A paper in Nature microbiology in February 2024 presents the results of investigations into whether human genetic variation “underlies the heterogeneity” of Lassa fever, caused by infection with Lassa virus. Among the techniques used, the researchers carried out genome-wide association studies (GWAS) to demonstrate how GWAS can “provide insight into viral pathogenesis”. They were able to identify variants and genes that may influence the risk of severe Lassa fever.
Lassa: a substantial threat
WHO describes Lassa fever as an “acute viral haemorrhagic” illness that can result from infection with Lassa virus (LASV), initially causing fever symptoms and sometimes progressing quickly to respiratory distress, mucosal bleeding, shock, and multiorgan failure. Although “about 80% of people” who become infected with LASV present no symptoms, 1 in 5 infections results in “severe disease”.
The authors suggest that overall case fatality rates (CFRs) can be as high as 29.7% in laboratory-confirmed patients and over 50% in foetuses.
“This lethality, coupled with the aerosol-based route of exposure and lack of approved therapeutics or vaccines, means that LASV is a World Health Organisation risk group 4 pathogen, biosafety level 4 (BSL-4) agent, and substantial threat to public health.”
The virus is “ubiquitous” in “many regions of West Africa”. The main host and reservoir of LASV is the Mastomys natalensis, a rodent that lives “near houses in rural villages”. Transmission to humans occurs through “aerosolization of viral particles” from rodent excrement. Person-to-person transmission “usually only” occurs in nosocomial settings, but the prevalence and transmissibility of LASV lead to an estimated 100,000-300,000 infections annually.
Variability
Despite high prevalence, “only hundreds to thousands” of cases of Lassa fever are diagnosed each year, which implies that most infections are undocumented and mild. It is not clear why severe disease and death only occurs in some infections. While old age and pregnancy are associated with “poor” outcomes, they do not explain all the variability in infection outcome, and variability in LASV lineages “has not been linked to severity of symptoms”.
The authors propose that human genetic variation may contribute to outcome variability for LASV infection, reflecting that host genetics has been linked to symptoms caused by infection with SARS-CoV-2, HIV, and dengue, among others.
“The link between host genetics and LASV infection is intriguing because LASV may have been an important selective force in endemic regions, driving variants that protect against Lassa fever to higher prevalence.”
Indeed, previous research identified a signal of positive selection in a Yoruba population in Nigeria, who live in a LASV endemic region at a locus overlapping the gene LARGE1. LARGE1 “encodes a protein that glycosylates α-dystroglycan, the primary cellular receptor for LASV.
“Given Lassa fever’s lethality among diagnosed cases and the high seroprevalence to LASV, it is plausible that host variants providing resistance might have an impact on reproductive fitness.”
Furthermore, phylogenetic dating suggests that LASV has been in Nigeria for over 1,000, which allows for the possibility that the virus has “exerted evolutionary pressure” on humans. However, no previous studies have systematically assessed the relation between host variation and LASV infection.
There are “practical obstacles” to studying Lassa fever in humans that the authors identify:
- LASV is a BSL-4 pathogen endemic in countries that have only recently obtained infrastructure for safe virus handling.
- Medical infrastructure is lacking in the villages where Lassa fever is most common, so most symptomatic cases are undocumented.
- Genetic diversity of LASV isolates means that diagnostics based on nucleic acid amplification or immunoassays can have low sensitivity. Without FDA-approved LASV diagnostics, proven diagnoses require viral culture, which is generally unfeasible.
The team behind the paper “anticipated that it would be challenging to obtain a sizeable enough cohort” for a Lassa fever genome-wide association study (GWAS) but considered that “increased power would arise if natural selection for resistance to Lassa fever was present”.
Preparations began in 2008, establishing public health and research capabilities for Lassa fever in Nigeria and Sierra Leone. Patients with Lassa fever were recruited and genotyped and matched with individuals who do not have LASV symptoms during a 7-year period from LASV endemic regions. Genome-wide association with Lassa fever susceptibility and fatal outcomes was tested, with sub-analyses to specifically consider variation at LARGE1 and human leukocyte antigen (HLA) loci.
GWAS for a group 4 pathogen
The “first GWAS of infection with a risk group 4 pathogen reported to date” was conducted over 10 years. It found that an intronic variant within GRM7 and a variant downstream of LIF are “significantly associated” with Lassa fever in the Nigeria cohorts and meta-analysis of the two cohorts respectively and identified candidate variants that approach, but do not reach, genome-wide significance in susceptibility analyses.
LIF encodes an interleukin 6 family cytokine that “could impact Lassa fever severity”. GRM7 “may function in viral entry akin to GRM2 in in coronavirus disease 2019” or “could be involved in immune activation”. Furthermore, GRM7 is involved in maintenance of hearing by inner-ear hair cells, and hearing loss is a “notable symptom” of Lassa fever.
The team also used their data to examine the hypothesis that positive selection for genetic variation at the LARGE1 locus provides protection, finding that a haplotype with long-range LD, indicative of recent positive selection, is “nominally associated with reduced likelihood” of Lassa fever in the Nigeria cohort but not in the Sierra Leone cohort.
“Larger cohorts and deeper phenotypic characterisation will be required to evaluate the hypothesis of LARGE1 mediated genetic resistance to Lassa fever susceptibility.”
Recognising the limitations of their study, the authors call for “continuing efforts” to improve understanding of genetic variation in African populations to provide more insight into the potential links between genetics and disease.
“Our work paves the way for follow-up studies on Lassa fever and other group 4 microbial pathogens and has contributed to an improved genetic data resource for African populations.”
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