|Year : 2017 | Volume
| Issue : 1 | Page : 27-32
Spoligotype defined lineages of Mycobacterium tuberculosis and drug resistance: Merely a casual correlation?
Nikita Panwalkar1, Devendra S Chauhan2, Prabha Desikan1
1 Department of Microbiology and NRL, Bhopal Memorial Hospital and Research Centre, Bhopal, Madhya Pradesh, India
2 National JALMA Institute for Leprosy and Other Mycobacterial Diseases, Indian Council of Medical Research, Agra, Uttar Pradesh, India
|Date of Web Publication||16-Mar-2017|
Department of Microbiology & NRL, Bhopal Memorial Hospital & Research Centre, Raisen Bypass Road, Karond, Bhopal, Madhya Pradesh
Source of Support: None, Conflict of Interest: None
Drug-resistant tuberculosis (TB) is a major challenge to TB control strategy worldwide. Analysis of genetic polymorphism among drug resistant Mycobacterium tuberculosis (MTB) strains may help provide some insight into the transmission dynamics of these strains. Spoligotyping is a widely used technique to identify genetic polymorphism, based on 43 known spacers interspersed between direct repeat regions. Considerable work has been done in various parts of the world using this technique to identify and analyse the polymorphic nature of MTB. Many studies have been carried out to determine the association of drug resistance with spoligotype defined lineages, and much data has been produced over the years. New information continues to be generated. This review aims to put together the findings of relevant studies in an attempt to understand the correlation of drug resistance with spoligotype defined lineages of MTB. This would help provide a perspective of the available data that can be used as a starting point to understand the molecular epidemiology of drug resistant TB.
Keywords: Correlation, drug resistance, Mycobacterium tuberculosis, spoligotype
|How to cite this article:|
Panwalkar N, Chauhan DS, Desikan P. Spoligotype defined lineages of Mycobacterium tuberculosis and drug resistance: Merely a casual correlation?. Indian J Med Microbiol 2017;35:27-32
|How to cite this URL:|
Panwalkar N, Chauhan DS, Desikan P. Spoligotype defined lineages of Mycobacterium tuberculosis and drug resistance: Merely a casual correlation?. Indian J Med Microbiol [serial online] 2017 [cited 2018 Jan 21];35:27-32. Available from: http://www.ijmm.org/text.asp?2017/35/1/27/202327
| ~ Introduction|| |
Drug-resistant tuberculosis (TB) presents a major challenge to TB control globally. An insight into the transmission dynamics of drug-resistant strains of TB would go a long way towards planning interventions for control of drug resistant TB. This has underlined the need to understand the correlation of drug resistance with genetic polymorphism among strains of Mycobacterium tuberculosis (MTB).
Considerable work has been done in various parts of the world towards describing the polymorphic nature of MTB.,, Several molecular techniques have been used in combination, or independently, in order to differentiate between the strains of MTB. Among these, a widely used technique is spoligotyping., It is used due to its robustness, reproducibility and ability to simultaneously detect and differentiate strains of MTB. Many studies have been carried out to determine the association of drug resistance with spoligotype defined lineages, and much data has been produced over the years. New information continues to be generated. This review aims to put together the findings of relevant studies in an attempt to understand the correlation of drug resistance with spoligotype defined lineages of MTB. This would help provide a perspective of the available data that can be used as a starting point to understand the molecular epidemiology of drug-resistant TB.
| ~ Spoligotype Defined Lineages and Drug Resistance|| |
The data generated by spoligotyping is based on the presence or absence of 43 known spacers, which is reduced to an octal code to compare with an international database called SITVITWEB which is an updated version of the SpolDB4 database. The SITVIT database incorporates a total of 7104 spoligotype patterns on 58,187 clinical isolates that are grouped into 2747 spoligotype international types (SITs) and 4357 orphan patterns. The term 'lineage' refers to a group of related genotypes that are defined by their spoligotype pattern.
Different lineages are represented differently in different geographic regions. This review discusses these lineages under the heads 'Beijing lineage' and 'non-Beijing lineages'. The Beijing lineage is prevalent in the East Asian and East European countries, but its global presence is noteworthy, particularly in the low incidence areas of the world indicating that human migration resulted in active cross-border dissemination of drug-resistant TB. A significant difference in the magnitude of drug resistance from different geographical regions has been documented.
