based on the GRADE instrument and the risk of bias was analyzed according to the Cochrane instrument. Results and Conclusion: 102 articles were found, 25 were evaluated in full and 09 were included and developed in the present systematic review study. Considering the Cochrane tool for risk of bias, the overall assessment resulted in 35 studies with a high risk of bias and 22 studies that did not meet GRADE and AMSTAR-2. Most studies did not show homogeneity in their results, with X2=79.2%<50%. It was concluded that, in the setting of endodontic therapy, the presence of microorganisms, particularly gramnegative anaerobes, in the root canal system and cementum resorption gaps after root canal treatment is considered one of the main causes of persistent periapical lesions and, therefore, of endodontic treatment failure. The gut microbiota or specific microbial metabolites not only locally influence the patient's inflammatory responses, nutritional intake, or intestinal barrier function, but are also related to the immune and metabolic systems. The change in the microbiota of the oral-gut axis and its interactions with Helicobacter pylori may be potential targets for the diagnosis and infectious treatment of Helicobacter pylori. Calcium hydroxide in endodontics is the most widely used medication to combat pathology-causing bacteria, but when used alone it may not be able to eliminate these microorganisms. The combination of other medications incorporated into calcium hydroxide contributes to positive results with the elimination of more resistant bacteria.

Circadian metabolic adaptations to infections.

Circadian clocks are biological oscillators that evolved to coordinate rhythms in behaviour and physiology around the 24-hour day. In mammalian tissues, circadian rhythms and metabolism are highly intertwined. The clock machinery controls rhythmic levels of circulating hormones and metabolites, as well as rate-limiting enzymes catalysing biosynthesis or degradation of macromolecules in metabolic tissues, such control being exerted both at the transcriptional and post-transcriptional level. During infections, major metabolic adaptation occurs in mammalian hosts, at the level of both the single immune cell and the whole organism. Under these circumstances, the rhythmic metabolic needs of the host intersect with those of two other players: the pathogen and the microbiota. These three components cooperate or compete to meet their own metabolic demands across the 24 hours. Here, we review findings describing the circadian regulation of the host response to infection, the circadian metabolic adaptations occurring during host-microbiota-pathogen interactions and how such regulation can influence the immune response of the host and, ultimately, its own survival.This article is part of the Theo Murphy meeting issue 'Circadian rhythms in infection and immunity'.

Activation and modulation of the host response to DNA damage by an integrative and conjugative element.

Mobile genetic elements help drive horizontal gene transfer and bacterial evolution. Conjugative elements and temperate bacteriophages can be stably maintained in host cells. They can alter host physiology and regulatory responses and typically carry genes that are beneficial to their hosts. We found that ICEBs1, an integrative and conjugative element (ICE) of Bacillus subtilis, inhibits the host response to DNA damage (the SOS response). Activation of ICEBs1 before DNA damage reduced host cell lysis that was caused by SOS-mediated activation of two resident prophages. Further, activation of ICEBs1 itself activated the SOS response in a subpopulation of cells, and this activation was attenuated by the functions of the ICEBs1 genes ydcT and yddA (now ramT and ramA; ram for RecA modulator). Double-mutant analyses indicated that RamA functions to inhibit and RamT functions to both inhibit and activate the SOS response. Both RamT and RamA caused a reduction in RecA filaments, one of the early steps in activation of the SOS response. We suspect that there are several different mechanisms by which mobile genetic elements that generate single-stranded DNA (ssDNA) during their life cycle inhibit the host SOS response and RecA function, as RamT and RamA differ from the known SOS inhibitors encoded by conjugative elements.IMPORTANCEBacterial genomes typically contain mobile genetic elements, including bacteriophages (viruses) and integrative and conjugative elements, that affect host physiology. ICEs can excise from the chromosome and undergo rolling-circle replication, producing ssDNA, a signal that indicates DNA damage and activates the host SOS response. We found that following excision and replication, ICEBs1 of B. subtilis stimulates the host SOS response and that ICEBs1 encodes two proteins that limit the extent of this response. These proteins also reduce the amount of cell killing caused by resident prophages following their activation by DNA damage. These proteins are different from those previously characterized that inhibit the host SOS response and represent a new way in which ICEs can affect their host cells.

I "Gut" Rhythm: the microbiota as a modulator of the stress response and circadian rhythms.

