Abstract
While tuberculosis (TB) remains a global disease, the WHO estimates that 62% of the incident TB cases in 2016 occurred in the WHO South-East Asia and Western Pacific regions. TB in the Pacific is composed predominantly of two genetic families of Mycobacterium tuberculosis (Mtb): Beijing and Manila. The Manila family is historically under-studied relative to the families that comprise the majority of TB in Europe and North America (e.g. lineage 4), and it remains unclear why this lineage has persisted in Filipino populations despite the predominance of more globally successful Mtb lineages in most of the world. The Beijing family is of particular interest as it is increasingly associated with drug resistance throughout the world. Both of these lineages are important to the State of Hawaii, where they comprise over two-thirds of TB cases. Here, we performed whole genome sequencing on 82 Beijing family, Manila family, and outgroup clinical Mtb isolates from Hawaii to identify lineage-specific SNPs (SNPs found in all isolates from their respective families, and exclusively in those families) in established virulence factor genes. Six non-silent lineage-specific virulence factor SNPs were found in the Beijing family, including mutations in alternative sigma factor sigG and polyketide synthases pks5 and pks7. The Manila family displayed more than eleven non-silent lineage-specific and characteristic virulence factor mutations, including in genes coding for MCE-family protein Mce1B, two mutations in fatty-acid-AMP ligase FadD26, and virulence-regulating transcriptional regulator VirS. This study further identified an ancient clade that shared some virulence factor mutations with the Manila family, and investigated the relationship of those and other “Manila-like” spoligotypes to the Manila family with this SNP dataset. This work identified a set of virulence genes that are worth pursuing to determine potential differences in transmission or virulence displayed by these two Mtb families.
Highlights
Despite sustained control efforts, tuberculosis (TB) remains the ninth leading cause of death worldwide [1]
A Mycobacterium bovis BCG P3 isolate was used as an outgroup for phylogenetic analysis, as M. bovis has been shown to have diverged from the M. tuberculosis ancestor prior to the differentiation of the TB lineages examined in this study [5]
Disruption of Pks7 produced a strain that was deficient in the production of phthiocerol dimycocerosates (PDIMs), which has been known to attenuate growth during in vivo infection, and in this case attenuated growth in mice infected by respiratory inoculation [18, 26, 27]
Summary
Tuberculosis (TB) remains the ninth leading cause of death worldwide [1]. The World Health Organization (WHO) estimated that 62% of the incident TB cases in 2016 occurred in the WHO South-East Asia and Western Pacific Regions [1]. Within those regions, TB in both China and the Philippines in characterized by distinct families of TB–the Beijing family in China and the Manila family in the Philippines [2, 3]. As noted in the report, the Fourth National Survey of the Prevalence of TB Disease in the Philippines was conducted from March to December of 2016, and the survey revealed that tuberculosis was not well controlled in the country [1]. In contrast to the steady or increasing incidence of TB in the Philippines, TB incidence in China is thought to be declining, with the WHO’s estimate being
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