MicroRNAs Regulated by the LPS/TLR2 Immune Axis as Bona Fide Biomarkers for Diagnosis of Acute Leptospirosis

ABSTRACT Leptospirosis remains a significant human health issue due to its systemic complications. Therefore, biomarkers that are more effective are urgently needed for the early diagnosis of leptospirosis. MicroRNAs (miRNAs) are evolutionarily conserved regulatory RNAs that have shown the potential...

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Autores principales:	Charles Solomon Akino Mercy, Natarajaseenivasan Suriya Muthukumaran, Prema Velusamy, Palanisamy Bothammal, Krishnamoorthi Sumaiya, Perumal Saranya, Dianne Langford, Santhanam Shanmughapriya, Kalimuthusamy Natarajaseenivasan
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	leptospirosis LPS microRNA TLR2 biomarkers PPI network Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/479cf5288b1f4020945f528c506fcfe7
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spelling	oai:doaj.org-article:479cf5288b1f4020945f528c506fcfe72021-11-15T15:30:51ZMicroRNAs Regulated by the LPS/TLR2 Immune Axis as Bona Fide Biomarkers for Diagnosis of Acute Leptospirosis10.1128/mSphere.00409-202379-5042https://doaj.org/article/479cf5288b1f4020945f528c506fcfe72020-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00409-20https://doaj.org/toc/2379-5042ABSTRACT Leptospirosis remains a significant human health issue due to its systemic complications. Therefore, biomarkers that are more effective are urgently needed for the early diagnosis of leptospirosis. MicroRNAs (miRNAs) are evolutionarily conserved regulatory RNAs that have shown the potential to be used as biomarkers for diagnosis, prognosis, and therapy of infectious diseases. In this study, we performed an unbiased screen using the miRNome miRNA array to identify circulating miRNAs with the potential to serve as authentic biomarkers for early diagnosis of leptospirosis. Because leptospiral lipopolysaccharide (LPS) is the predominant leptospiral antigen and plays a vital role in immunological and biological activities, we used LPS treated and untreated in vitro (THP1 cells) and in vivo (BALB/c mice) surrogate models to identify the LPS-specific miRNAs. Differential expression analysis revealed 18 miRNAs to be associated strongly with LPS stimulation in THP1 cells. Of these, three (miR-let-7b-5p, miR-144-3p, and miR-21-5p) were observed to be present at increased levels in vivo. The identified miRNAs were validated for their biomarker potential using serum samples from leptospirosis-negative patients and patients with confirmed cases of leptospirosis. Identified miRNAs were able to discriminate the acute leptospiral infection from other febrile diseases with a test sensitivity and specificity of 93.2% and 88.19%, respectively. Gene functional enrichment and protein-protein interaction (PPI) network analysis revealed that the identified miRNAs play important roles in disease signal transduction, signaling by interleukins, the stress-activated protein kinase signaling cascade, the mitogen-activated protein kinase (MAPK) signaling pathway, and the cellular response to a transforming growth factor β (TGF-β) stimulus with a notable interconnection between these biological processes. IMPORTANCE Here, we used miRNAs that are differentially regulated by the LPS/TLR2 immune axis to devise a miRNA-based diagnosis for leptospirosis. The study established the role of the circulating stable miRNAs (miR-21-5p, miR-144-3p, and miR-let-7b-5p) as an early diagnostic marker for leptospirosis. These miRNAs can be used to diagnose acute leptospirosis and also to differentiate leptospiral infection from other bacterial and spirochetal infections, as proved by the use of human clinical samples. Thus, our findings indicate that miRNAs can play a crucial role in the diagnosis of infectious diseases, like leptospirosis, that are generally misdiagnosed.Charles Solomon Akino MercyNatarajaseenivasan Suriya MuthukumaranPrema VelusamyPalanisamy BothammalKrishnamoorthi SumaiyaPerumal SaranyaDianne LangfordSanthanam ShanmughapriyaKalimuthusamy NatarajaseenivasanAmerican Society for MicrobiologyarticleleptospirosisLPSmicroRNATLR2biomarkersPPI networkMicrobiologyQR1-502ENmSphere, Vol 5, Iss 4 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	leptospirosis LPS microRNA TLR2 biomarkers PPI network Microbiology QR1-502
