After Covid, can genome sequencing help identify gene responsible for drug-resistant TB?

In the past two years, genome sequencing enabled scientists to rapidly identify the SARS-CoV-2 virus and its variants. Now, can the gains made during the Covid-19 pandemic be expanded to more uses and help frame public health responses for other infectious diseases such as tuberculosis — which India hopes to end by 2025? Taking a lead in this direction is the Pune-based BJ Medical College and Sassoon General Hospital, which plans to utilize their year-old genome sequencing facility to identify genes responsible for drug-resistant TB.

Tuberculosis is the leading infectious disease killer in the world and was only recently overtaken by Covid-19. Compared to 2019, tuberculosis cases in 2020 reduced by 18% globally (from 7.1 million to 5.8 million cases) and by up to 24% in the ten worst-affected countries with high tuberculosis burden, as per the new Lancet Respiratory Medicine series published on March 23 this year.

Scientists are keen on exploring whole genome sequencing (WGS) for TB investigation and this concept further got a fillip when a joint study by BJMC with Johns Hopkins University School of Baltimore, USA, and others, highlighted the need for increased surveillance of TB antibiotic resistance in India. Findings of their study that compared transmissibility across four major lineages (L1-4) of Mycobacterium tuberculosis (Mtb) has shown that there are inherent differences between the lineages with implications for TB control, surveillance, and monitoring.

Published recently on medRxiv, the pre-print server for health sciences, the study showed that modern Mtb lineages (L2 and L4) were more recently introduced in Western India, compared to older lineages (L1 and L3). L2 shows a higher frequency of drug-resistance as well as higher transmissibility.

“Our findings highlight the need for contact tracing around cases of TB due to L2, and heightened surveillance of TB antibiotic resistance in India,” said Dr Rajesh Karyakarte, coordinator of Maharashtra’s genome sequencing project and head of the department of microbiology at BJ Medical College and Sassoon General Hospital, the largest government hospital in Maharashtra

“While there is geographic variation in the lineage prevalence, L1 comprises approximately two thirds (67%) of the Mtb isolates in the country. However, all four major lineages are found in circulation. The Mtb transmissibility may vary between lineages (or variants) and this may contribute to the slow decline of tuberculosis (TB) incidence,” Dr Karyakarte explained.

“As modern and more drug-resistant lineages take further hold in India, the proportion of TB with drug resistance may continue to rise, along with the number of possible new resistance associated variants. To achieve control, resources will need to be directed towards interrupting transmission by increasing efforts towards active case finding, contact tracing, early diagnosis, and treatment. The wider adoption of WGS can assist these efforts allowing clinicians to tailor therapy sooner and in turn help decrease transmission. Hence an improved understanding of these characteristics is important to improve the ability to control TB transmission,” he said.

Whole Genome Sequencing (WGS) can be used to assist efforts in providing quicker genotype-based drug susceptibility testing (DST) results of Mycobacterium tuberculosis, and with the genome sequencing facility set up at BJMC a year ago, Dr Karyakarte and his team have been assured funding from Maharashtra government, and are set to begin on the exercise soon.

The molecular laboratory at BJMC has been extremely busy in the last two years of the Covid pandemic. From using molecular scissors to prepare DNA for sequencing machines to studying changes in the genetic structure of SARS-CoV2 virus and identifying variants, scientists were able to sequence 3,000 samples at the college itself.

As part of a memorandum of understanding with IISER, NCL and Pune Knowledge Cluster, they sequenced more than 10,000 samples. Every month, the BJMC coordinated the collection of 100 samples from each of Maharashtra’s 36 districts and sent it to the Council of Scientific and Industrial Research-Institute of Genomics and Integrative Biology as part of a state project for genome sequencing.

Analyzing results and reporting it to the state government, the National Center for Disease Control and Indian SARS-CoV-2 Genomics Consortium soon became a norm, and it was through the genome sequencing project at BJMC that it was confirmed that the Omicron variant had arrived in the country in December and not November 2021.

“We are ready to use this methodology to detect more genes responsible for drug resistant TB,” Dr Karyakarte said. Scientists at the laboratory also suggest that just as Indian companies (aided by the Department of Biotechnology, Government of India) devised probe and primer sets for Covid, the same could be done for rapid identification of TB. “The government can procure them in mission mode and distribute them to 877 Indian Council of Medical Research approved laboratories across India for diagnosis of TB,” he said.

India, Indonesia, the Philippines, and China have together seen a reduction of 1.3 million cases (93%) in tuberculosis; and major reductions in notified cases have been seen in the Philippines (37%), Indonesia (31%), South Africa (26%), and India (25%). In 2019, India notified 2 1.76, 677 cases of TB to the World Health Organisation, while in 2020 the drop was significant — only 16,29,301 cases of TB were notified.

Data from Maharashtra — among the states with a high burden of TB — shows that over 2.27 lakh new cases were notified in 2019. There was a significant drop in 2020 (1.6 lakh new cases of TB) owing to the Covid pandemic. The figure rose to 2 lakh in 2021 as efforts to detect active TB cases intensified. Last year, Maharashtra reported 9,445 multi-drug resistant TB cases and 254 Extremely drug resistant (XDR) TB cases.

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