The Beijing lineage is typically characterised by the absence of initial 34 spacer oligonucleotides and presence of spacers 35–43. This lineage was first identified in 1995 by Soolingen from the People's Republic of China. Since then, its ubiquitous presence has been reported from various parts of the world and studied extensively. However, there is a poor representation of Beijing strains in some parts of Latin America, South America, Central and North Europe.,,,
Association of Beijing lineage with drug resistance is well documented from different geographic areas including the Indian subcontinent and neighbouring countries.,,,, The drug-resistant classical SIT1 Beijing lineage is prominent in the Soviet countries and Saudi Arabia.,,, Drug resistance is thought to have developed independently among the different clones of Beijing strains., It has been proposed that the Beijing lineage has an increased ability to acquire drug resistance and disease transmissibility. It has also been suggested that infection with Beijing lineage strain is more common among younger people., Strains of the Beijing lineage have a higher capacity to proliferate within the human monocytes and the resistant Beijing strains display rapid growth compared to susceptible isolates. The emergence of multiple variants of Beijing lineage may be a reflection of genetic polymorphism leading to greater transmissibility and ability to acquire drug resistance.
Beijing lineage and multidrug-resistance
While the virulent nature of the Beijing lineage is well described, its association with drug-resistant relapse cases has also been documented. A study team from Bangladesh found that Beijing was the most prevalent lineage in that area, comprising 75% strains with multidrug resistance (MDR) in previously treated patients. Beijing strains associated with MDR have also been reported in the northern and central India., In Vietnam, MDR-TB was strongly associated with Beijing lineage, however, the association between genotype and resistance among treatment failures was not clear since the Beijing genotype was not an independent predictor of failure.
Studies from Estonia, China, Korea and Taiwan demonstrated significantly higher frequencies of MDR among the Beijing lineage., 27, ,, Colombia had 15.6% Beijing isolates, and most of them had MDR. Here, two subtypes of Beijing lineage were isolated-SIT1 and ST190. The latter was found to be associated with extensively drug-resistant TB (XDR-TB) and represented the largest cluster among isolates with MDR. A study conducted in Sweden identified 13% Beijing strains over a period of 15 years. The proportion of strains with MDR was significantly higher among Beijing strains than in non-Beijing strains. Turkey, with merely 6.3% prevalence of Beijing lineage, had 66.7% MDR in the lineage. The newly emerging virulent forms of Beijing lineage have been associated with high rates of MDR in South Africa.,, The Beijing strain was found to be linked with an outbreak of MDR-TB in the United States.,
However, a study from China reported that, though Beijing and Beijing-like strains were the most predominant circulating lineages, there was no significant association with MDR. A report from Finland documented 19 MDR cases over a period of 12 years, of which only 7 (36.8%) were of Beijing lineage. Although there was no association of MDR with the Beijing lineage in Peru.
Beijing lineage and other drug-resistance patterns
Beijing lineage and resistance to rifampicin
Beijing strains resistant to only rifampicin (RIF) have also been observed. Association of Beijing lineage with only RIF resistance have been reported from China  with most common mutations at codon 531, 526 and 511. RIF-resistant Beijing isolates were also found to be clustered, suggestive of active transmission of those resistant strains in that region. A study from Russia has reported genetic homogeneity among classical ST1 Beijing isolates conferring mutations associated with RIF resistance.
Beijing lineage and resistance to isoniazid
Studies from China demonstrated an active transmission of isoniazid (INH) resistant Beijing lineage strains with frequent mutation at katG 315, and comparatively less frequent mutation at-15 inh, locus., Similar findings were reported from the West Bank, Palestinian territories. Association between Beijing lineage and mutations in the katG gene was also documented in a study from Sweden. The authors of this study found that a majority of the Beijing strains with INH resistance had katG 315 substitution, whereas some of the Beijing strains had-15 inhA mutations.
Beijing lineage and resistance to streptomycin, ethambutol, pyrazinamide
An association of Beijing lineage and mutations conferring resistance to streptomycin (STR) was demonstrated in a study from Poland. A study carried out at Barcelona, Spain, reported 4.47% Beijing strains with mutations in the rpsL gene at codons 88 and 43. A study from China had documented significant association of ethambutol resistance with Beijing genotype. A strong association of pyrazinamide (PZA) resistance with MDR among strains of Beijing lineage was reported in a study from Iran.
