While combing the human genome in 2007, computational geneticist Pardis Sabeti made a discovery that would transform her research career. At the time, as a postdoctoral fellow at the Broad Institute of MIT and Harvard, Sabeti discovered potential evidence that some unknown mutation in a gene called LARGE1 had a beneficial effect on the Nigerian population. Other scientists 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, which is endemic to West Africa and can be deadly for some people and only mild for others.
To find out, Sabeti decided later in 2007, as a new faculty member at Harvard University, that one of the first projects his new lab at the Broad would take on would be a genome-wide association study (GWAS) of Lassa susceptibility. She contacted her collaborator Christian Happi, now Director of the African Center of Excellence for Genomics of Infectious Diseases (ACEGID) at Redeemer University in Nigeria, and together they launched the study.
Now, his groups and collaborators report the results of this study in Nature Microbiology – the first GWAS of a biosafety level 4 (BSL-4) virus. The team discovered two important human genetic factors that could help explain why some people develop severe Lassa fever and a set of LARGE1 variants associated with a reduced chance of getting Lassa fever. The work could lay the groundwork for better treatments for Lassa fever and other similar illnesses. Scientists are already working on a similar genetic study on susceptibility to Ebola.
The document also describes the many challenges the team had to overcome during their 16-year collaborative effort, such as studying a dangerous virus and recruiting patients with a disease that is not well documented in West Africa. Dozens of scientists contributed to the work and spent seven years recruiting patients in Nigeria and Sierra Leone and many additional years establishing the research program and analyzing the results. “It really took a lot of work to achieve this,” said Happi, a co-senior author with Sabeti.
“Generations of people in our labs, across institutions and countries, have spent significant parts of their careers bringing this to fruition,” added Sabeti, a Broad Fellow, Howard Hughes Medical Institute Investigator, Professor in the Center for Systems Biology and the Department of Organismic and Evolutionary Biology at Harvard University, and professor in the Department of Immunology and Infectious Diseases at the Harvard TH Chan School of Public Health.
Study co-authors are Dylan Kotliar, an internal medicine resident at Brigham and Women’s Hospital and an MD/PhD student in Sabeti’s lab while the project was underway; Siddharth Raju, a graduate student in the Sabeti laboratory; Shervin Tabrizi, postdoctoral researcher at Broad; and Ikponmwosa Odia, researcher at Irua Specialist Teaching Hospital, Nigeria.
Sabeti recalls the team’s first discussions at the launch of the project. They knew they had to be cautious at every step: To work with a BSL-4 virus, scientists must wear pressurized 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 challenging study to get off the ground,” said Kotliar, who worked on the project throughout his PhD in the Sabeti lab. “I think the battle scars, the things we learned along the way about how to do a project like this, will be important for future virus research in developing countries.”
Finding participants for the study would also be a challenge. There are currently no FDA-approved diagnostics for Lassa, and Lassa virus cases are typically not documented. There are fewer than 1,000 cases 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 do not have the technology to detect the virus. Infections with other viruses and genomic complexity between different strains of the same Lassa virus can complicate analysis. Furthermore, African populations have historically been underrepresented in previous genetic studies, which reduces statistical power in data analyzes and can make it difficult to identify important genetic variants.
When Sabeti began thinking about how to start the project, he contacted Happi, whom he knew through mutual work on the pathogen that causes malaria, Plasmodium falciparum. With the help of collaborators including Peter Okokhere, a doctor who treats Lassa patients at Irua Specialized Teaching Hospital, they began recruiting patients from Nigeria and Sierra Leone. They then compared the genomes of about 500 people who had Lassa fever and almost 2,000 who didn’t.
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 contract Lassa fever. Sabeti, Happi and their colleagues also found genomic regions associated with Lassa’s fatality: in the LIF1 gene, which encodes an immune signaling molecule, and, in the Nigerian cohort, in the GRM7 gene, which is involved in the central nervous system. 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.
The researchers say that to improve the detection and treatment of Lassa fever, more diagnostic centers and diagnostic facilities that work in the field are needed, along with better health infrastructure to connect remote locations to main hospitals.
“This really highlights the need for continued investment in understanding the genetics of the African population,” Raju added. “Even with a relatively limited sample set, we have increased our understanding of some African populations, specifically in genes related to the immune system – and this shows how much there is still to do in the future.”
Sixteen years after they began thinking about the genetics of Lassa fever, Sabeti and Happi are excited about the study’s findings, which may explain the biological differences between mild and severe illnesses. They said the work also shows that with careful 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 greater pathogen surveillance and scientific training in Africa.
“We are at a point where we can really start to develop point diagnostics for Lassa virus and test much more broadly,” Happi said. “We need better infrastructure, but I think we have demonstrated that this type of study is worthwhile.”
This work was supported in part by the National Institutes of Health, the German Research Foundation, and the Howard Hughes Medical Institute.
Kotliar DK, Raju S, Tabrizi S, Odia I, et al. Genome-wide association study identifies human genetic variants associated with fatal outcome of Lassa fever. Microbiology of Nature. Online February 7, 2024. DOI: 10.1038/s41564-023-01589-3.
About the Broad Institute of MIT and Harvard
The Broad Institute of MIT and Harvard was launched in 2004 to empower this generation of creative scientists to transform medicine. The Broad Institute seeks to describe the molecular components of life and their connections; discover the molecular basis of major human diseases; develop new effective approaches to diagnosis and therapy; and disseminate discoveries, tools, methods and data openly to the entire scientific community.
Founded by MIT, Harvard, Harvard-affiliated hospitals, and visionary Los Angeles philanthropists Eli and Edythe L. Broad, the Broad Institute includes faculty, professionals, and students from across the biomedical research communities at MIT and Harvard and beyond, with collaborations that cover more than a hundred public and private institutions in more than 40 countries around the world.
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