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 Table of Contents  
Year : 2013  |  Volume : 2  |  Issue : 4  |  Page : 220-226

Comparative proteomic analysis of Mycobacterium tuberculosis strain H37Rv versus H37Ra

1 Bioinformatics Centre, Biochemistry & JBTDRC, MGIMS, Sevagram, Maharashtra, India
2 GeNext Genomics Pvt. Ltd., Nagpur, Maharashtra, India

Date of Web Publication28-Feb-2017

Correspondence Address:
Bhaskar C Harinath
JB Tropical Disease Research Centre, Mahatma Gandhi Institute of Medical Sciences, Sevagram 442 102, Wardha, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.1016/j.ijmyco.2013.10.004

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Background: Mycobacterium tuberculosis (MTB) H37Ra is an attenuated tubercle bacillus closely related to the virulent type strain MTB H37Rv. In spite of extensive study, variation in virulence between the MTB H37Rv and MTB H37Ra strains is still to be understood. The difference in protein expression or structure due to mutation may probably be an important factor for the virulence property of MTB H37Rv strain.
Methods: In this study, a whole proteome comparison between these two strains was carried out using bioinformatics approaches to elucidate differences in their protein sequences.
Results: On comparison of whole proteome using NCBI standalone BLAST program between these two strains, 3759 identical proteins in both the strains out of 4003 proteins were revealed in MTB H37Rv and 4034 proteins were revealed in MTB H37Ra; 244 proteins of MTB H37Rv and 260 proteins of MTB H37Ra were found to be non-identical. A total of 172 proteins were identified with mutations (Insertions/deletions/substitutions) in MTB H37Ra while 53 proteins of MTB H37Rv and 85 proteins of MTB H37Ra were found to be distinct. Among 244 non-identical proteins, 19 proteins were reported to have an important biological function; In this study, mutation was shown in these proteins of MTB H37Ra.
Conclusion: This study reports the protein differences with mutations between MTB H37Rv and H37Ra, which may help in better understanding the pathogenesis and virulence properties of MTB H37Rv.

Keywords: MTB, Proteome, Virulence, Comparative proteomics, Bioinformatics

How to cite this article:
Jena L, Kashikar S, Kumar S, Harinath BC. Comparative proteomic analysis of Mycobacterium tuberculosis strain H37Rv versus H37Ra. Int J Mycobacteriol 2013;2:220-6

How to cite this URL:
Jena L, Kashikar S, Kumar S, Harinath BC. Comparative proteomic analysis of Mycobacterium tuberculosis strain H37Rv versus H37Ra. Int J Mycobacteriol [serial online] 2013 [cited 2021 Oct 25];2:220-6. Available from: https://www.ijmyco.org/text.asp?2013/2/4/220/201121

  Introduction Top

Tuberculosis (TB) is a complex disease caused by Mycobacterium tuberculosis (MTB), which has evolved with highly successful mechanisms to equivocate host defenses and existing classes of antibiotics. Decades after the discovery of MTB, TB remains a major cause of morbidity and mortality in many developing countries. One third of the World's population is considered to be infected with MTB, with 8.7 million new patients and 1.4 million deaths in the year 2011, including 1 million deaths among HIV-negative and 430,000 HIV-positive individuals [1]. Multi-drug-resistant strains of this pathogen, emerging in association with HIV, have added a frightening dimension to the problem [2]. Outbreaks of extensively drug-resistant (XDR) TB have also been an increasing threat in certain regions around the world [3]. Despite abundant research on MTB diagnostics, vaccinations and treatments, this disease poses a considerable risk in many developed countries. MTB is very virulent, but there has been no simple answer found yet for what makes MTB so virulent. Historically, MTB H37Ra is the avirulent counterpart of the virulent strain MTB H37Rv, and both strains were derived from their virulent parent strain H37 discovered in 1935 by William Steenken through a process of aging and dissociation from in vitro culture [4]. These strains are phenotypically and genotypically different from each other, but the virulence power is different among these strains, which could probably be owing to a difference in protein expression. Owing to the advancement of Bioinformatics and the genome sequencing project, whole genome and proteome sequences of both the strains are available in the public domain. Current evidence suggests that as a species, MTB exhibits very little genomic sequence diversity [5],[6]. MTB H37Rv is virulent and susceptible to most of the anti-tuberculous drugs, while MTB H37Ra is an avirulent strain and the MTB KZN (KwaZulu-Natal, South Africa) strain is resistant to different drugs like isoniazid, rifampicin, kanamycin, ofloxacin, ethambutol, pyrazinamide, etc. [7]. This may be due to a genetic mutation resulting in the generation of mutated proteins. Therefore, there is a need for genomic as well as proteomic analysis among different strains of MTB to understand the variation among them.