Beijing lineage and resistance to linezolid, moxifloxacin
The Beijing lineage was found to be significantly associated with linezolid resistance in MDR and XDR-TB in China. No association was found between moxifloxacin resistance and Beijing genotype in China.
Various non-Beijing lineages have been reported from different geographical regions of the world. The Central Asian (CAS) and East-African Indian (EAI) lineage are prevalent in Tanzania, India and in the Indian subcontinent.,,, Haarlem (H), LAM, and T lineages are frequently isolated in Africa, Central America, Europe and South America.,, These lineages have been documented to be associated with varying degrees of drug resistance.,, In many high incidence countries, EAI lineage has been reported to be associated with reduced transmissibility and drug resistance when evaluated with other lineages whilst drug-resistant mutant strains have also been reported from CAS lineage.,,,,,
Non-Beijing lineages and multidrug-resistance
A study group from Saudi Arabia reported over-representation of EAI lineage among strains with MDR. A report from Mumbai, India showed that a significant number of strains of CAS, T1, EAI5 and EAI3 lineages were associated with XDR-TB. Association of CAS lineage with XDR TB has also been reported from Pakistan. From the same region, a high prevalence of H lineage has been identified among MDR stains. An association of PZA resistance with MDR strains of the H lineage was documented in a study from Iran. A study from Iraq reported CAS as a major lineage associated with MDR amongst previously treated patients. CAS could be correlated significantly with MDR in Sudan. MDR was found to be associated with LAM_CAM sub-lineage in Nigeria. A study from Brazil found an association of MDR with a highly dominant RD Rio sub-lineage of LAM lineage. Association of MDR with RD Rio sub-lineage was reported in another study among Latin American and Spanish population. A study from Poland found that the LAM lineage was associated with MDR., A study from southern Brazil identified LAM and T as the predominant lineages, both associated with RIF and INH resistance.
Non-Beijing lineages and other resistance patterns
A study from Myanmar reported preponderance of EAI lineage in that region associated with monoresistance to anti-TB drugs. RIF and STR mono-resistance were identified from India among strains of the CAS and T lineage. A study team from Iran found that PZA mono-resistance was more frequent among strains of CAS and EAI lineage. A study team from Poland analysed INH monoresistant phenotypes and identified T, H, U and S as the most prevalent lineages associated with INH monoresistance. INH-resistant MTB isolates harbouring mutations at codon S315G, associated with LAM lineage, were reported from West Bank, Palestinian Territories. An association of monoresistance to STR, INH and RIF was observed with LAM and H lineages in French Departments of Americas. A Mexican study group observed non-MDR, RIF or INH resistance in LAM9 and T1 lineages but not in H3 lineages.
The LAM lineage was found to be prevalent among HIV-positive patients in Mexico. However, the investigators could not correlate the drug resistance to spoligotype pattern. A study group from Peru did not find any association between drug resistance and specific spoligotypes among HIV-negative TB patients. However, MDR, but not INH or RIF mono-resistance, was found to be associated with SIT42/LAM9 and SIT53/T1 strains among HIV-associated TB patients. The authors of this study, therefore, did not support the hypothesis of strain-specific propensity for the acquisition of resistance among the genetically diversified MTB strains in that region. In Italy, T, H, LAM, S and X, lineages were found to be highly prevalent but none of them had significant drug resistance. In South-Western Uganda, there is a prevalence of Uganda lineage though no significant association with drug resistance was detected. A study from Karachi, Pakistan, revealed that no specific lineage was associated with fluoroquinolone resistance.
To summarise, genetic polymorphism exists within all lineage of MTB. The spoligotype defined lineages are represented differently in different geographical areas of the world. High rates of drug resistance may not be necessarily associated with the prevalent lineages in that region. Different lineages have shown association with some patterns of drug resistance. Beijing lineage has been consistently reported to have a significantly higher drug resistance compared to other lineages, though in certain parts of the world, this is not the case. The spoligotype lineages other than Beijing were found to be comparatively less associated with drug resistance. However, it is still uncertain whether correlation with drug resistance is merely casual or whether there is a firm link between the two.
This review was inspired by a project on genetic polymorphism of MTB strains that was funded by the Indian Council of Medical Research, India.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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