In-host population dynamics of Mycobacterium tuberculosis complex during active disease

Roger Vargas,Max Salfinger,David Durbin,Luca Freschi,Irina Oussenko,Maximillian Marin,Melissa Smith,L Elaine Epperson,Michael Strong,Maha Reda Farhat

doi:10.7554/elife.61805

Abstract

Tuberculosis (TB) is a leading cause of death globally. Understanding the population dynamics of TB's causative agent Mycobacterium tuberculosis complex (Mtbc) in-host is vital for understanding the efficacy of antibiotic treatment. We use longitudinally collected clinical Mtbc isolates that underwent Whole-Genome Sequencing from the sputa of 200 patients to investigate Mtbc diversity during the course of active TB disease after excluding 107 cases suspected of reinfection, mixed infection or contamination. Of the 178/200 patients with persistent clonal infection >2 months, 27 developed new resistance mutations between sampling with 20/27 occurring in patients with pre-existing resistance. Low abundance resistance variants at a purity of ≥19% in the first isolate predict fixation in the subsequent sample. We identify significant in-host variation in 27 genes, including antibiotic resistance genes, metabolic genes and genes known to modulate host innate immunity and confirm several to be under positive selection by assessing phylogenetic convergence across a genetically diverse sample of 20,352 isolates.

Highlights

Tuberculosis (TB) and its causative pathogen Mycobacterium tuberculosis complex (Mtbc) remain a major public health threat (World Health Organization, 2018)
We found evidence for mixed infection with two or more Mtbc lineages (Wyllie et al, 2018) for 31 patients (Figure 1B and Figure 1—figure supplement 1); 44 patients had evidence for re-infection with a different Mtbc strain between the first and second time points, using a pairwise genetic distance >7 fixed Single-nucleotide polymorphism (SNP) (Materials and methods, Figure 1C and Figure 1—figure supplement 1)
Median fixed SNP (fSNP) distance for the 44 patients identified as reinfection was 708 (IQR 250–1086)

Summary

Introduction

Tuberculosis (TB) and its causative pathogen Mycobacterium tuberculosis complex (Mtbc) remain a major public health threat (World Health Organization, 2018). The majority of individuals exposed to Mtbc clear or contain the infection, and only 5–10% of those infected develop active TB disease at some point in their lifetime (Pai et al, 2016). While basic human immune mechanisms to Mtbc have been identified, attempts at effective vaccine development guided by these mechanisms have repeatedly failed (Ernst, 2018). Mtbc is an obligate human pathogen (Gagneux, 2018). Infection and disease involve a complex human host-pathogen interaction that is both physically and temporally heterogeneous (Lin et al, 2014). All selective forces acting on Mtbc will originate within the host, and the study

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