Modern habits are becoming more and more disruptive to health. As our days are often filled with circadian disruption and stress exposures, we need to understand how our responses to these external stimuli are shaped and how their mediators can be targeted to promote health. A growing body of research demonstrates the role of the gut microbiota in influencing brain function and behavior. The stress response and circadian rhythms, which are essential to maintaining appropriate responses to the environment, are known to be impacted by the gut microbiota. Gut microbes have been shown to alter the host's response to stress and modulate circadian rhythmicity. Although studies demonstrated strong links between the gut microbiota, circadian rhythms and the stress response, such studies were conducted in an independent manner not conducive to understanding the interface between these factors. Due to the interconnected nature of the stress response and circadian rhythms, in this review we explore how the gut microbiota may play a role in regulating the integration of stress and circadian signals in mammals and the consequences for brain health and disease.

Cell deconvolution-based integrated time-series network of whole blood transcriptome reveals systemic antiviral activities and cell-specific immunological changes against PRRSV infection

Porcine reproductive and respiratory syndrome (PRRS) causes significant economic losses in the swine industry. However, the molecular mechanisms behind the common and cell type-specific systemic responses during PRRS virus (PRRSV) infection are not well understood. In this study, we collected viremia data, antibody levels, and whole-blood RNA-seq data obtained from eight PRRSV-infected piglets. We utilised a cell deconvolution approach to calculate cell type enrichment, constructed a time-serial gene co-expression network with differentially expressed genes, and conducted functional annotations. Three significant modules were identified within the network. The changes associated with viremia revealed an upregulated expression of genes related to antiviral activity. In the T-cell- and NK-cell-specific modules, infection led to an increased T-cell population and upregulation of genes related to T-cell defence responses. Conversely, in the monocyte- and neutrophil-specific module, genes involved in inflammatory responses were downregulated due to a decrease in monocyte proportion. This study highlights the time-series antiviral activities associated with viremia and the transcriptomic changes associated with immune responses in specific cell types. The findings provide comprehensive insights into host responses to PRRSV infection, including diagnostic biomarkers.

P0069 TP-317, a Novel BLT1 Agonist Oral Therapy for Inflammatory Bowel Disease, Exhibits Anti-Inflammatory and Epithelial Barrier Protective Efficacy in Murine DSS Colitis and TNFΔARE Ileitis

Abstract Background Resolvin E1 (RvE1) and leukotriene B4 (LTB4) are both BLT1 receptor agonists but elicit distinct biological outcomes through biased agonism. LTB4, a pro-inflammatory lipid mediator, initiates and regulates inflammatory responses by stimulating recruitment and activation of immune cells. In contrast, RvE1, a pro-resolution lipid mediator, selectively engages BLT1 to promote immune homeostasis and repair. TP-317, a stabilized RvE1 molecule, is being investigated as an oral therapy for inflammatory bowel disease (IBD). The subject studies describe the efficacy and mechanism of TP-317 in two preclinical colitis models. Methods DSS colitis: 8-wk old C57Bl6/J mice (n=12/group) were given two 5-day cycles of DSS (1%, 2%) separated by a 10-day recovery period, followed by 7 days of daily oral treatment starting on day 20 with TP-317 (0.04, 0.4 or 4 mg/kg), cyclosporin (25 mg/kg), the JAK1 inhibitor filgotinib (36 mg/kg), or vehicle. Colitis symptoms were scored daily using disease activity index (DAI). Mice were sacrificed on day 27 for histology. TNFΔARE Ileitis:8-10 wk old TNFΔARE mice were treated with daily oral TP-317 at 0.04, 0.4 and 4 mg/kg for 14 days (n=3/group). On Day 13, mice were administered FITC-Dextran (0.4 g/kg/d) by oral gavage and blood drawn after 4 hrs to measure intestinal permeability. Animals were sacrificed on day 14, intestinal tissue was harvested and cytokine levels were measured in whole tissue lysates by ELISA; disease activity was scored by histology. Results In DSS colitis, 0.4 mg/kg TP-317 showed similar efficacy to cyclosprin and filgotinib in reducing DAI scores. Overall histology scores (a composite of inflammation severity, inflammation depth and crypt loss) were reduced by 14% (NS), 22% (NS) and 33% (p<0.01) by 0.04, 0.4 and 4 mg/kg TP-317, respectively, compared to 33% (p<0.01) for cyclosporin and 44% (p<0.001) for filgotinib. All doses of TP-317 significantly reduced Crypt Damage score (34%, 37%, 39%), showing greater effects than cyclosporin or filgotinib. In TNFΔARE ileitis, TP-317 treatment was associated with reduced intestinal permeability and disease activity, while reducing pro- inflammatory IL-17 and increasing anti-inflammatory L-10 in mucosal tissue. Conclusion Oral TP-317 demonstrates anti-inflammatory, mucosal immuno-modulatory and epithelial barrier protective actions in preclinical colitis and ileitis. These findings align with reports of have exacerbated DSS colitis in BLT1-/- mice and RvE1’s promotion of BLT1-dependent wound repair in an in vitro model using human intestinal epithelial cells.1 2 Together, these studies support positioning of TP-317 as a novel, oral BLT1 agonist for treating ileal and colonic disease in IBD patients. References 1 Jala VR, Maturu P, Bodduluri SR, Krishnan E, Mathis S, Subbarao K, Wang M, Jenson AB, Proctor ML, Rouchka EC, Knight R, Haribabu B. Leukotriene B4-receptor-1 mediated host response shapes gut microbiota and controls colon tumor progression. Oncoimmunology. 2017 Aug 10;6(12):e1361593. PMID 29209564 2 Hayashi S, Muraleedharan CK, Oku M, Tomar S, Hogan SP, Quiros M, Parkos CA, Nusrat A. Intestinal epithelial BLT1 promotes mucosal repair. JCI Insight. 2022 Dec 8;7(23):e162392. PMID 36301666

