Metagenome sequencing is transforming pathogen surveillance

With SARS-CoV-2, scientists didn’t go the more time-consuming microbiology route; instead, in a break from tradition, the samples were directly subjected to genome-sequencing and bioinformatic analysis, an approach called metagenomics

August 13, 2023 10:00 am | Updated 10:23 am IST

A computer-generated rendering of a whole influenza (flu) virus, in semi-transparent blue with a navy-blue background.

A computer-generated rendering of a whole influenza (flu) virus, in semi-transparent blue with a navy-blue background. | Photo Credit: Dan Higgins/CDC

If we are to define one global life-altering event of our generation, COVID-19 is likely to top the list. All of us witnessed the devastation that the COVID-19 pandemic wrought, at a scale so unprecedented that people almost everywhere paused what they were doing and started searching for answers together to end it quickly.

One of the initial breakthroughs in the definitive identification of SARS-CoV-2 as the causative agent of COVID-19 came from the application of unbiased genome sequencing technologies to infected patient samples. Scientists didn’t go the more time-consuming microbiology route with these samples; instead, and in a break from tradition, they were directly subjected to genome-sequencing and bioinformatic analysis, which helped the scientists quickly identify the virus.

This new approach – called metagenomics – was not only rapid but could also be deployed directly on patient samples, without any a priori knowledge of the infectious agent. Indeed the scale of sequencing during the pandemic rendered SARS-CoV-2 one of the most sequenced organisms in global history. The technique and its adoption also drastically changed the way pathogen identification would be undertaken thereafter.

Genomic tech to the frontline

Scientists in countries worldwide have since developed scores of technologies based on genome-sequencing – including the very popular CovidSeq assay – spawning several national and international SARS-CoV-2 genome surveillance activities. GISAID, a popular repository on the internet to which SARS-Co-V-2 genome-sequence data could be submitted, is a testimony to such high-throughput genome surveillance activities.

(‘High-throughput’ refers to sequencing techniques that can parse large quantities of DNA at the same time, including a whole genome at once.)

The importance and impact of the way SARS-CoV-2 was being surveilled also became evident when national and international organisations started implementing public health policies based on the genomic data. India also initiated a national SARS-CoV-2 genome-sequencing and surveillance program supplemented by several State government and private initiatives.

The success has provided a template for applying sophisticated genomic technologies as frontline tools to surveil known and unknown organisms and to tracking emerging pathogens in an unbiased and high-throughput manner.

The Nigerian study

In an August 4 paper in Nature Communications, scientists from the Nigerian Centre for Disease Control applied metagenomic sequencing for pathogen surveillance and detection in three cohorts of patients. They investigated 593 febrile Nigerian individuals with unbiased sequencing.

The first cohort represented population-level surveillance of individuals presenting with symptoms consistent with Lassa fever, a viral haemorrhagic fever caused by the Lassa virus endemic to West African countries. The second cohort consisted of people from outbreaks with suspected infectious aetiologies. The third cohort consisted of people with clinically challenging but undiagnosed conditions.

The scientists were able to identify 13 distinct viruses afflicting the individuals. The genomic approach also helped them pinpoint the second and third documented cases of human blood-associated dicistrovirus, which the team named the human blood-associated dicistrovirus 2, among the cohorts.

The scientists also identified pegivirus C as a common co-infection in patients with Lassa fever as well as that the presence of pegivirus C was associated with a lower viral load in patients. Further investigations revealed the presence of yellow fever virus and mpox virus in patients.

As it happened, the metagenome-sequencing approach also allowed the scientists to rule out viral infections in some individuals and link their symptoms to pesticide poisoning instead.

The study demonstrated the power of metagenomic sequencing investigations for pathogen detection and disease diagnosis, and to inform public health outbreak responses.

Tracking avian influenza

In 2022, the world witnessed a global mpox virus outbreak. It was attributed to a super-spreader event and threatened the planet with another epidemic, but which fortunately ‘fizzled’ out. One reason is that scientists were able to apply genome-sequencing technologies perfected during the COVID-19 pandemic to understanding the origin and spread of the mpox virus.

Avian influenza viruses are another prime candidate for genome surveillance as they trigger seasonal outbreaks of avian influenza, or bird flu. Given the highly mobile and migratory nature of their hosts – including both wild birds and poultry – avian influenza viruses are capable of causing mass death in birds and some animals, and with little warning. These outbreaks pose a risk to human health as well as human livelihoods and biosecurity.

In the last decade, avian influenza viruses have also spread rapidly to humans. While rapid detection kits and vaccines for these viruses are widely available, they need to be complemented by a well-organised genomic surveillance programme so that scientists can identify which virus strains are circulating, as well as monitor the impact of vaccination.

The worldwide deployment of large-scale genome sequencing infrastructure during the COVID-19 pandemic is now holding us in good stead, by allowing us to conduct avian influenza genomic surveillance at source. For example, scientists working at the Institut Pasteur du Cambodge, Cambodia, demonstrated earlier this year the power of such surveillance when they successfully decoded the full genome sequence of the Cambodian H5N1 virus in under 24 hours.


Key to early response

Such initiatives have also been mooted for other seasonal pathogenic viruses, including Zika and dengue. More recently, experts have used genome sequencing technologies as frontline tools to motivate the detection and surveillance of lumpy skin disease in cattle and the emergence of drug-resistant tuberculosis, among other use-cases.

It is heartening that several initiatives worldwide are taking advantage of the speed, accuracy, and high-throughput nature of advanced genome sequencing technologies to detect pathogens from diverse environmental sources, such as wastewater, air, soil, and animals.

Since genome surveillance provides the sort of information that experts can use to devise an early response strategy, identify emerging viral strains, and undertake risk-based surveillance of key animal species, genomic technologies are likely to become mainstays of our arsenal against pathogens of the future.

The authors are former scientists at the CSIR Institute of Genomics and Integrative Biology. All opinions expressed here are personal.

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