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1.
EMBO Rep ; 25(3): 951-970, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38287192

RESUMO

The exquisite specificity of antibodies can be harnessed to effect targeted degradation of membrane proteins. Here, we demonstrate targeted protein removal utilising a protein degradation domain derived from the endogenous human protein Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9). Recombinant antibodies genetically fused to this domain drive the degradation of membrane proteins that undergo constitutive internalisation and recycling, including the transferrin receptor and the human cytomegalovirus latency-associated protein US28. We term this approach PACTAC (PCSK9-Antibody Clearance-Targeting Chimeras).


Assuntos
Pró-Proteína Convertase 9 , Serina Endopeptidases , Humanos , Pró-Proteína Convertase 9/metabolismo , Pró-Proteína Convertases/metabolismo , Proteínas de Membrana , Receptores de LDL/metabolismo
2.
J Infect Dis ; 227(4): 543-553, 2023 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-36408607

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has caused widespread morbidity and mortality since its onset in late 2019. Here, we demonstrate that prior infection with human cytomegalovirus (HCMV) substantially increases infection with SARS-CoV-2 in vitro. HCMV is a common herpesvirus carried by 40%-100% of the population, which can reactivate in the lung under inflammatory conditions, such as those resulting from SARS-CoV-2 infection. We show in both endothelial and epithelial cell types that HCMV infection upregulates ACE2, the SARS-CoV-2 cell entry receptor. These observations suggest that HCMV reactivation events in the lung of healthy HCMV carriers could exacerbate SARS-CoV-2 infection and subsequent COVID-19 symptoms. This effect could contribute to the disparity of disease severity seen in ethnic minorities and those with lower socioeconomic status, due to their higher CMV seroprevalence. Our results warrant further clinical investigation as to whether HCMV infection influences the pathogenesis of SARS-CoV-2.


Assuntos
COVID-19 , Infecções por Citomegalovirus , Superinfecção , Humanos , SARS-CoV-2/metabolismo , Enzima de Conversão de Angiotensina 2 , Estudos Soroepidemiológicos , Peptidil Dipeptidase A , Células Epiteliais/metabolismo
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