spellingShingle	leptospirosis LPS microRNA TLR2 biomarkers PPI network Microbiology QR1-502 Charles Solomon Akino Mercy Natarajaseenivasan Suriya Muthukumaran Prema Velusamy Palanisamy Bothammal Krishnamoorthi Sumaiya Perumal Saranya Dianne Langford Santhanam Shanmughapriya Kalimuthusamy Natarajaseenivasan MicroRNAs Regulated by the LPS/TLR2 Immune Axis as Bona Fide Biomarkers for Diagnosis of Acute Leptospirosis
description	ABSTRACT Leptospirosis remains a significant human health issue due to its systemic complications. Therefore, biomarkers that are more effective are urgently needed for the early diagnosis of leptospirosis. MicroRNAs (miRNAs) are evolutionarily conserved regulatory RNAs that have shown the potential to be used as biomarkers for diagnosis, prognosis, and therapy of infectious diseases. In this study, we performed an unbiased screen using the miRNome miRNA array to identify circulating miRNAs with the potential to serve as authentic biomarkers for early diagnosis of leptospirosis. Because leptospiral lipopolysaccharide (LPS) is the predominant leptospiral antigen and plays a vital role in immunological and biological activities, we used LPS treated and untreated in vitro (THP1 cells) and in vivo (BALB/c mice) surrogate models to identify the LPS-specific miRNAs. Differential expression analysis revealed 18 miRNAs to be associated strongly with LPS stimulation in THP1 cells. Of these, three (miR-let-7b-5p, miR-144-3p, and miR-21-5p) were observed to be present at increased levels in vivo. The identified miRNAs were validated for their biomarker potential using serum samples from leptospirosis-negative patients and patients with confirmed cases of leptospirosis. Identified miRNAs were able to discriminate the acute leptospiral infection from other febrile diseases with a test sensitivity and specificity of 93.2% and 88.19%, respectively. Gene functional enrichment and protein-protein interaction (PPI) network analysis revealed that the identified miRNAs play important roles in disease signal transduction, signaling by interleukins, the stress-activated protein kinase signaling cascade, the mitogen-activated protein kinase (MAPK) signaling pathway, and the cellular response to a transforming growth factor β (TGF-β) stimulus with a notable interconnection between these biological processes. IMPORTANCE Here, we used miRNAs that are differentially regulated by the LPS/TLR2 immune axis to devise a miRNA-based diagnosis for leptospirosis. The study established the role of the circulating stable miRNAs (miR-21-5p, miR-144-3p, and miR-let-7b-5p) as an early diagnostic marker for leptospirosis. These miRNAs can be used to diagnose acute leptospirosis and also to differentiate leptospiral infection from other bacterial and spirochetal infections, as proved by the use of human clinical samples. Thus, our findings indicate that miRNAs can play a crucial role in the diagnosis of infectious diseases, like leptospirosis, that are generally misdiagnosed.
format	article
author	Charles Solomon Akino Mercy Natarajaseenivasan Suriya Muthukumaran Prema Velusamy Palanisamy Bothammal Krishnamoorthi Sumaiya Perumal Saranya Dianne Langford Santhanam Shanmughapriya Kalimuthusamy Natarajaseenivasan
author_facet	Charles Solomon Akino Mercy Natarajaseenivasan Suriya Muthukumaran Prema Velusamy Palanisamy Bothammal Krishnamoorthi Sumaiya Perumal Saranya Dianne Langford Santhanam Shanmughapriya Kalimuthusamy Natarajaseenivasan
author_sort	Charles Solomon Akino Mercy
title	MicroRNAs Regulated by the LPS/TLR2 Immune Axis as Bona Fide Biomarkers for Diagnosis of Acute Leptospirosis
title_short	MicroRNAs Regulated by the LPS/TLR2 Immune Axis as Bona Fide Biomarkers for Diagnosis of Acute Leptospirosis
title_full	MicroRNAs Regulated by the LPS/TLR2 Immune Axis as Bona Fide Biomarkers for Diagnosis of Acute Leptospirosis
title_fullStr	MicroRNAs Regulated by the LPS/TLR2 Immune Axis as Bona Fide Biomarkers for Diagnosis of Acute Leptospirosis
title_full_unstemmed	MicroRNAs Regulated by the LPS/TLR2 Immune Axis as Bona Fide Biomarkers for Diagnosis of Acute Leptospirosis
title_sort	micrornas regulated by the lps/tlr2 immune axis as bona fide biomarkers for diagnosis of acute leptospirosis
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/479cf5288b1f4020945f528c506fcfe7
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MicroRNAs Regulated by the LPS/TLR2 Immune Axis as Bona Fide Biomarkers for Diagnosis of Acute Leptospirosis

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