Team:SMMU-China/Human Practices

At the very first stage of our project, we visited professor Chaofeng Han, an innate immunologist, to get a clear and thorough grasp of the infection mechanism of SARS-CoV-2. He highlighted that SARA-CoV-2 is not a ferocious virus but actually a mild one. It invades the body in a dormant and a mitigatory way. At the beginning of the infection, SARS-CoV-2 can not only suppress the innate immune response by inhibition of interferon Ⅰ mediated inflammatory cells recruitment, but it can also escape the murder of acquired immune cells by lowering the expression of surface antigen. And the virus can consequently get mass propagation in alveolar epithelia cells without the worry of being destructed by the immune response. Finally, when the quantity of SARS-CoV-2 reaches a certain level, a grand number of alveolar epithelial cells will phagocyte and a large number of virus will be released into the internal environment, inducing the irreversible inflammatory cascades. Such a sudden attack to the body will not leave the reaction time to our body and some significant viscera will be damaged because of systemic inflammatory reaction syndrome, including the lungs and the kidney.

We also revealed the intention of inventing a new treatment against SARS-CoV-2 by reducing the inflammatory side effects, he then warned us we should be very careful about the drug administration time, as the introduction above, SARS-CoV-2 can mediate some immune escape by also reducing the inflammatory reaction of innate immune response. He reminded us our reducing inflammatory drugs can be theoretically employed in the late stage of severe cases.

After designing our project under the principal of reducing inflammatory reaction in severe cases of SARS-CoV-2, we finally determined the CAR-MERTK macrophages as our main force. This time, we interviewed professor Chaofeng Han for the second time with the expectation of some advice from him. When we introduce our CAR-MERTK macrophages to him, he paid much attention to the extracellular part of our CAR. He noticed that our extracellular of the CAR is an scFv derived from an antibody recognizing SARS-CoV-2 spike protein and thus our CAR-MERTK macrophages can only theoretically targeted to the virus. He then warns us that the inflammation reaction is not only initialed by the virus, but also by the cell debris of the apoptotic alveolar epithelial cells. He suggested that we should pay more attention to the cell debris mediated pathway of inflammation activation of SARS-CoV-2.

The second time we visited professor Chaofeng Han, he reminded us to be vigilant of cell debris mediated inflammatory reaction of SARS-CoV-2. After researching related articles, we discovered that the macrophages itself have a strong capability to phagocytosis the alveolar epithelial cells debris, its actually the innate ability of macrophages and so do our CAR-MERTK macrophages. What’s more, the dissociative S protein in the extracellular fluid can actually mediated the phagocytosis of CAR-MERTK macrophages. There is a highly repetitive carboxyl sequences in the amino terminal of S protein and the carboxyl can bind with the exposed Phosphatidylserine in the alveolar epithelial cell debris, acting as a bridge between alveolar epithelial cells debris and CAR-MERTK macrophages. And the inflammatory reaction mediated by the alveolar epithelial cell debris can also be reduced.

We introduced this mechanism to professor Chaofeng Han, he agreed that there is indeed a possibility like that, but he also reminded us the practical anti-inflammatory efficiency of the CAR-MERTK macrophages is what really matters.

At the beginning of our project, we interviewed the head of infection division doctor Chengzhong Li, for the expectation of some present treatment methods of SARS-CoV-2. He mentioned that the present treatment methods can be divided into two parts: the antiviral medicine for etiological treatment and anticoagulant treatment and hemotherapy for the symptomatic treatment. As for the severe cases, the effective treatment is currently lacking and supportive treatment occupied in the main position. He also mentioned some highly anticipated recovered patient’s serum treatment, but it was abandoned by scientist after the clinical trial. The reason why the therapeutic effect of recovered patient’s serum treatment is unsatisfactory is that the inflammatory cascades is initiated before any treatment and the further phagocytosis of SARS-CoV-2 through the antibody mediated pathway is useless. We then introduced our idea of the inhibition of inflammatory cascades by CAR-MERTK macrophages to him, he told us our project can work in some extent theoretically, which firms the determination of finishing our project.