Many tools have also been developed for the complete determination of the genome sequence of a huge number of bacteria, but still, their proteomes remain relatively poorly defined. In the post-genomic era, proteomics is a rapidly growing field of research that is becoming increasingly important, because it deals with the study of proteins involved in carcinogenesis as well as a novel biomarker discovery for clinical use, such as screening, diagnosis, prognosis, detection of recurrent disease, etc. [8]. While a genome remains unchanged to a larger extent, the proteins in any particular cell change dramatically as genes are turned on or off in response to the environment.

Comparative genomic analysis of MTB H37Ra versus H37Rv by Zheng et al. revealed the genetic basis of virulence among these two strains [9]. However, proteomics is still nascent and requires extensive study. Since it is proteins that are directly involved in both normal and disease-related biochemical processes, a more comprehensive understanding of disease may be achieved by looking directly into the proteins within a disease cell or tissue [10]. Proteomics has much promise in novel drug discovery by targeting proteins of pathogenic organisms causing different diseases in the host, whereas comparative proteomics is very significant in studying the proteomic variations among different pathogens.

Identification of the virulence factors of MTB is a fundamental goal if new vaccines and anti-mycobacterial drugs against this pathogen are to be developed. A single amino acid mutation in protein sequence may cause alteration in the protein structure and function that may account for virulence and drug resistance properties of pathogenic organisms. Therefore, the development of an in silico technology to study the proteomic variations of different strains of genetically intractable pathogens such as MTB will enhance the analysis of virulence and drug resistance properties and significantly advance the understanding of the mechanisms of disease. In this study, the proteomic variations in these two strains (MTB H37Rv and H37Ra) were determined, and the proteins that had undergone mutations (insertions/deletions/substitutions) were identified in the same variations. The findings of the present study provide a unique platform for the discovery of proteomic variation in other strains/species of Mycobacterium as well as the discovery and development of TB drugs, vaccines, biomarkers, etc.

  Materials and methods Top

Dataset preparation

The dataset was prepared by retrieving the whole proteome of MTB H37Rv (NCBI RefSeq: NC_000962.2) and H37Ra (NCBI RefSeq: NC_009525.1) from the NCBI FTP site (ftp://ftp.ncbi.nih.gov/genomes/). The protein sequence data (H37Rv and H37Ra proteome) were formatted using in-house developed PERL Script for quick analysis. NCBI Standalone BLAST-2.2.26 (ftp://ftp.ncbi.nlm.nih.gov/blast/executables/release/LATEST/) was used to perform protein BLAST [11] between the proteome of MTB H37Rv against MTB H37Ra and vice versa to discover protein variation and duplication.

Proteome comparison and database designing

Whole proteome comparison of these two organisms was done using PERL script and standalone BLAST. The output of the BLAST result was parsed and stored in MS SQL relational database tables using in-house developed PERL script. While parsing BLAST output results, percentage identities, positivities, number of gaps, identical residues, bits, bits score, e-value, query length, subject length, query sequence, subject sequence, consensus sequence, etc., of the first hit obtained were taken into consideration for each protein comparison.

Data retrieval and analysis

Different SQL queries were written to retrieve comparison data from MS SQL database tables. Sub-cellular localization (integral membrane, cytoplasmic, secretory and membrane attached by lipid anchor) of the selected MTB protein with variations were predicted by TBpred Prediction server [12].

