Modeling COVID-19 with Human Pluripotent Stem Cell-Derived Cells Reveals Synergistic Effects of Anti-inflammatory Macrophages with ACE2 Inhibition Against SARS-CoV-2

Abstract

Dysfunctional immune responses contribute critically to the progression of Coronavirus Disease-2019 (COVID-19) from mild to severe stages including fatality, with pro-inflammatory macrophages as one of the main mediators of lung hyper-inflammation. Therefore, there is an urgent need to better understand the interactions among SARS-CoV-2 permissive cells, macrophage, and the SARS-CoV-2 virus, thereby offering important insights into new therapeutic strategies. Here, we used directed differentiation of human pluripotent stem cells (hPSCs) to establish a lung and macrophage co-culture system and model the host-pathogen interaction and immune response caused by SARS-CoV-2 infection. Among the hPSC-derived lung cells, alveolar type II and ciliated cells are the major cell populations expressing the viral receptor ACE2 and co-effector TMPRSS2, and both were highly permissive to viral infection. We found that alternatively polarized macrophages (M2) and classically polarized macrophages (M1) had similar inhibitory effects on SARS-CoV-2 infection. However, only M1 macrophages significantly up-regulated inflammatory factors including IL-6 and IL-18, inhibiting growth and enhancing apoptosis of lung cells. Inhibiting viral entry into target cells using an ACE2 blocking antibody enhanced the activity of M2 macrophages, resulting in nearly complete clearance of virus and protection of lung cells. These results suggest a potential therapeutic strategy, in that by blocking viral entrance to target cells while boosting anti-inflammatory action of macrophages at an early stage of infection, M2 macrophages can eliminate SARS-CoV-2, while sparing lung cells and suppressing the dysfunctional hyper-inflammatory response mediated by M1 macrophages.

Induction of exaggerated cytokine production in human peripheral blood mononuclear cells by a recombinant SARS-CoV-2 spike glycoprotein S1 and its inhibition by dexamethasone

“…Interestingly, flow cytometry measurements of the human peripheral blood-derived immune cells revealed little or no expression of ACE2, while high expressions were reported in human tissue macrophages, such as alveolar macrophages, liver Kupffer cells, and brain microglia [45]. Other studies have reported expression of ACE2 in alveolar macrophages and human monocyte THP-1 cells [46]. Studies to further determine the roles of ACE2 in spike glycoprotein S1-induced inflammation are therefore needed.…”

Kobophenol A Inhibits Binding of Host ACE2 Receptor with Spike RBD Domain of SARS-CoV-2, a Lead Compound for Blocking COVID-19

“… 42 Caragana extract along with Kobophenol A is also used for chronic bronchitis in the form of a daily decoction, without any toxicity. 43 SARS-CoV-2 can trigger an excessive immune response known as cytokine storm, which can lead to multiple organ failure and death because of the inflammation 44 of the organs. The additional anti-inflammatory, bronchodilator, cardioprotective, and antioxidant activities of Kobophenol A can be an additive health benefit for COVID-19 patients and may potentially help to reduce mortality in COVID-19 patients.…”

Developing Cytokine Storm-Sensitive Therapeutic Strategy in COVID-19 Using 8P9R Chimeric Peptide and Soluble ACE2

“…Protective phase in which immune responses especially adaptive immune responses have important roles in elimination of the virus at early stages of the disease. Damaging phase in which immune responses can also cause tissue damage via release of pro-inflammatory cytokines at severe stages (Duan et al, 2020). In severe conditions, excessive and uncontrolled production of pro-inflammatory cytokines including IL-6, IL-1, and TNF-α results in convergence of immune cells and leads to systemic inflammatory response, known as cytokine storm.…”