HigB1 Toxin in Mycobacterium tuberculosis Is Upregulated During Stress and Required to Establish Infection in Guinea Pigs

The extraordinary expansion of Toxin Antitoxin (TA) modules in the genome of Mycobacterium tuberculosis has received significant attention over the last few decades. The cumulative evidence suggests that TA systems are activated in response to stress conditions and are essential for M. tuberculosis...

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Autores principales:	Arun Sharma, Kalpana Sagar, Neeraj Kumar Chauhan, Balaji Venkataraman, Nidhi Gupta, Tannu Priya Gosain, Nikhil Bhalla, Ramandeep Singh, Amita Gupta
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	Mycobacterium tuberculosis HigBA1 toxin antitoxin loci virulence stringent response Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/b61fa7e107e847b4af96e47ba13261e8
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spelling	oai:doaj.org-article:b61fa7e107e847b4af96e47ba13261e82021-12-01T15:37:15ZHigB1 Toxin in Mycobacterium tuberculosis Is Upregulated During Stress and Required to Establish Infection in Guinea Pigs1664-302X10.3389/fmicb.2021.748890https://doaj.org/article/b61fa7e107e847b4af96e47ba13261e82021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fmicb.2021.748890/fullhttps://doaj.org/toc/1664-302XThe extraordinary expansion of Toxin Antitoxin (TA) modules in the genome of Mycobacterium tuberculosis has received significant attention over the last few decades. The cumulative evidence suggests that TA systems are activated in response to stress conditions and are essential for M. tuberculosis pathogenesis. In M. tuberculosis, Rv1955-Rv1956-Rv1957 constitutes the only tripartite TAC (Toxin Antitoxin Chaperone) module. In this locus, Rv1955 (HigB1) encodes for the toxin and Rv1956 (HigA1) encodes for antitoxin. Rv1957 encodes for a SecB-like chaperone that regulates HigBA1 toxin antitoxin system by preventing HigA1 degradation. Here, we have investigated the physiological role of HigB1 toxin in stress adaptation and pathogenesis of Mycobacterium tuberculosis. qPCR studies revealed that higBA1 is upregulated in nutrient limiting conditions and upon exposure to levofloxacin. We also show that the promoter activity of higBA1 locus in M. tuberculosis is (p)ppGpp dependent. We observed that HigB1 locus is non-essential for M. tuberculosis growth under different stress conditions in vitro. However, guinea pigs infected with higB1 deletion strain exhibited significantly reduced bacterial loads and pathological damage in comparison to the animals infected with the parental strain. Transcriptome analysis suggested that deletion of higB1 reduced the expression of genes involved in virulence, detoxification and adaptation. The present study describes the role of higB1 toxin in M. tuberculosis physiology and highlights the importance of higBA1 locus during infection in host tissues.Arun SharmaKalpana SagarKalpana SagarNeeraj Kumar ChauhanBalaji VenkataramanNidhi GuptaTannu Priya GosainNikhil BhallaRamandeep SinghAmita GuptaAmita GuptaFrontiers Media S.A.articleMycobacterium tuberculosisHigBA1toxin antitoxin locivirulencestringent responseMicrobiologyQR1-502ENFrontiers in Microbiology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Mycobacterium tuberculosis HigBA1 toxin antitoxin loci virulence stringent response Microbiology QR1-502
spellingShingle	Mycobacterium tuberculosis HigBA1 toxin antitoxin loci virulence stringent response Microbiology QR1-502 Arun Sharma Kalpana Sagar Kalpana Sagar Neeraj Kumar Chauhan Balaji Venkataraman Nidhi Gupta Tannu Priya Gosain Nikhil Bhalla Ramandeep Singh Amita Gupta Amita Gupta HigB1 Toxin in Mycobacterium tuberculosis Is Upregulated During Stress and Required to Establish Infection in Guinea Pigs
description	The extraordinary expansion of Toxin Antitoxin (TA) modules in the genome of Mycobacterium tuberculosis has received significant attention over the last few decades. The cumulative evidence suggests that TA systems are activated in response to stress conditions and are essential for M. tuberculosis pathogenesis. In M. tuberculosis, Rv1955-Rv1956-Rv1957 constitutes the only tripartite TAC (Toxin Antitoxin Chaperone) module. In this locus, Rv1955 (HigB1) encodes for the toxin and Rv1956 (HigA1) encodes for antitoxin. Rv1957 encodes for a SecB-like chaperone that regulates HigBA1 toxin antitoxin system by preventing HigA1 degradation. Here, we have investigated the physiological role of HigB1 toxin in stress adaptation and pathogenesis of Mycobacterium tuberculosis. qPCR studies revealed that higBA1 is upregulated in nutrient limiting conditions and upon exposure to levofloxacin. We also show that the promoter activity of higBA1 locus in M. tuberculosis is (p)ppGpp dependent. We observed that HigB1 locus is non-essential for M. tuberculosis growth under different stress conditions in vitro. However, guinea pigs infected with higB1 deletion strain exhibited significantly reduced bacterial loads and pathological damage in comparison to the animals infected with the parental strain. Transcriptome analysis suggested that deletion of higB1 reduced the expression of genes involved in virulence, detoxification and adaptation. The present study describes the role of higB1 toxin in M. tuberculosis physiology and highlights the importance of higBA1 locus during infection in host tissues.
format	article
author	Arun Sharma Kalpana Sagar Kalpana Sagar Neeraj Kumar Chauhan Balaji Venkataraman Nidhi Gupta Tannu Priya Gosain Nikhil Bhalla Ramandeep Singh Amita Gupta Amita Gupta
author_facet	Arun Sharma Kalpana Sagar Kalpana Sagar Neeraj Kumar Chauhan Balaji Venkataraman Nidhi Gupta Tannu Priya Gosain Nikhil Bhalla Ramandeep Singh Amita Gupta Amita Gupta
author_sort	Arun Sharma
title	HigB1 Toxin in Mycobacterium tuberculosis Is Upregulated During Stress and Required to Establish Infection in Guinea Pigs
title_short	HigB1 Toxin in Mycobacterium tuberculosis Is Upregulated During Stress and Required to Establish Infection in Guinea Pigs
title_full	HigB1 Toxin in Mycobacterium tuberculosis Is Upregulated During Stress and Required to Establish Infection in Guinea Pigs
title_fullStr	HigB1 Toxin in Mycobacterium tuberculosis Is Upregulated During Stress and Required to Establish Infection in Guinea Pigs
title_full_unstemmed	HigB1 Toxin in Mycobacterium tuberculosis Is Upregulated During Stress and Required to Establish Infection in Guinea Pigs
title_sort	higb1 toxin in mycobacterium tuberculosis is upregulated during stress and required to establish infection in guinea pigs
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/b61fa7e107e847b4af96e47ba13261e8
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HigB1 Toxin in Mycobacterium tuberculosis Is Upregulated During Stress and Required to Establish Infection in Guinea Pigs

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