ABSTRACT
Exploring the cross-talk between the immune system and advanced biomaterials to treat SARS-CoV-2 infection is a promising strategy. Here, we show that ACE2-overexpressing A549 cell-derived microparticles (AO-MPs) are a potential therapeutic agent against SARS-CoV-2 infection. Intranasally administered AO-MPs dexterously navigate the anatomical and biological features of the lungs to enter the alveoli and are taken up by alveolar macrophages (AMs). Then, AO-MPs increase the endosomal pH but decrease the lysosomal pH in AMs, thus escorting bound SARS-CoV-2 from phago-endosomes to lysosomes for degradation. This pH regulation is attributable to oxidized cholesterol, which is enriched in AO-MPs and translocated to endosomal membranes, thus interfering with proton pumps and impairing endosomal acidification. In addition to promoting viral degradation, AO-MPs also inhibit the proinflammatory phenotype of AMs, leading to increased treatment efficacy in a SARS-CoV-2-infected mouse model without side effects. These findings highlight the potential use of AO-MPs to treat SARS-CoV-2-infected patients and showcase the feasibility of MP therapies for combatting emerging respiratory viruses in the future.
Subject(s)
Angiotensin-Converting Enzyme 2/administration & dosage , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , COVID-19/therapy , Cell- and Tissue-Based Therapy/methods , Cell-Derived Microparticles/metabolism , Cholesterol/metabolism , Endosomes/chemistry , Macrophages, Alveolar/metabolism , SARS-CoV-2/metabolism , A549 Cells , Angiotensin-Converting Enzyme 2/genetics , Animals , COVID-19/virology , Chlorocebus aethiops , Disease Models, Animal , Female , Humans , Hydrogen-Ion Concentration , Lysosomes/chemistry , Mice , Mice, Inbred ICR , Mice, Transgenic , Oxidation-Reduction , RAW 264.7 Cells , Treatment Outcome , Vero CellsSubject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/enzymology , Lung/enzymology , Receptors, Aryl Hydrocarbon/metabolism , SARS-CoV-2/pathogenicity , Angiotensin-Converting Enzyme 2/genetics , Animals , Basic Helix-Loop-Helix Transcription Factors , Binding Sites , COVID-19/genetics , COVID-19/virology , Cell Line , Disease Models, Animal , Host-Pathogen Interactions , Humans , Lung/virology , Macaca , Mice , Promoter Regions, Genetic , Receptors, Aryl Hydrocarbon/geneticsABSTRACT
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) invades the alveoli, where abundant alveolar macrophages (AMs) reside. How AMs respond to SARS-CoV-2 invasion remains elusive. Here, we show that classically activated M1 AMs facilitate viral spread; however, alternatively activated M2 AMs limit the spread. M1 AMs utilize cellular softness to efficiently take up SARS-CoV-2. Subsequently, the invaded viruses take over the endo-lysosomal system to escape. M1 AMs have a lower endosomal pH, favoring membrane fusion and allowing the entry of viral RNA from the endosomes into the cytoplasm, where the virus achieves replication and is packaged to be released. In contrast, M2 AMs have a higher endosomal pH but a lower lysosomal pH, thus delivering the virus to lysosomes for degradation. In hACE2 transgenic mouse model, M1 AMs are found to facilitate SARS-CoV-2 infection of the lungs. These findings provide insights into the complex roles of AMs during SARS-CoV-2 infection, along with potential therapeutic targets.