Disease surveillance can detect any virus

During the Zika virus outbreak, public health officials attempting to stop the virus from spreading further and scientists trying to understand its genetics were limited by the fact that the blood of a sick patient does not contain very many Zika virus capsids. In response to the outbreak, researchers in Broad Institute scientist Pardis Sabeti’s laboratory developed a new computational method known as the Compact Aggregation of Targets for Comprehensive Hybridization (CATCH) method, which they believe can help overcome that major hurdle in disease detection.

This new method involves designing molecular baits for infectious viruses and each of their possible strains. Baits are molecular probes composed of short DNA or RNA strands, which pair with complementary viral DNA strands. Because this method is more adaptable to different viruses, it allows smaller sequencing centers worldwide to conduct disease surveillance in a cheaper and more efficient manner.

The study was led by Hayden Metsky, a graduate student from MIT, and Katie Siddle, a postdoctoral researcher also from MIT. According to Christian Matranga, a co-senior author of the study, advanced genomic sequencing tools like CATCH will help scientists to detect outbreaks earlier and gather more data on pathogens than previously possible.

Older virus surveillance tools are not quite as effective as CATCH. In the past, scientists have often made use of metagenomic sequencing, a method of sequencing which scans through all the genetic material in a given clinical sample, making low-abundance viruses like Zika detectable. However, the major flaw of this method is that it typically misses some viral material which is hidden within a variety of other microbes as well as the patient’s DNA.

Another method was enriching a sample for some given virus by immobilizing a target virus’s genetic material with a genetic bait. The rest of the genetic material is then washed away, leaving only the virus’s genetic material. Although this has worked successful in the past for analyzing the viral genomes of Ebola and Lassa, the probe designs only worked for a single microbe. Therefore, researchers had to know exactly what they were looking for when using molecular baits.

Compared to past approaches, CATCH is a major improvement. The CATCH method permits those using it to design custom probes which can capture the genetic material of any microbial species, including any virus which can infect humans. A user then inputs genomes taken from the National Center for Biotechnology Information’s sequencing database into CATCH. CATCH then determines the sets of probes most fitting for whatever a user would like to recover and sends this information to a company that synthesizes probes.

Tests of some CATCH probes have already shown promise. A few probe sets’ sequencing data contained more than 18 times the viral content than before enrichment, which allows researchers to generate more complete genomes from this data than they were able to before. Another set of CATCH-designed probes were able to rescue samples of Lassa virus from 2018 that were unable to be sequenced without enrichment. The research team also greatly improved viral detection in samples composed of unknown sequences coming from both patients and mosquitoes.

The research team has been working with other scientists in West Africa to establish laboratories and furnish them with equipment capable of analyzing pathogen sequences. In this region, viral outbreaks and fevers that cannot be clearly diagnosed are common, so Siddle hopes that CATCH will allow scientists to more efficiently perform metagenomic sequencing. For fevers especially, CATCH allows for further investigation if they are suspected of having a viral cause. As for future applications, the research team hopes it can be useful for clinical diagnoses. The team believes that CATCH can also improve large scale high-resolution studies of microbial communities.