  Results Top

Genomic features and proteomic comparison of MTB H37Rv and its avirulent counterpart H37Ra

MTB H37Rv contains a single circular chromosome of 4,411,532bp with an average G+C content of 65.6% (NCBI RefSeq: NC_000962.2), which is 8445bp smaller than the MTB H37Ra genome (NCBI RefSeq: NC_009525.1 and 4,419,977bp length). A total of 4003 protein-coding sequences (CDS) are identified amongst 4062 genes in the H37Rv genome, while there are 4084 genes with 4034 protein-coding sequences in the genome of MTB H37Ra ([Table 1]). The proteomic comparison of MTB H37Rv and MTB H37Ra in this study revealed 3759 identical proteins between these two strains, while a reverse comparison, i.e., the proteome of MTB H37Ra against MTB H37Rv, revealed 3774 identical proteins. Upon further analysis of this difference in number, it was found that there were 16 multiple copies of one protein, i.e., IS6110 transposase in MTB H37Ra while there were only four in MTB H37Rv of the same protein, and a mutation was observed in the form of an amino acid deletion in the remaining 12 copies of IS6110 transposase.
Table 1: Genomic comparison between MTB H37Rv and MTB H37Ra.

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There were also three extra proteins found to be duplicate in number in MTB H37Ra (MRA_1050˜MRA_1160, MRA_3421˜MRA_3514, MRA_2373˜MRA_2376), which were found as a single copy in MTB H37Rv (Rv1041c, Rv3474, Rv2352c). There were 244 proteins of MTB H37Rv found to be non-identical relative to MTB H37Ra, and 260 proteins of MTB H37Ra were non-identical relative to MTB H37Rv ([Table 2]). Similar proteins with mutations (amino acid variations/substitutions, insertions and deletions of any size) and proteins without any significant similarity in their amino acid sequences among these two strains of MTB were considered non-identical proteins. Amongst 244 and 260 non-identical proteins, a total of 172 proteins were identified with mutations in MTB H37Ra when compared with MTB H37Rv; 19 proteins with variations out of 244 in MTB H37Rv and three proteins out of 260 in MTB H37Ra may have no significant effect on the variation in the properties of these two strains as those proteins have extra copies in the respective strains. The rest of the proteins with respect to each strain were extensively varying in identities and query coverage. A few of them were unique to particular strains as they have no significant similarity against proteins of other strains like one hypothetical protein in MTB H37Ra (MRA_2157) and three hypothetical proteins (Rv0500B, Rv4012, Rv3599c) and two PE-PGRS family proteins (Rv3344c, Rv3512) in MTB H37Rv .
Table 2: Comparison of proteomic variations between MTB H37Rv and MTB H37Ra.

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Among those 172 mutated proteins, 46 were identified with amino acid substitutions, while 47 insertions, 64 deletions, one with insertion and deletion, four with insertions and substitutions, nine with deletions and substitutions and one with insertion, deletion and substitution in MTB H37Ra relative to MTB H37Rv ([Table 2]). Among the 46 proteins with amino acid variations, 40 have single amino acid mutations, while three with variations of two, two with four, and one with 12 amino acid substitutions were identified. There were 12 proteins of MTB H37Rv and 13 proteins of MTB H37Ra were found to have multiple copies.

Sub-cellular distribution of non-identical proteins with amino acid variation in MTB H37Ra

A total of 172 proteins identified with variations in MTB H37Ra relative to MTB H37Rv were subjected to TBpred Prediction server [12] to discover their sub-cellular localization. It was found that most of the mutated proteins were either integral membrane proteins or cytoplasmic proteins. Out of the 172 proteins in MTB H37Rv 89 integral membrane proteins, 74 were cytoplasmic, six were secreted and three were attached to a membrane by a lipid anchor ([Table 3]).
Table 3: Sub-cellular distribution of non-identical proteins with amino acid variations.

