Asunto(s)
Animales de Laboratorio/genética , Modelos Animales de Enfermedad , Ingeniería Genética , Laboratorios/organización & administración , Ratones Transgénicos/genética , Animales , COVID-19/epidemiología , COVID-19/genética , COVID-19/virología , Dieta Alta en Grasa/efectos adversos , Corazón/fisiología , Humanos , Maine/epidemiología , Ratones , SARS-CoV-2/genética , SARS-CoV-2/patogenicidad , SARS-CoV-2/fisiologíaRESUMEN
Clinical outcomes of severe acute respiratory syndrome 2 (SARS-CoV-2) infection are highly heterogeneous, ranging from asymptomatic infection to lethal coronavirus disease 2019 (COVID-19). The factors underlying this heterogeneity remain insufficiently understood. Genetic association studies have suggested that genetic variants contribute to the heterogeneity of COVID-19 outcomes, but the underlying potential causal mechanisms are insufficiently understood. Here we show that common variants of the apolipoprotein E (APOE) gene, homozygous in approximately 3% of the world's population1 and associated with Alzheimer's disease, atherosclerosis and anti-tumour immunity2-5, affect COVID-19 outcome in a mouse model that recapitulates increased susceptibility conferred by male sex and advanced age. Mice bearing the APOE2 or APOE4 variant exhibited rapid disease progression and poor survival outcomes relative to mice bearing the most prevalent APOE3 allele. APOE2 and APOE4 mice exhibited increased viral loads as well as suppressed adaptive immune responses early after infection. In vitro assays demonstrated increased infection in the presence of APOE2 and APOE4 relative to APOE3, indicating that differential outcomes are mediated by differential effects of APOE variants on both viral infection and antiviral immunity. Consistent with these in vivo findings in mice, our results also show that APOE genotype is associated with survival in patients infected with SARS-CoV-2 in the UK Biobank (candidate variant analysis, P = 2.6 × 10-7). Our findings suggest APOE genotype to partially explain the heterogeneity of COVID-19 outcomes and warrant prospective studies to assess APOE genotyping as a means of identifying patients at high risk for adverse outcomes.
Asunto(s)
Apolipoproteínas E , COVID-19 , Genética Humana , Ratones Transgénicos , SARS-CoV-2 , Animales , Humanos , Masculino , Ratones , Apolipoproteína E2/genética , Apolipoproteína E3/genética , Apolipoproteína E4/genética , Apolipoproteínas E/genética , COVID-19/genética , COVID-19/mortalidad , COVID-19/virología , Ratones Transgénicos/genética , Ratones Transgénicos/virología , Estudios Prospectivos , SARS-CoV-2/patogenicidad , Modelos Animales de EnfermedadRESUMEN
COVID-19 has spread worldwide since 2019 and is now a severe threat to public health. We previously identified the causative agent as a novel SARS-related coronavirus (SARS-CoV-2) that uses human angiotensin-converting enzyme 2 (hACE2) as the entry receptor. Here, we successfully developed a SARS-CoV-2 hACE2 transgenic mouse (HFH4-hACE2 in C3B6 mice) infection model. The infected mice generated typical interstitial pneumonia and pathology that were similar to those of COVID-19 patients. Viral quantification revealed the lungs as the major site of infection, although viral RNA could also be found in the eye, heart, and brain in some mice. Virus identical to SARS-CoV-2 in full-genome sequences was isolated from the infected lung and brain tissues. Last, we showed that pre-exposure to SARS-CoV-2 could protect mice from severe pneumonia. Our results show that the hACE2 mouse would be a valuable tool for testing potential vaccines and therapeutics.