Variants of APOE found in the germline that are common can contribute to various COVID-19 outcomes.


SARS-CoV-2 infection ranges from asymptomatic to deadly. Multiple epidemiological studies have linked male gender, old age, comorbidities, and genetics to COVID-19 outcomes. Why COVID-19 clinical outcomes vary widely in humans is unknown. Identifying the mechanisms underlying COVID-19 vulnerability is critical.

Scientists discovered a link between germline genetics and COVID-19 severity. Candidate gene methods and GWA research found multiple COVID-19 genomic locations. Their effects remain unknown.

APOE affects innate and adaptive immunity against pathogens and malignancies. It’s important for lipid metabolism. Nearly 40% of the global population possesses APOE2 or APOE4 allele, however only 3% are homozygous. It encouraged researchers to study how APOE allelic variations affect COVID-19 outcomes, including death risk.

This work used APOE knock-in mice with human APOE germline variants to examine whether APOE modulates SARS-CoV-2 in vivo. Human research were used to confirm their mouse findings. A mouse-adapted (MA) 10 strain of SARS-CoV-2 was used to infect 328 APOE knock-in mice. On day four post-infection, researchers performed quantitative real-time PCR on APOE knock-in mice lungs (pi).

The researchers also profiled the lungs of non-infected APOE knock-in mice on days 2 and 4 pi. WGCNA was used to identify clusters of highly correlated genes and compare their expression to genotype and timepoint during SARS-CoV-2 MA10 infection. The scientists sequenced 41,500 cells from 29 mice of all three genotypes with and without COVID-19.

Female mice outlived male mice of the same age. APOE4 animals died from COVID-19 compared to 30% of APOE3 mice, with male mice more severely affected. APOE2 and APOE4 mice had higher viral loads than APOE3. Histopathology on day 4 pi showed APOE4 mice had more severe lung damage. Downregulated modules in APOE2 and APOE4 animals on day 4 pi were enriched in T and B cell activation and positive immune response genes.

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Flow cytometry (FC) on dissociated lungs on day 4 pi corroborated an expansion of myeloid cells and relative depletion of lymphoid cells in APOE2 and APOE4 mice relative to APOE3 mice, showing that adaptive immune responses were attenuated in APOE2 and APOE4 mice during early COVID-19 development. scRNAseq showed myeloid cell growth in infected animals, which was more evident in APOE2 and APOE4 mice than APOE3 mice.

Previous GWA research couldn’t find a statistically significant link between COVID-19 and APOE. The current study used candidate gene analysis and reverse genetics to find two processes controlling APOE-genotype-dependent COVID-19 results in mice. These data revealed a link between APOE4 genotype and COVID-19 outcomes in humans.

APOE2 and APOE4 mice have decreased immunological responses to SARS-CoV-2. APOE4 mice demonstrated a divergent T cell antiviral response later in COVID-19, with enhanced SARS-CoV-2-specific CD8+ T cells. APOE2 mice displayed hyperactivated proinflammatory signalling, according to single-cell transcriptional profiling.

Only recombinant APOE3 suppressed SARS-CoV-2 in vitro, researchers noted. A recent study found that APOE4 mice had more SARS-CoV-2 infection than APOE3 mice. APOE3 allele represses SARS-CoV-2 infection more than APOE2 and APOE4.

Clinical consequences are huge. Prospective clinical trials should evaluate if APOE genotyping may be used to risk stratify SARS-CoV-2 so patients can benefit from early booster vaccines, antiviral medicines, and monoclonal antibody treatments. Since common genetic variants, like APOE genes, cause diverse COVID-19 outcomes, it’s important to investigate immunisation efficacy in different APOE genotypes.

APOE2 and APOE4 affect COVID-19 phenotypes differently. APOE4 is the strongest monogenetic Alzheimer’s risk factor. These factors may assist researchers comprehend COVID-19 and Alzheimer’s neurocognitive alterations. Studies should examine how APOE variations affect COVID-19 molecularly.


Journal reference:
  • Ostendorf, B. et al. (2022) “Common human genetic variants of APOE impact murine COVID-19 mortality”, Naturedoi10.1038/s41586-022-05344-2.

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