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  Discussion Top

In spite of several studies in the past, the potential causes for variations in virulence between MTB H37Rv and MTB H37Ra have remained unclear. In this study, a comparative proteomic analysis was performed on two widely used MTB strains: H37Rv (virulent) and its avirulent counterpart H37Ra, and their proteomic variations were studied through the Bioinformatics approach. As genome and proteome sequences of these two strains are available in the public domain, there is recently immense interest in analyzing the differences between the two strains in more detail.

Comparative genomic analysis of MTB H37Ra versus MTB H37Rv by Zheng et al. revealed 53 insertions and 21 deletions in MTB H37Ra relative to MTB H37Rv along with 198 single nucleotide variations (SNVs), 102 transitions, and 96 transversions in these two strains [9]. Malen et al. (2011) used label-free quantitative proteomic approach and estimated differences in protein abundance between these two strains [13]. They identified more than 1700 proteins from both strains, out of which 29 membrane-associated proteins were reported with five- or more-fold difference in their relative abundance in one strain compared with the other [13]. In a previous study, an MTB proteome comparison database (MTB-PCDB) was developed, which provides integrated access to protein sequence comparison with identical and non-identical protein data for five strains of MTB (H37Rv, H37Ra, CDC 1551, F11 and KZN 1435) [14]. The present study reports protein comparison of MTB H37Rv versus MTB H37Ra with respect to a detailed analysis of variation in different classes of proteins (secretory proteins, etc.) with mutation. This analysis identified 3759 identical proteins between these two strains, whereas 244 proteins of MTB H37Rv were found to be non-identical relative to MTB H37Ra along with some proteins with multiple copies in both the strains. Proteomic comparison information obtained from this study would be useful for a better understanding of the pathogenesis of MTB.

MTB comprises 11 serine/threonine protein kinases (STPKs) [15] which probably function in signal transduction pathways and may direct important cellular decisions such as dormancy and cell division [16],[17]. Out of the 11 proteins, 10 proteins (Rv0014c, Rv0015c, Rv0410c, Rv0931c, Rv1743, Rv1746, Rv2088, Rv2176, Rv2914c and Rv3080c) were found to be identical in both the strains in this study, while a single amino acid substitution (R607Q) was identified in one of the proteins of MTB H37Rv (Rv1266c) compared with H37Ra (MRA_1274). Out of 19 proteins of MTB H37Rv reported as responsible proteins for cell division [16], only two, i.e., Rv0012 (probable conserved membrane protein) and Rv3919c (glucose inhibited division protein B), were found to have single amino acid substitutions, i.e., C233R and S100F, when compared with the proteins of MTB H37Ra, i.e., MRA_0014 and MRA_3958, respectively, in this study.

Intensive research effort has shown that many proteins are associated with virulence factors of MTB [16], such as catalase-peroxidase [18], Mammalian cell entry (mce) operon [19], sigma factor gene (sigA) [20], Virulence Regulator EspR [21], Rv0485 regulon [22], Virulence Associated Protein (VapC) [23], PhoP regulon [24], etc. In this study, mutations in some of the virulent associated proteins were identified. Out of 33 mce family proteins of MTB H37Rv, two proteins–Rv0175 and Rv0176–were found to have deletions in their amino acid sequences when compared with corresponding proteins of MTB H37Ra, i.e., MRA_0183 and MRA_0184, respectively. Also, two proteins associated with virulence regulator EspR were identified with mutations, i.e., single amino acid substitution (G237V) in MRA_1078 related to Rv1068c (PE-PGRS family protein) and deletion of 57 amino acids in MRA_3527 related to Rv3487c (esterase). Besides, mutations were also observed in PhoP regulon and proteins associated with Rv0485 regulon ([Table 4]). Previous studies on non-identical proteins of MTB H37Rv by other researchers revealed the importance of those proteins ([Table 4]). This might account for the difference in the virulence and pathogenic properties among these two strains.
Table 4: Mutation study of important functional proteins in MTB H37Ra.

