Feline Chronic Gingivostomatitis Diagnosis and Treatment through Transcriptomic Insights

Feline chronic gingivostomatitis (FCGS) is a debilitating inflammatory oral mucosal disease with a multifactorial etiology. The clinical diagnosis of FCGS is made based on inspection of severe inflammatory lesions and histological confirmation rather than a molecular diagnostic outcome. This gap limits the ability to provide an early diagnosis. In this report, we seek to provide additional diagnostic tools using genomics to aid in providing clinically relevant information. The use of in-depth diagnostic tools, like transcriptomics of diseased tissues, to diagnose FCGS and stratify patients into predictive treatment response groups would dramatically improve both clinical decisions and patient outcomes. In this study, we addressed the gap in diagnostic options using transcriptomic analysis of caudal oral mucosal swab specimens coupled to detailed medical record linkage of FCGS-affected cats undergoing tooth extractions and in some cases administration of mesenchymal stromal cells (MSCs). To better identify markers of disease and potential response to treatment, the transcriptomes of FCGS-afflicted cats were compared to those of healthy cats and those with chronic periodontitis to clearly establish diagnostic biomarker signal transduction connections. Phosphatidylinositol 3-kinase/Ak strain transforming (PI3K/AKT) and stress-activated protein kinases/Jun N-terminal kinase (SAP/JNK) signaling pathways were significantly differentially regulated in FCGS-afflicted cats. Activation of these pathways also differed in the treatment response groups. In conjunction, the enzymes Caspase 4 (CASP4), matrix metalloproteinase-8 (MMP8), and prostaglandin-endoperoxide synthase 2 (PTGS2) were identified as potential biomarkers for the prediction of treatment response outcomes. The observations in the case study support the use of transcriptomics of FCGS patients to contribute to improved molecular diagnostics for the diagnosis and treatment of FCGS.

[1]  A. Tsugawa,et al.  The Oral Microbiome across Oral Sites in Cats with Chronic Gingivostomatitis, Periodontal Disease, and Tooth Resorption Compared with Healthy Cats , 2023, Animals : an open access journal from MDPI.

[2]  B. Arzi,et al.  Feline chronic gingivostomatitis current concepts in clinical management , 2023, Journal of feline medicine and surgery.

[3]  J. Grenier,et al.  Transcriptomic signatures of feline chronic gingivostomatitis are influenced by upregulated IL6 , 2023, Research Square.

[4]  N. Vapniarsky,et al.  Mesenchymal stromal cell therapy for feline chronic gingivostomatitis: Long term experience , 2023, Frontiers in Veterinary Science.

[5]  Yaguang Zhang,et al.  The Molecular Mechanisms of Liver Fibrosis and Its Potential Therapy in Application , 2022, International journal of molecular sciences.

[6]  A. Webb,et al.  Caspase-4/11 exacerbates disease severity in SARS–CoV-2 infection by promoting inflammation and immunothrombosis , 2022, Proceedings of the National Academy of Sciences of the United States of America.

[7]  R. Enciso,et al.  Oral Lichen Planus: A review of clinical features, etiologies, and treatments , 2021, Dentistry Review.

[8]  Karla D. Passalacqua,et al.  Akt Plays Differential Roles during the Life Cycles of Acute and Persistent Murine Norovirus Strains in Macrophages , 2021, Journal of virology.

[9]  L. Mestrinho,et al.  A Case Series Analysis of Dental Extractions’ Outcome in Cats with Chronic Gingivostomatitis Carrying Retroviral Disease , 2021, Animals : an Open Access Journal from MDPI.

[10]  B. Arzi,et al.  Multipotent Stromal Cells and Viral Interaction: Current Implications for Therapy , 2021, Stem cell reviews and reports.

[11]  S. Dandekar,et al.  Gut germinal center regeneration and enhanced antiviral immunity by mesenchymal stem/stromal cells in SIV infection , 2021, JCI insight.

[12]  M. Siebeck,et al.  The PI3K pathway as a therapeutic intervention point in inflammatory bowel disease , 2021, Immunity, inflammation and disease.

[13]  William A. Fried,et al.  Use of unbiased metagenomic and transcriptomic analyses to investigate the association between feline calicivirus and feline chronic gingivostomatitis in domestic cats. , 2021, American journal of veterinary research.

[14]  R. Bicalho,et al.  Preliminary functional analysis of the subgingival microbiota of cats with periodontitis and feline chronic gingivostomatitis , 2021, Scientific Reports.

[15]  C. Fowler,et al.  Relative Deficiency of Anti-Inflammatory N-Acylethanolamines Compared to Prostaglandins in Oral Lichen Planus , 2020, Biomedicines.

[16]  A. Duarte,et al.  A pilot study to evaluate the serum Alpha-1 acid glycoprotein response in cats suffering from feline chronic gingivostomatitis , 2020, BMC Veterinary Research.

[17]  S. Heymans,et al.  Myocarditis and inflammatory cardiomyopathy: current evidence and future directions , 2020, Nature Reviews Cardiology.

[18]  N. Vapniarsky,et al.  Histological, Immunological, and Genetic Analysis of Feline Chronic Gingivostomatitis , 2020, Frontiers in Veterinary Science.

[19]  N. Vapniarsky,et al.  A multicenter experience using adipose-derived mesenchymal stem cell therapy for cats with chronic, non-responsive gingivostomatitis , 2020, Stem Cell Research & Therapy.

