Sub-Lineage Specific Phenolic Glycolipid Patterns in the Mycobacterium tuberculosis Complex Lineage 1.

Nicolas Gisch,Silke Gerdes,Solomon Ali,Christian Utpatel,Roland Diel,Ursula Schombel,Danny C Hesser,Lisa M Gronbach,Susanne Homolka,Glennah Kerubo,Dominik Schwudke,Norbert Reiling,Celso Khosa,Karen M Dobos,Florian P Maurer,Andrea Rachow,Stefan Niemann,Sven Malm,Udo Götsch,Yassir Adam Shuaib ,Sofía Viegas ,Thomas Köhl ,Perpetual Wangui Ndung’u ,Sahal Al‐Hajoj ,Michael Höelscher ,Nyanda Elias Ntinginya

doi:10.3389/fmicb.2022.832054

Abstract

“Ancestral” Mycobacterium tuberculosis complex (MTBC) strains of Lineage 1 (L1, East African Indian) are a prominent tuberculosis (TB) cause in countries around the Indian Ocean. However, the pathobiology of L1 strains is insufficiently characterized. Here, we used whole genome sequencing (WGS) of 312 L1 strains from 43 countries to perform a characterization of the global L1 population structure and correlate this to the analysis of the synthesis of phenolic glycolipids (PGL) – known MTBC polyketide-derived virulence factors. Our results reveal the presence of eight major L1 sub-lineages, whose members have specific mutation signatures in PGL biosynthesis genes, e.g., pks15/1 or glycosyltransferases Rv2962c and/or Rv2958c. Sub-lineage specific PGL production was studied by NMR-based lipid profiling and strains with a completely abolished phenolphthiocerol dimycoserosate biosynthesis showed in average a more prominent growth in human macrophages. In conclusion, our results show a diverse population structure of L1 strains that is associated with the presence of specific PGL types. This includes the occurrence of mycoside B in one sub-lineage, representing the first description of a PGL in an M. tuberculosis lineage other than L2. Such differences may be important for the evolution of L1 strains, e.g., allowing adaption to different human populations.

Highlights

The genetic diversity of Mycobacterium tuberculosis complex (MTBC) strains has been shown to influence transmission and virulence of clinical MTBC isolates as well as the immune response and clinical outcome
This study aimed to link the population structure of L1 strains to the presence of distinct phenolic glycolipids (PGL) types and to address their potential correlation with differences in virulence
To analyze the global population structure of L1 strains we compiled a Whole Genome Sequencing (WGS) dataset of 312 L1 strains from 43 countries, spanning 13 UN-regions that comprise all major geographical areas with reported occurrence of L1 strains (Figure 2, Supplementary Figure 1, and Supplementary Table 1)

Summary

Introduction

The genetic diversity of Mycobacterium tuberculosis complex (MTBC) strains has been shown to influence transmission and virulence of clinical MTBC isolates as well as the immune response and clinical outcome (reviewed in Coscolla and Gagneux, 2014; Tientcheu et al, 2017). Loss of TbD1 in “modern” MTBC strains has been associated with a better circumvention of and persistence against oxidative stress and hypoxic conditions within the host cell micro-environments. This may generate an important advantage for those MTBC pathogens especially during prolonged stages of infection (Bottai et al, 2020). These observations are in line with data from own experiments using in vitro and in vivo model systems, since we previously showed that “modern” MTBC strains from L2 or L4 exhibit significantly enhanced growth rates in human monocyte-derived and alveolar macrophages as well as in aerogenically infected mice, when compared to L1 strains (Reiling et al, 2013)

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