Illumina - How NGS helps in the fight against drug-resistant TB

How did you get involved with Genoscreen? And is your research applied by the company?

Philip Supply: My research group developed and internationally standardised a portable 24-marker genotyping method for the molecular tracing of the TB-causing pathogens. I worked with Genoscreen to develop genotyping kits, which facilitated the adoption of these markers for global surveillance of the disease. The knowledge acquired through our research on the strong clonality and other biological peculiarities of the organism are now used within the company to develop new molecular tools for the rapid detection of bacterial drug resistance.

Can you tell us about Genoscreen and its involvement in 'eradicating tuberculosis (TB)'?

Genoscreen is a biotech company that offers a large range of next-generation sequencing (NGS) including Illumina instruments, genome and metagenome analysis services. The company prioritises developing innovative tools for microbial research and applications. TB is one of the top causes of human death and the first contributor to mortality due to antimicrobial resistance. A large part of the company's R&D is devoted to fighting it.

How do you incorporate NGS in your workflow? And what are the benefits?

In our research, we use NGS as a molecular approach to study factors underlying the high or low-epidemiological success of different strain lineages worldwide, and to track the evolution of drug resistance. Whole genome sequencing (WGS) provides us with a comprehensive view on the molecular mechanisms involved. At a basic scientific level, we can thereby identify early branches and key mutational events involved in the evolution of the organism towards pathogenicity. We can also track the epidemic spread of major multidrug-resistant clones, and understand their origins. We now use targeted deep sequencing to better detect the emergence of resistance, especially to recent anti-TB drugs. That recently helped us to identify an outbreak of drugresistant TB in South Africa, undetected by WHO-endorsed tests. These TB strains unexpectedly presented mutational signs of emerging resistance to bedaquiline, the newest antibiotic used to treat multidrugresistant TB.

What improvements do you see now that NGS has been incorporated in TB genotyping?

TB genotyping is widely used for molecular-guided outbreak control and prevention. TB is typically concentrated in vulnerable and hard-to-reach risk groups. This complicates contact investigation around TB cases, which represents a central component of outbreak control and prevention. WGS offers ultimate resolution at strain level, and its use allows for more precisely guided investigations of probable transmission links among patients.

You were chosen in WHO's technical guide on the use of NGS for detecting mutations associated with drug resistance in Mycobacterium TB. How did this come about?

This is the result of the meticulous development with Genoscreen of a novel targeted deep sequencing solution, called Deeplex-MycTB, for culture-free detection of drug-resistant M. tuberculosis. In contrast to WGS, this amplicon-based test can be directly applied on clinical specimens. This authorises diagnostics and patient treatments at least one week faster than WGS, and weeks faster than phenotypic tests. The assay consists of a single 24-plex amplification of 18 drug resistance-associated gene targets, plus mycobacterial identification and M. tuberculosis genotyping targets. This molecular compartment is coupled to a fully parameterised and automated web application for quick, efficient analysis, making the test a unique end-to-end solution.

How do you see NGS being used in detection of multidrugresistant TB?

The use of NGS, either targeted or even more so by WGS, permits more comprehensive detection of drug resistance-associated mutations than existing molecular tests. Especially with a targeted format, deep sequencing of the resulting amplicons provides a highly accurate analysis of drug resistance mutations, including in minority populations causing heteroresistance. Moreover, the already extensive catalogue of known drug resistance mutations is expected to be almost comprehensively covered soon, thanks to international collaborative efforts by the CRyPTIC and ReSeqTB consortia, involving WHO. These collaborations are causing several countries to transition to NGS-based TB diagnostics. As a result of lighter infrastructures needed for molecular tests rather than for culture-based assays, NGS also has a great potential to help closing diagnostic gaps existing in high-multidrugresistant TB incidence settings.

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