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Mutations affecting integral membrane proteins

Most of the protein mutations were found in this category. A total of 89 proteins of MTB H37Ra identified with mutations relative to MTB H37Rv were predicted as integral membrane proteins. A deletion of 12 amino acids at N-terminal region was identified in the protein encoded by MRA_3163 in MTB H37Ra when compared with Rv3131 of MTB H37Rv. This protein codes for a putative classical nitroreductase, which may be involved in detoxification of nitrogen-containing by-products in the host as reported by Purkayastha, et al. (2002) [25].

Rv3347c (PPE55) is reported to be recognized by antibodies elicited during subclinical TB infection of guinea pigs [26]. This protein when compared with proteins of H37Ra (MRA_3387) deletion of 12N-terminal amino acids was revealed.

Deletion of 3N-terminal amino acids in MRA_0763 with respect to Rv0754 was identified in the study. PE_PGRS11 protein encoded by Rv0754 recognizes TLR2 (toll-like receptor 2) and induces maturation and activation of Human Dendrite Cells [27]. Another PE-PGRS (Rv3367) protein has undergone mutation (insertion of three amino acids) in MRA_3407. This protein belongs to the PE protein family and has multiple tandem repeats of unique amino acid sequences and has characteristics of surface or secreted proteins like the other two proteins–PirG (Rv3810) and proline-threonine repetitive protein (PTRP) (Rv0538) [28].

It has been reported that Rv3654c and Rv3655c putative secreted proteins suppress apoptosis by blocking the extrinsic pathway [29]. These two proteins when compared with proteins of MTB H37Ra in this study also identified mutations (i.e., insertions in case of MRA_3689 and both insertion and deletion in case of MRA_3690).

Insertions of 80 amino acids in the C-terminal region of the nutrient stress–induced antigen Rv2660c (expressed during infection) [30] is identified when compared with MRA_2690 (hypothetical protein).

According to Goldstone et al., the pe13 (Rv1195) and ppe18 (Rv1196) gene pair is part of the Rv0485 regulon that is required for virulence of the pathogen during in vivo growth in mice [22]. In this study, it was also found that there were mutations (Insertions / Deletions / Substitutions) in the proteins of MTB H37Ra, i.e., MRA_1370 and MRA_1205, when compared with the protein encoded by Rv1196 and Rv1195, respectively. Rv2829c is a hypothetical protein found to be unique in MTB H37Rv in the present study (as there is no significant similar protein in MTB H37Ra). This protein was explored by Ahidjo et al. (2011) as a Virulence Associated Protein C (vapC) which belongs to the VapBC family that potentially provides an abundant source of RNase activity in MTB, which might profoundly impact the physiology of the organism [23].

Mutations affecting cytoplasmic proteins

A total of 74 proteins of MTB H37Ra identified with mutations were predicted as cytoplasmic proteins. Therefore, cytoplasmic proteins were found to be more prone to mutation, next to integral membrane proteins. Some of these proteins were found to be involved in important pathways of MTB.

It has been reported that the dihydroxy-acid dehydratase (DHAD) encoded by Rv0189c is essential for the survival of MTB and as it is absent in mammals, it could be a potential drug/vaccine target [31]. This protein is also known to be involved in five important pathways of MTB (Valine, leucine and isoleucine biosynthesis; Pantothenate and CoA biosynthesis; Biosynthesis of secondary metabolites; 2-Oxocarboxylic acid metabolism; Biosynthesis of amino acids) (http://www.genome.jp/dbget-bin/www_bget?mtu:Rv0189c). During this analysis, it was also found that this protein (Rv0189c) has undergone mutations of a single amino acid, i.e., Valine to Glycine at 284 position (V284G) in the corresponding protein of MTB H37Ra (MRA_0197).

Nucleoside triphosphate pyrophosphohydrolase enzyme encoded by Rv1021 is required to maintain the full capacity of the mycobacterium to respond to oxidative stress via the degradation of oxidation-induced damaged nucleotides [32]. It is known to be involved in two important pathways of MTB, i.e., Purine metabolism and Pyrimidine metabolism (http://www.genome.jp/dbget-bin/www_bget?mtu:Rv1021). The present analysis identified that a point mutation occurs at 219 position of the amino acid sequence of the corresponding protein of MTB H37Ra (MRA_1029), i.e., A219E, which is known to be important for catalytic activity. A mutation at this point reduced the activity of Pyrophosphohydrolase by 20-fold, which affects the magnesium binding and the protein structure [32].