Mgl2+ cDC2s coordinate fungal allergic airway type 2, but not type 17, inflammation in mice

Fungal spores are abundant in the environment and a major cause of asthma. Originally characterised as a type 2 inflammatory disease, allergic airway inflammation that underpins asthma can also involve type 17 inflammation, which can exacerbate disease causing failure of treatments tailored to inhibit type 2 factors. However, the mechanisms that determine the host response to fungi, which can trigger both type 2 and type 17 inflammation in allergic airway disease, remain unclear. Here we find that CD11c+ DCs and CD4+ T cells are essential for development of both type 2 and type 17 airway inflammation in mice repeatedly exposed to inhaled spores. Single cell RNA-sequencing with further multi-parameter cytometry shows that allergic inflammation dramatically alters the proportion of numerous DC clusters in the lung, but that only two of these (Mgl2+ cDC2s and CCR7+ DCs) migrate to the dLNs. Targeted removal of several DC subsets shows that Mgl2+ cDC2 depletion reduces type 2, but not type 17, fungal allergic airway inflammation. These data highlight distinct DC subsets as potential therapeutic targets for the treatment of pulmonary fungal disease.

Understanding Host–Pathogen Interactions in Congenital Chagas Disease Through Transcriptomic Approaches

Chagas disease, caused by Trypanosoma cruzi, is a parasitic zoonosis with significant health impacts, particularly in Latin America. While traditionally associated with vector-borne transmission, increased migration has expanded its reach into urban and non-endemic regions. Congenital transmission has become a critical route of infection, involving intricate maternal–fetal immune interactions that challenge diagnosis and treatment. This review synthesizes findings from three RNA-seq studies that explore the molecular underpinnings of congenital Chagas disease, emphasizing differentially expressed genes (DEGs) implicated in host–pathogen interactions. The DAVID tool analysis highlighted the overexpression of genes associated with the innate immune response, including pro-inflammatory cytokines that drive chemotaxis and neutrophil activation. Additionally, calcium-dependent pathways critical for parasite invasion were modulated. T. cruzi exploits the maternal–fetal immune axis to establish a tolerogenic environment conducive to congenital transmission. Alterations in placental angiogenesis, cellular regeneration, and metabolic processes further demonstrate the parasite’s ability to manipulate host responses for its survival and persistence. These findings underscore the complex interplay between the host and pathogen that facilitates disease progression. Future research integrating transcriptomic, proteomic, and metabolomic approaches is essential to unravel the molecular mechanisms underlying congenital Chagas disease, with a particular focus on the contributions of genetic diversity and non-coding RNAs in immune evasion and disease pathogenesis.

Prevalence of <i>Trypanasomiasis</i> in Northern Nigeria: A review

Trypanosomiasis, a parasitic disease caused by protozoan parasites of the genus Trypanosoma, is a significant public health concern in sub-Saharan Africa, including Northern Nigeria. The disease, transmitted by tsetse flies, poses a significant threat to human health, livestock production, and economic development. Animal African trypanosomiasis (AAT), also known as Nagana, is caused by various trypanosome species, including T. brucei, T. congolense, T. vivax, T. equiperdum, T. evansi, T. simiae, T. suis, and T. theileri. Cattle are the most affected, but other animals such as goats, dogs, sheep, pigs, and wild animals are also susceptible. Symptoms of AAT include parasitaemia, anemia, loss of weight, reduced productivity, and high mortality, which limit the pace of rural development in tropical Africa. The current threat of AAT ranks among the top cattle diseases on sustainable livestock production and mixed farming. At least 3 million livestock deaths each year are caused by AAT, with a loss in livestock production and mixed agriculture valued at $5 billion US dollars yearly in Africa. Effective and sustainable control measures can result in up to threefold increases in the estimated livestock population in Nigeria. Trypanosomiasis is considered a haemoparasites, posing a major threat for the development of the cattle industry in Africa, Asia, and Latin America. It kills a variety of domestic and wild animals and causes anemia, weight loss, miscarriage, and productivity losses. In Northern Nigeria, both human African trypanosomiasis (HAT) and animal African trypanosomiasis (AAT) are prevalent. The epidemiology of trypanosomosis depends on the distribution of vectors, the virulence of the parasite, and the host's response.

