Researchers discover genetic factors responsible for severe Lassa fever

While scanning the human genome in 2007, computational geneticist Pardis Sabeti made a discovery that would transform her research career. As a postdoctoral researcher at the Broad Institute of MIT and Harvard, Sabeti discovered potential evidence that an unknown mutation in a gene called LARGE1 had a beneficial effect on the Nigerian population.

Other scientists had discovered that this gene was essential for the Lassa virus to enter cells. Sabeti wondered whether a mutation in LARGE1 could prevent Lassa fever, an infection caused by the Lassa virus that is endemic in West Africa and can be fatal in some people while mild in others.

To find out, Sabeti later decided in 2007, as a new faculty member at Harvard University, that one of the first projects his new lab at the Broad would undertake would be a genome-wide association study (GWAS). of susceptibility to Lassa. She contacted her collaborator Christian Happi, now director of the African Center of Excellence for Infectious Disease Genomics (ACEGID) at Redeemer University in Nigeria, and together they launched the study.

Today, their groups and collaborators report the results of this study in Natural microbiology—the first ever GWAS of a biosafety level 4 (BSL-4) virus. The team discovered two key human genetic factors that could help explain why some people develop severe Lassa fever, as well as a set of LARGE1 variants linked to a reduced risk of getting Lassa fever. This work could lay the foundation for better treatments for Lassa fever and other similar illnesses. Scientists are already working on a similar genetic study on susceptibility to the Ebola virus.

The paper also describes the many challenges the team had to overcome during their 16 years of collaborative efforts, such as studying a dangerous virus and recruiting patients with a poorly documented disease in South Africa. ‘West. Dozens of scientists contributed to the work and spent seven years recruiting patients in Nigeria and Sierra Leone, plus many more years establishing the research agenda and analyzing the results.

“It really took a village to achieve this,” said Happi, co-senior author with Sabeti.

“Generations of people in our laboratories, in different institutions and countries, have dedicated a significant part of their careers to making this project a reality,” Sabeti added.

Co-first authors of the study are Dylan Kotliar, an internal medicine resident at Brigham and Women’s Hospital and an M.D./Ph.D. student in Sabeti’s lab while the project was underway; Siddharth Raju, a graduate student in Sabeti’s lab; Shervin Tabrizi, postdoctoral researcher at the Broad; and Ikponmwosa Odia, a researcher at Irrua University Specialist Hospital in Nigeria.

Lassa learning

Sabeti remembers the team’s first discussions when the project was launched. They knew they had to be careful at every step: To work with a BSL-4 virus, scientists must wear pressure suits connected to HEPA-filtered air in a special containment laboratory. The virus causes fever, sore throat, cough and vomiting, but can quickly progress to organ failure in some people.

“This was an extremely difficult study to get started,” said Kotliar, who worked on the project throughout his doctorate. at the Sabeti laboratory. “I think the battle scars, the things we’ve learned over time about how to carry out a project like this, will be important for future virus research in developing countries.”

Finding study participants would also be a challenge. There is currently no FDA-approved diagnostic for Lassa, and cases of Lassa virus are generally not documented. Fewer than 1,000 cases are reported each year in Nigeria, the most populous country where the virus is endemic, and cases often occur in rural areas far from diagnostic centers, many of which lack the technology to detect the virus.

Infections with other viruses and the genomic complexity of different strains of the same Lassa virus can complicate analysis. Additionally, African populations have been historically underrepresented in previous genetic studies, which reduces the statistical power of data analyzes and can make it difficult to identify major genetic variants.

When Sabeti began thinking about how to start the project, she contacted Happi, whom she knew from their joint work on the malaria pathogen, Plasmodium falciparum. With the help of collaborators, including Peter Okokhere, the doctor treating Lassa’s patients at Irrua University Specialist Hospital, they began recruiting patients from Nigeria and Sierra Leone. Next, they compared the genomes of about 500 people who had Lassa fever and nearly 2,000 others.

In the Nigerian cohort, the team found that people with a set of variants in the LARGE1 gene, which modifies a cellular receptor that binds to certain viruses, were less likely to get Lassa fever. Sabeti, Happi and their colleagues also discovered genomic regions associated with Lassa death: in the LIF1 gene, which codes for an immune signaling molecule, and, in the Nigerian cohort, in the GRM7 gene, involved in the nervous system. central. The team then used a large-scale screen called a massively parallel reporter assay to determine which variants within these genomic regions might be functional and could be targets for new treatments.

Better detection

Researchers say that to improve detection and treatment of Lassa fever, more diagnostic centers and diagnostics working on the ground are needed, as well as better health infrastructure to connect remote sites to main hospitals.

“This really highlights the need for continued investment in understanding the genetics of African populations,” Raju added. “Even with a relatively limited sample set, we have improved our understanding of some African populations, particularly genes related to the immune system, showing how much more remains to be done in the future.”

Sixteen years after they began thinking about the genetics of Lassa fever, Sabeti and Happi are excited about the study’s results, which could explain the biological differences between mild and severe illness. They said the work also shows that through thoughtful collaborations between countries, genome-wide association studies of BSL-4 viruses are possible. Researchers have already begun conducting a similar study on Ebola in Sierra Leone and Liberia, and other scientists are calling for increased pathogen surveillance and increased scientific training in Africa.

“We’re at a point where we can actually start to develop point diagnostics for Lassa virus and do testing much more broadly,” Happi said. “We need better infrastructure, but I think we’ve shown that this type of study is worth it.”