The phoP encoded by Rv0757 is an essential protein with two-component response regulator activity. This analysis identified a point mutation S219L in the corresponding protein of MTB H37Ra (MRA_0767). Lee et al. (2008) also demonstrated that a mutation in the phoP of H37Ra results in an amino acid change from serine to leucine and is partially responsible for the decreased virulence of H37Ra [24].

Deletion of 22N-terminal amino acids was identified in the protein encoded MRA_1110 when compared with Rv1099c, which was reported to be expressed at significant levels in MTB, and encodes the major fructose-1,6-bisphosphatase II (FBPase) of this pathogen [33]. This protein also found to be involved in six important pathways of MTB (http://www.genome.jp/dbget-bin/www_bget?mtu:Rv1099c).

Rv1248c is reported to be conserved in mycobacteria and other actinomycetes and predicted to be essential for growth of MTB [34]. It encodes multifunctional alpha-ketoglutarate metabolic enzymes and N-terminal deletion of 17 amino acids and is also identified in the corresponding protein (MRA_1256) of H37Ra.

Rv0496 (MTB-PPX1) is reported as a T-cell antigen with potential for vaccine development [35]. This protein is known to be involved in purine metabolism pathways and has undergone N-terminal deletion of 16 amino acids along with amino acids variation in the avirulent counterpart H37Ra (MRA_0503). Rv1738 encodes a conserved hypothetical protein of unknown but essential function [34]. Insertion of 16 amino acids at the N-terminal end was identified in the corresponding proteins of H37Ra (MRA_1749).

There is a hypothetical protein (Rv2466c) found to be unique in MTB H37Rv in this study (as there is no significant similar protein in MTB H37Ra). Raman et al. (2001) revealed the presence of glutaredoxin motif in Rv2466c and might play an important role in the SigH-regulated response to oxidative stress in MTB [36].

Mutations affecting secreted proteins and proteins attached to a membrane by lipid anchor

A total of 6 proteins of MTB H37Ra identified with mutations were predicted as secreted protein, while only three were predicted as proteins attached to a membrane by lipid anchor. The Rv0050 locus encodes the bi-functional penicillin-binding protein ponA1 and is essential to mycobacterial survival [37]. This analysis on this protein revealed a single amino acid mutation, i.e., Proline to Serine at 631 position (P631S) in the corresponding protein of MTB H37Ra (MRA_0197).

  Conclusion Top

MTB H37Rv is virulent and susceptible to most of the anti-tuberculous drugs, while MTB H37Ra is an avirulent strain. In spite of several studies in the past, the potential causes for variation in virulence between MTB H37Rv and MTB H37Ra have remained unclear. In this study, a comparative proteomic analysis of H37Ra against its virulent counterpart H37Rv was performed. These analyses provide proteomic differences between H37Rv and H37Ra, which may useful for better understanding the basis of pathogenesis of MTB and virulence attenuation in MTB H37Ra. Non-identical proteins identified in MTB H37Ra and MTB H37Rv must have some important role in the variation among these two strains directly or indirectly. 172 proteins were identified with mutations (Insertions/Deletions/Substitutions) and unique proteins identified in particular strains may be responsible for the variation. These proteins may be potential targets for the development of effective anti-mycobacterial strategy against this notorious pathogen and thus may be subject for further study, intending to carry out virulence determinants among the virulent and avirulent strains of MTB.

  Acknowledgements Top

The authors thank the Department of Biotechnology, Ministry of Science & Technology, Government of India, for financial support to Bioinformatics Centre wherein this study has been carried out. The authors convey thanks to Shri Dhiru S Mehta, President, KHS, for his keen interest and encouragement.

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  [Table 1], [Table 2], [Table 3], [Table 4]

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