Mutation of Mycobacterium tuberculosis and Implications for Using Whole-Genome Sequencing for Investigating Recent Tuberculosis Transmission.

Clinton J. McDaniel,James Posey,Sarah Talarico,Martin Cilnis,Benjamin J. Silk,Tambi Shaw,Wendy S. Noboa,Shameer Poonja,Kala Raz,Kristin N. Nelson,Lauren Cowan,Alicia H. Chang

doi:10.3389/fpubh.2021.790544

Abstract

Tuberculosis (TB) control programs use whole-genome sequencing (WGS) of Mycobacterium tuberculosis (Mtb) for detecting and investigating TB case clusters. Existence of few genomic differences between Mtb isolates might indicate TB cases are the result of recent transmission. However, the variable and sometimes long duration of latent infection, combined with uncertainty in the Mtb mutation rate during latency, can complicate interpretation of WGS results. To estimate the association between infection duration and single nucleotide polymorphism (SNP) accumulation in the Mtb genome, we first analyzed pairwise SNP differences among TB cases from Los Angeles County, California, with strong epidemiologic links. We found that SNP distance alone was insufficient for concluding that cases are linked through recent transmission. Second, we describe a well-characterized cluster of TB cases in California to illustrate the role of genomic data in conclusions regarding recent transmission. Longer presumed latent periods were inconsistently associated with larger SNP differences. Our analyses suggest that WGS alone cannot be used to definitively determine that a case is attributable to recent transmission. Methods for integrating clinical, epidemiologic, and genomic data can guide conclusions regarding the likelihood of recent transmission, providing local public health practitioners with better tools for monitoring and investigating TB transmission.

Highlights

Tuberculosis (TB) control programs use molecular characterization and surveillance of Mycobacterium tuberculosis (Mtb) for detecting TB case clusters, indicating or refuting possible epidemiologic links between patients, and defining an outbreak’s magnitude and scope [1]
TB patients included in the final analytic data set of source–secondary case pairs were similar to all patients who had undergone investigation, but were on average younger, belonged to smaller clusters, were more likely to be of Hispanic ethnicity, and were less likely to have been homeless during the year before their TB diagnosis (Table 1)
Our analysis of 59 source–secondary case pairs derived from a diverse set of clustered cases investigated in Los Angeles County did not indicate a linear association between single nucleotide polymorphism (SNP) distance and modified case-pair interval, a proxy for duration of latent Mtb infection and TB disease

Summary

Introduction

Tuberculosis (TB) control programs use molecular characterization and surveillance of Mycobacterium tuberculosis (Mtb) for detecting TB case clusters, indicating or refuting possible epidemiologic links between patients, and defining an outbreak’s magnitude and scope [1]. Genotyping can provide evidence that cases are attributable to recent TB transmission vs reactivation of latent Mtb infection that was acquired during the remote past. During 2012, the US Centers for Disease Control and Prevention’s (CDC) Division of Tuberculosis Elimination (DTBE) began selectively performing whole-genome sequencing (WGS) for investigating clusters of genotype-matched TB cases for which recent transmission was suspected. As of 2018, CDC began prospectively performing WGS for all culture-confirmed TB cases in the United States, and clusters detected by genotyping undergo rapid genomic characterization [3]

Objectives

Methods

Results

Conclusion