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Lassa Virus Sequence Gives Insight into Viral Origins, Evolution

NEW YORK (GenomeWeb) – The Lassa virus, unlike its Ebola cousin, appears to have ancient origins and its appearances in humans seem to mostly be due to reservoir-to-human transmissions, according to an analysis of some 200 Lassa virus sequences.

"The reason Lassa hasn't yet grown into this huge epidemic is because there is limited transmission between humans," first author Kristian Andersen from the Scripps Research Institute said in a statement. "That's a major difference between Lassa virus and Ebola virus."

Lassa virus causes hemorrhagic fevers in people, similar to the Ebola and Marburg viruses, though it is more common and causes endemic disease in West Africa. It's estimated to hospitalize tens of thousands of people each year and cause thousands of deaths. Most patients become infected through contact with feces from Mastomys natalensis, or the Natal multimammate mouse, though some human-to-human transmissions do occur, mostly within hospitals.

Andersen and his colleagues sequenced 183 Lassa virus genomes obtained from patients, 11 from M. natalensis, and two lab isolates to generate a catalog of Lassa genomes, as they reported in Cell today.

"This [catalog] gives us a clear view of how the virus is evolving, which is important to know as we develop vaccines and therapies," Andersen said..

The 196 viruses the researchers sequenced harbored high levels of nucleotide diversity, and fell into four major clades: three from Nigeria and one encompassing Sierra Leone, Guinea, and Liberia. They noted that the samples did not cluster by host.

Andersen and his colleagues found that only about 3 percent of the clinical samples they studied followed the phylogenetic tree clustering pattern that's expected of human-to-human transmissions. However, half of the samples obtained from rodents did show such a pattern. At the same time, they reported that the average pairwise divergence for Lassa viruses from Sierra Leone was higher that that seen in Ebola virus lineages there from the 2013 to 2015 epidemic — which spread person to person — even with similar observed substitution rates.

All together, Andersen and his colleagues said this suggests that most human Lassa virus infections stem from independent transmissions from the rodent reservoir.

In addition, molecular dating of the Lassa virus strains indicated that existing viral strains can trace their origins back a thousand years in modern-day Nigeria, and these strains then spread during the last few hundred years into other West African countries, the researchers reported. Ebola strains, by contrast, have a common ancestor that's some 50 years old.

Strains of Lassa virus found outside of Nigeria, the researchers noted, exhibited a higher degree of codon adaptation to existing in a mammalian host, which influences translational efficiency.

This increased codon optimization, the researchers hypothesized, might lead to increased viral output and higher viral titers in hosts for non-Nigerian strains. Using qPCR to quantify viral loads, the researchers found more Lassa virus genomes in patients from Sierra Leone than from Nigeria.

Higher viral load, they added, is correlated to higher fatality rates, though other factors like delays in clinical care also influence fatality rates.

"The increase in [codon adaptation index] of non-Nigerian strains, along with higher viral copy numbers, and [case fatality rates] in human patients, would seem to suggest that the virus evolved toward greater human virulence," Andersen and his colleagues wrote in their paper. "There are indeed many examples suggesting that pathogens with natural reservoirs may evolve toward greater human virulence, so long as they remain avirulent in the reservoir host."

They researchers also found that the Lassa virus glycoprotein, the only part of the virus partially exposed outside the viral particle, appears to be under natural selection.

Getting a better understanding of the Lassa virus genome and how it varies suggests strategies for dealing with infections, the researchers said.

For instance, Andersen and his colleagues said that as the strains cluster by region, developing vaccines, diagnostics, and therapeutics tailored for variations seen in those areas or that target conserved parts of the viral genome could be a useful strategy.

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