Multi-omic signatures of host response associated with presence, type, and outcome of enterococcal bacteremia.

Enterococcus infections have emerged as the second most common nosocomial infection, with enterococcal bacteremia (EcB) contributing to thousands of patient deaths annually. To address a lack of detailed understanding regarding the specific systemic response to EcB, we conducted a comprehensive multi-omic evaluation of the systemic host response observed in patient plasma. Our findings reveal significant features in the metabolome and proteome associated with the presence of infection, species differences, and survival outcome. We identified features capable of discriminating EcB infection from healthy states and survival from mortality with excellent accuracy, suggesting potential practical clinical utility. However, our study also established that systemic features to distinguish Enterococcus faecalis from Enterococcus faecium EcB show only a moderate degree of discriminatory accuracy, unlikely to significantly improve upon current diagnostic methods. Comparisons of differences in the plasma proteome relative to healthy samples between bacteremia caused by Enterococcus and Staphylococcus aureus suggest the presence of bacteria-specific responses alongside conserved inflammatory reactions.

Cold suppresses virus accumulation and alters the host transcriptomic response in the turnip mosaic virus ̶ Arabidopsis halleri system.

Since plant viruses cause lifelong infections, virus-plant interactions are exposed to large temperature fluctuations in evergreen perennials. In such circumstances, virus-plant interactions are expected to change significantly between the warm and cold seasons. However, few studies have investigated the effects of cold temperatures on virus-plant interactions. Here, we show that in a persistent infection system of the turnip mosaic virus (TuMV) -Arabidopsis halleri, cold temperatures lead to slow viral replication/spreading within the host, slow attenuation of host symptoms, and slow cold-specific transcriptomic responses. Many differentially expressed genes (DEGs) were detected between virus-inoculated and mock-inoculated plants under warm and cold conditions; however, the sets of DEGs and response timings were temperature-dependent. Under cold temperatures, the expression of photosynthesis-related genes decreased in the early stages of infection. However, it recovered to the same level as that in uninfected plants in the later stages. In contrast, the transcriptomic changes under warm conditions suggest that viral infections cause auxin-signaling disruption. These responses coincided with the inhibition of host growth. We identified 6 cold- and 38 warm-specific DEGs, that changed their expression in response to TuMV infection under more than half of the conditions for either cold or warm temperatures. Further validation of the putative relationships between transcriptomic and phenotypic responses of the host is required. Our findings on temperature-dependent host responses at both symptomatic and transcriptomic levels help us understand how warm and cold temperatures affect virus-plant interactions in seasonal environments.

Factors associated with delayed referrals of patients with sepsis from primary to tertiary healthcare in Blantyre, Malawi: a qualitative study

BackgroundSepsis is defined as invasion of pathogens into the blood stream together with the host response to this invasion. Thus, sepsis consists of the systemic inflammatory response syndrome (SIRS)caused by infection. It is a life-threatening condition that requires prompt detection and early definitive medical intervention. Globally, sepsis is common, with an estimated 31.5 million cases per year. Sepsis accounts for a significant in-hospital mortality rate of 17% in high-income countries, while in Malawi, it ranges from 17 to 50%. For Malawi, the trend can be reversed with improvements in patient referral system within the healthcare system. The study sets out to establish factors associate with delay referral of patients with sepsis from primary healthcare to tertiary hospitals and to understand healthcare workers and patients’ perspectives on barriers associated with delayed referral of patients with sepsis from primary to tertiary healthcare.MethodsA qualitative descriptive study in six health centres within Blantyre District health office. In-depth interviews were conducted with 22 respondents: healthcare providers [n = 12]; patients [n = 10] using semi-structured interview guides. Purposive sampling techniques were used in selecting healthcare providers (health centre in charges) and patients.ResultsThe study demonstrating that the main referral pathways for patients with sepsis include community-to-facility and facility-to-facility referrals. Ambulances and personal transport are common transportation mode used during referrals. Primary care facilities face several challenges that delay referrals from primary to tertiary health facility of patients with sepsis, such as lack of referral transport, poor communication, poor road network, shortage of skilled healthcare workers, patient preferences, delayed treatment-seeking action, and ambulances prioritising maternal conditions.ConclusionsPatients’ delay and failure to access prompt and timely referral services result from the healthcare system’s lack of transport, communication problems, bad road networks and shortage of well-trained personnel. Referral delays have deleterious effects on patient-care outcomes.