Distinct uptake, amplification, and release of SARS-CoV-2 by M1 and M2 alveolar macrophages

AbstractSevere 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.

Download Full-text

SARS-CoV-2 treatment effects induced by ACE2-expressing microparticles are explained by the oxidized cholesterol-increased endosomal pH of alveolar macrophages

Cellular and Molecular Immunology ◽

10.1038/s41423-021-00813-6 ◽

2022 ◽

Author(s):

Zhenfeng Wang ◽

Jiadi Lv ◽

Pin Yu ◽

Yajin Qu ◽

Yabo Zhou ◽

...

Keyword(s):

Alveolar Macrophages ◽

Ph Regulation ◽

Proton Pumps ◽

Lysosomal Ph ◽

Oxidized Cholesterol ◽

Endosomal Acidification ◽

Endosomal Membranes ◽

Endosomal Ph ◽

Advanced Biomaterials ◽

Potential Use

AbstractExploring 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.

Download Full-text

A bispecific monomeric nanobody induces spike trimer dimers and neutralizes SARS-CoV-2 in vivo

Nature Communications ◽

10.1038/s41467-021-27610-z ◽

2022 ◽

Vol 13 (1) ◽

Author(s):

Leo Hanke ◽

Hrishikesh Das ◽

Daniel J. Sheward ◽

Laura Perez Vidakovics ◽

Egon Urgard ◽

...

Keyword(s):

Severe Acute Respiratory Syndrome ◽

Mouse Model ◽

Therapeutic Potential ◽

Cell Receptor ◽

Transgenic Mouse Model ◽

Viral Antigens ◽

Host Cell Receptor ◽

Virus Escape ◽

Therapeutic Molecules

AbstractAntibodies binding to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike have therapeutic promise, but emerging variants show the potential for virus escape. This emphasizes the need for therapeutic molecules with distinct and novel neutralization mechanisms. Here we describe the isolation of a nanobody that interacts simultaneously with two RBDs from different spike trimers of SARS-CoV-2, rapidly inducing the formation of spike trimer–dimers leading to the loss of their ability to attach to the host cell receptor, ACE2. We show that this nanobody potently neutralizes SARS-CoV-2, including the beta and delta variants, and cross-neutralizes SARS-CoV. Furthermore, we demonstrate the therapeutic potential of the nanobody against SARS-CoV-2 and the beta variant in a human ACE2 transgenic mouse model. This naturally elicited bispecific monomeric nanobody establishes an uncommon strategy for potent inactivation of viral antigens and represents a promising antiviral against emerging SARS-CoV-2 variants.

Download Full-text

A bispecific monomeric nanobody induces SARS-COV-2 spike trimer dimers

10.1101/2021.03.20.436243 ◽

2021 ◽

Author(s):

Leo Hanke ◽

Hrishikesh Das ◽

Daniel Sheward ◽

Laura Perez Vidakovics ◽

Egon Urgard ◽

...

Keyword(s):

Severe Acute Respiratory Syndrome ◽

Mouse Model ◽

Transgenic Mouse ◽

Therapeutic Potential ◽

Transgenic Mouse Model ◽

Electron Cryomicroscopy ◽

Viral Antigens ◽

Virus Escape ◽

Therapeutic Molecules ◽

Novel Strategy

Antibodies binding to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike have therapeutic promise, but emerging variants show the potential for virus escape. Thus, there is a need for therapeutic molecules with distinct and novel neutralization mechanisms. Here we isolated a nanobody that potently neutralizes SARS-CoV-2, including the B.1.351 variant, and cross-neutralizes SARS-CoV. We demonstrate the therapeutic potential of the nanobody in a human ACE2 transgenic mouse model. Using biochemistry and electron cryomicroscopy we show that this nanobody simultaneously interacts with two RBDs from different spike trimers, rapidly inducing the formation of spike trimer-dimers. This naturally elicited bispecific monomeric nanobody establishes a novel strategy for potent immobilization of viral antigens.

Download Full-text