[20]  S. Lima,et al.  The subgingival microbial community of feline periodontitis and gingivostomatitis: characterization and comparison between diseased and healthy cats , 2019, Scientific Reports.

[21]  D. Lin,et al.  Tumour biomarkers—Tracing the molecular function and clinical implication , 2019, Cell proliferation.

[22]  Arihito Sakusabe,et al.  Evaluation of the efficacy of the subcutaneous low recombinant feline interferon-omega administration protocol for feline chronic gingivitis-stomatitis in feline calicivirus-positive cats. , 2018, Research in veterinary science.

[23]  A. Amer,et al.  CASP4/caspase-11 promotes autophagosome formation in response to bacterial infection , 2018, Autophagy.

[24]  R. Wek.  Role of eIF2α Kinases in Translational Control and Adaptation to Cellular Stress. , 2018, Cold Spring Harbor perspectives in biology.

[25]  Lin Zhang,et al.  Salivary matrix metalloproteinase (MMP)-8 as a biomarker for periodontitis , 2018, Medicine.

[26]  P. Hennet,et al.  Relationship between Feline calicivirus Load, Oral Lesions, and Outcome in Feline Chronic Gingivostomatitis (Caudal Stomatitis): Retrospective Study in 104 Cats , 2017, Front. Vet. Sci..

[27]  Pushpa Tandon,et al.  Biomarkers of chronic inflammation in disease development and prevention: challenges and opportunities , 2017, Nature Immunology.

[28]  N. Vapniarsky,et al.  Therapeutic Efficacy of Fresh, Allogeneic Mesenchymal Stem Cells for Severe Refractory Feline Chronic Gingivostomatitis , 2017, Stem cells translational medicine.

[29]  Y. Izumi,et al.  Periodontitis and myocardial hypertrophy , 2016, Hypertension Research.

[30]  N. Vapniarsky,et al.  Therapeutic Efficacy of Fresh, Autologous Mesenchymal Stem Cells for Severe Refractory Gingivostomatitis in Cats , 2015, Stem cells translational medicine.

[31]  M. Greabu,et al.  Possible salivary and serum biomarkers for oral lichen planus , 2015, Biotechnic & histochemistry : official publication of the Biological Stain Commission.

[32]  S. Khan,et al.  Role of salivary matrix metalloproteinase-8 (MMP-8) in chronic periodontitis diagnosis , 2015, Frontiers of Medicine.

[33]  J. R. Lewis,et al.  Effect of tooth extraction on stomatitis in cats: 95 cases (2000-2013). , 2015, Journal of the American Veterinary Medical Association.

[34]  E. Jabłońska,et al.  PI3K-Akt/PKB signaling pathway in neutrophils and mononuclear cells exposed to N-nitrosodimethylamine , 2014, Journal of immunotoxicology.

[35]  Dengwen Li,et al.  Identification of a Role for the PI3K/AKT/mTOR Signaling Pathway in Innate Immune Cells , 2014, PloS one.

[36]  F. Verstraete,et al.  Dental radiographic findings in cats with chronic gingivostomatitis (2002-2012). , 2014, Journal of the American Veterinary Medical Association.

[37]  M. Lommer.  Efficacy of Cyclosporine for Chronic, Refractory Stomatitis in Cats: A Randomized, Placebo-Controlled, Double-Blinded Clinical Study , 2013, Journal of veterinary dentistry.

[38]  D. Lappin,et al.  The influence of oral bacteria on tissue levels of Toll-like receptor and cytokine mRNAs in feline chronic gingivostomatitis and oral health. , 2013, Veterinary immunology and immunopathology.

[39]  G. R. Persson,et al.  Rheumatoid arthritis and periodontitis – inflammatory and infectious connections. Review of the literature , 2012, Journal of oral microbiology.

[40]  T. Gruffydd-Jones,et al.  Immunohistochemical characterization of oral mucosal lesions in cats with chronic gingivostomatitis. , 2011, Journal of comparative pathology.

[41]  G. Nilsson,et al.  Expression of prostaglandin E synthases in periodontitis immunolocalization and cellular regulation. , 2011, The American journal of pathology.

[42]  S. Kato,et al.  PPAR-γ Signaling Crosstalk in Mesenchymal Stem Cells , 2010, PPAR research.

[43]  R. Ionescu,et al.  PI3K/Akt signaling in peripheral T lymphocytes from systemic lupus erythematosus patients. , 2009, Roumanian archives of microbiology and immunology.

[44]  L. Masetti,et al.  Surgical therapy in chronic feline gingivostomatitis (FCGS) , 2008, Veterinary Research Communications.

[45]  T. J. Gruffydd-Jones,et al.  Cytokine mRNA Expression in Lesions in Cats with Chronic Gingivostomatitis , 1999, Clinical Diagnostic Laboratory Immunology.

[46]  T. Gruffydd-Jones,et al.  Determination of salivary and serum immunoglobulin concentrations in the cat. , 1998, Veterinary immunology and immunopathology.

[47]  H. Eun,et al.  Therapeutic effects of recombinant feline interferon-omega on feline leukemia virus (FeLV)-infected and FeLV/feline immunodeficiency virus (FIV)-coinfected symptomatic cats. , 2004, Journal of veterinary internal medicine.