Variation in Mycobacterium tuberculosis population structure in Iran: a systemic review and meta-analysis

Tuberculosis (TB) remains the most lethal infectious disease with an estimated rate of 1.4 million deaths in 2018 [ 1]. Human-adapted Mycobacterium tuberculosis complex (MTBC), as a causative agent of TB infection, belong to eight phylogenetic branches with a phylogeographical population structure [ 2, 3]. These lineages include Indo-Oceanic lineage (Lineage 1), East Asian (Lineage 2), Central Asian (Lineage 3), Euro-American (Lineage 4), Ethiopian (Lineage 7), known as Mycobacterium tuberculosis sensu stricto, West African 1 (Lineage 5) and West African 2 (Lineage 6), referred to as Mycobacterium africanum and Lineage 8 (L8) which geographically restricted to the African Great Lakes region [ 2– 4].

Different studies have shown that genomic differences among MTBC lineages or sublineages can affect the clinical and epidemiological characteristics of TB infection [ 5– 8]. In recent decades, some Mycobacterium tuberculosis ( Mtb) lineages/sublineages have attracted wide attention due to certain features such as transmission potential, pathogenic properties and association with drug resistance [ 9, 10]. Lineages 2 and 4 are widely distributed and seem to have a higher pathogenic power compared to geographically restricted lineages [ 2, 11, 12]. In West and South Asia, a sharp increase has been documented in the circulation of certain sublinages such as NEW-1 (Lineage 4) and CAS (Lineage 3) strains that are prone to emerging as resistant clones [ 13– 15]. This growing increase seems be more important in Iran with the national average TB rate of 14 cases per 100,000 population, due to the influx of Afghan refugees and population growth [ 1]. Accordingly, acquiring comprehensive insight into the dynamics of Mtb population structure is an essential step to adopt effective TB control strategies and improve therapeutic methods and vaccines.

Therefore, the current systematic review and meta-analysis was conducted to determine (1) the overall prevalence of Mtb genotypes/sublineages and (2) to determine the dominant multidrug-resistant (MDR) Mtb genotypes in TB patients in Iran.

Based on the pooled data investigated, all MTBC lineages, except lineage 7 and 8, were found in Iran, which reflects the presence of high diversity in MTBC strains. Phylogeographical population structure of the MTBC stems from the interplay between different factors such as human migration, geography, genetic drift and host-pathogen interaction [ 4, 5, 56]. Iran is the main host country for Afghan refugees, but the main factor contributing to formation of MTBC lineages phylogeography in Iran has not been identified.

Study of global variation in MTBC strains showed that the prevalence of lineages 2, 3 and 4 strains may be increasing in West Asia, while the prevalence of lineage 1 is declining [ 15]. The summary of Mtb strains diversity in Iran, based on families/sublineage, showed that NEW1(L4) (21.94, 95% CI: 16.41–28.05%), CAS (L3) (19.21, 95% CI: 14.95–23.86%), EAI(L1) (12.95, 95% CI: 7.58–19.47%), and T (L4) (12.16, 95% CI: 9.18–15.50%) were the dominant circulating Mtb genotypes. EAI (L1) and CAS (L3) are mainly confined to the areas around the Indian Ocean [ 11]. Movement of strains with people from these regions may explain the presence of these genotypes in Iran. Besides, appearing CAS as a one of the prevalent Mtb subpopulations in Iran may reflect the pathogenic properties of this genotype.

In a recent study, the global proportion of MDR in CAS population was estimated at 30.63% [ 57]. In our study, based on the pooled prevalence of MDR genotype, CAS was found (1.21%) as a one of the dominant genotypes. This finding reflects the needs for more understanding and monitoring of this subpopulation.

Despite the global dissemination of Beijing genotype as a prototype of lineage 2, it had low prevalence in our geographical region. However, the highest pooled prevalence of MDR strains was found in the Beijing (2.52%) genotype. This result is consistent with the previously published reports about the prevalence of Beijing among MDR-TB isolates in Iran [ 58]. The low prevalence of Beijing genotype compared to other genotypes in Iran may be explained by the prevalent Beijing sublineage, affecting its pathobiological properties and epidemiological dynamics. Further studies are warranted to identify the distribution pattern of the Beijing sublineages in Iran, which can improve the management of their infection.

The dominance of NEW1 as a specialist sublineage of Euro-American lineage (L4) in Iran was not unexpected. Some evidence has shown that Iran is the probable origin of this family/sublineage, which may reflect ecological adaption in this subpopulation [ 59]. It is noteworthy that NEW1 genotype is prone to MDR [ 13]. The pooled prevalence of MDR in NEW1 was 0.8% (95% CI). However, the results of overall MDR estimation may be less representative of the target population, as in the some of the included studies in our analysis; drug susceptibility testing was not reported based on the identified genotype, which may lead to variation in the final results. Other sublineages of lineage 4 such as T, Haarlem, Uganda and S in varying proportions were also observed. This distribution pattern in the subtypes of lineage 4 in Iran may be explained by the effect of human migration and genetic and phenotypic characteristics of each sublineage.

In addition, we observed that lineage 5/6 subtype had the lowest prevalence in our geographical region. Based on the fact that these strains are geographically restricted [ 2], we can only speculate human migration as the determinant of this distribution. A limitation of this study is that most of the included studies were conducted in Tehran (Capital of Iran). Thus, our finding may not be completely representative of the overall prevalence of different Mtb populations in Iran. In addition, the most of the included studies were based on Spoligotyping and MIRU-VNTR typing methods while WGS provides a superior resolution compared with these PCR-based genotyping methods to identification of diversity in Mtb strains.

In summary, this systematic review showed that Mtb population are genetically diverse in Iran and the NEW1 (L4) and West African (L5/6) genotypes had the highest and lowest pooled prevalence rates, respectively. This type of evidence can contribute to better clinical and epidemiological management of Mtb infections. Also, there is a need for further in-depth studies to gain a deeper insight into the national diversity of Mtb populations and their drug resistance pattern.