Project description:Purpose: Comparison of the effect on the host immune response of feline coronavirus infection with or without feline infectious peritonitis Results: FIP was associated with higher pro-inflammatory pathway enrichment; whilst non-FIP FCoV-positive cats showed lower enrichment of humoral immunity pathways, below that of uninfected cats in the case of immunoglobulin production pathways Conclusions: Reinforces host differences in disease susceptibility in addition to any viral factors, importance of cellular vs humoral response also highlighted.
Project description:Feline infectious peritonitis (FIP) is a fatal disease, if left untreated, caused by feline coronavirus (FCoV). Although the role of the immune system in the pathogenesis of FIP remains incompletely understood, an excessive and harmful immune response appears to be a key factor. In a recent study by the same authors, 18 cats with FIP were successfully cured with oral GS-441524. The present study aimed to analyze the molecular signatures of these treated cats using next-generation RNA-sequencing on full blood samples by highlighting key immune pathways involved in disease progression, treatment response, and recovery. Therefore, samples were analyzed at three stages: untreated (d0), treated with the antiviral drug (days 2, 7, 28), and fully cured (days 168, 252, 365). Additionally, gene expression profiles were compared to those of healthy FCoV-infected control cats (n=12) and uninfected healthy control cats (n=5). Multiple tests with adjusted p-value (adj.p<0.001) were performed. Within the first few days of treatment, massive changes in the RNA signature profile were observed, with approximately 75% of expressed genes significantly differentially regulated between d0 and later time points. Notably, a strong antiviral immune response, which was dominant at the onset of the disease, was significantly downregulated within two days, accompanied by a shift in blood cell composition from monocytes and neutrophils to B cells. Our findings revealed a rapid normalization of the blood RNA signature within the first week of treatment suggesting that elimination of the virus from the blood leads to a rapid down-regulation of the damaging immune response.
Project description:Background Feline infectious peritonitis is a viral disease caused by feline coronavirus an enveloped virus with a single-stranded RNA genome that is approximately 30 kb long. Although FCoV generally causes mild symptoms, approximately 5 % of cases progress to death in cats worldwide. FCoV shares certain virological features with severe acute respiratory syndrome coronavirus 2 that causes COVID-19, indicating that common therapeutic strategies may be applicable. GS-441524 the parent drug of remdesivir and a competitive inhibitor of nucleoside triphosphates in viral RNA synthesis is a well-known treatment for FIP. However, comparative transcriptome and gene ontology analyses of normal (Normal), FIP-diseased (FIPD), and FIP-recovered (FIPR) cats have not yet been conducted. Results In this study, we compared the mRNA expression profiles of peripheral blood mononuclear cells from Normal, FIPD, and FIPR cats to identify immunological alterations. We identified 715 (FIPD/Normal) and 1,164 (FIPR/FIPD) differentially expressed genes with statistical significance. These data were input into the bioinformatics program. As a result, the analysis revealed statistically significant and contrasting patterns of canonical pathways of neutrophil degranulation and interleukin-8 (IL-8) signaling pathways. Additionally, we observed that kruppel-like factor 6 (KLF6) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) were upstream molecules of IL-8, promoting neutrophil activation and function. Conclusions This study identified immunological alterations in PBMCs of Normal, FIPD, and FIPR cats. KLF-6 and NF-κB were found to regulate IL-8-mediated neutrophil activation.
Project description:Feline infectious peritonitis (FIP) is a lethal, viral induced immune-mediated disease that remains a challenge for diagnosis and treatment in cats. Proteomic profiling, which analyzes the protein content of biological samples, offers the potential to identify novel biomarkers that could enhance the diagnosis and management of FIP. This study aims to assess the serum proteome and identify proteins that differentiate healthy cats from cats diagnosed with effusive FIP, using liquid chromatography coupled with tandem mass spectrometry (LC–MS/MS).
Project description:The effect of natural feline coronavirus infection on the host immune response: a whole-transcriptome analysis on the mesenteric lymph nodes of cats with and without feline infectious peritonitis
Project description:Peripheral blood monocytes were isolated from 3 control and 3 diabetic cats using positive selection and expression profiled using the Affymetrix Feline 1.0ST array.
Project description:Adipose-derived mesenchymal stem cells (ASCs) are a promising cell therapy to treat inflammatory and immune-mediated diseases. Development of appropriate pre-clinical animal models is critical to determine safety and attain early efficacy data for the most promising therapeutic candidates. Naturally occurring diseases in cats already serve as valuable models to inform human clinical trials in oncologic, cardiovascular and genetic diseases. The objective of this study was to complete a comprehensive side-by-side comparison of human and feline ASCs with an emphasis on their immunomodulatory capacity and transcriptome. Similar to human ASCs, feline ASCs were highly proliferative at low passages and fit the minimal criteria of multipotent stem cells including a compatible surface protein phenotype, osteogenic capacity and normal karyotype. Like ASCs from all species, feline ASCs inhibited mitogen activated lymphocyte proliferation in vitro, with or without direct ASC-lymphocyte contact. Feline ASCs mimic human ASCs in their mediator secretion pattern including prostaglandin E2, indoleamine 2,3 dioxygenase, transforming growth factor beta and interleukin-6, all augmented by interferon gamma secretion by lymphocytes. The transcriptome of 3 unactivated feline ASC lines were highly similar. Functional analysis of the most highly expressed genes highlighted processes including: 1) the regulation of apoptosis, 2) cell adhesion, 3) response to oxidative stress, and 4) regulation of cell differentiation. Finally, feline ASCs had a similar gene expression profile to noninduced human ASCs. These data will help inform clinical trials using cats with naturally occurring diseases as surrogate models for human clinical trials in the regenerative medicine arena.
Project description:Fibrosarcomas (FSA) are rare malignant soft tissue tumors characterized by low chemo- and radiosensitivity. The development of novel treatment strategies for human FSA is hindered by the low incidence of the disease and the absence of suitable clinical models. Interestingly, aggressive FSA occur more frequently in domestic cats, representing a clinically amenable model for assessing novel therapies such as targeted imaging or theranostics. However, a lack of molecular characterization of FSA and adjacent normal tissue (NT) in both species hinders identification of tumor-specific targets and undermines the translational potential of feline FSA. Combining laser-capture microdissection, RNA sequencing and LC-MS/MS, we perform comprehensive profiling of 30 feline FSA and matched skeletal muscle, adipose and connective tissue. Clear inter-tissue differences allow the identification of significantly upregulated and tumor-exclusive features that represent potential targets for diagnostic and therapeutic approaches. While feline FSA are characterized by hyperactive EIF2, TP53 and MYC signaling, immune-related and neuronal pathways emerge as modulators of tumor aggressiveness and immunosuppression. A high degree of molecular similarity with canine and human FSA allows the identification of conserved cross-species tumor targets. Significant enrichment in DNA repair pathways in feline FSA are shown to be associated with aggressive clinical behavior in human STS. Finally, we leverage the molecular profiles to identify vulnerabilities, including sensitivity to ATR and PARP inhibition as potential treatment for feline FSA. In conclusion, this detailed landscape provides a rich resource to identify target candidates and therapeutic vulnerabilities within and across species and supports feline FSA as relevant models for the human disease.
Project description:Next generation sequencing for the feline transcriptome (mRNA and microRNA profiles) was carried out using myocardial samples from female and male young healthy cats, adult healthy cats, and cats with hypertrophic cardiomyopathy.