Team:CPU CHINA/Description
Description and Inspiration
How and why we chose our iGEM project
The source of inspiration often comes from life, the same is true for ours. The original idea of our program came from a public health emergency, tuberculosis, happened in a school campus. Jiatong Chen, a member of our team, known from a normal chat that the high school where his father works was closed for a few days because of a sudden outbreak of tuberculosis. Although the epidemic was still quickly contained, only several students and a math teacher were infected with this disease. He was shocked that tuberculosis, which is one of the top ten causes of humankind death in the world, would come out next to him. Soon after, the incident that many children at an early education center in Nanjing were infected with tuberculosis also illustrates that tuberculosis was not far from us. Through further research we realized that despite the scope of the disease, treatment remains intensive and long-term with multi- and extensively-drug resistant TB strains a growing problem, hence there is a continuing urgent need for novel improved anti-TB therapeutics. So we reached an agreement to choose tuberculosis treatment as our iGEM project.
How we selected our project goals
The staff of Centers for Disease Control and Prevention mentioned that the patients are likely to stop taking the medicine without authorization, which easily causes tuberculosis relapse. So, we searched the publications. The initial step against pathogen when the body senses it was our first aim to know about, we learnt that innate immunity can provide with first aid when a certain type of chemical compound from bacteria was detected, hence the Toll like receptors (TLRs) came into our sight. Meanwhile we sought out that the obstinacy of treatment of tuberculosis is that Mycobacterium tuberculosis (Mtb) can survive inside the macrophages, which reminded us of the exhausted T cells in tumor microenvironment——the function of whom are suppressed. Now that CAR-T has become a rising star in reversion of exhausted T cells, we wondered if it is feasible to introduce cell therapy into tuberculosis. But TLRs don’t exists in all cell types, yet the specificity isn’t as high as that of T cells, we therefore searched for the downstream pathways following the activation of TLRs, as well as the mechanisms of survival of Mtb in macrophages, looking for a possible method of modifying normal cells without TLRs, for further probability of extensive producing at a lower cost. Having constructed the rough framework, the specificity of targeting blocked us for a while, finally we hammering out the scheme that using exosomes as the vector for delivering miRNA into infected macrophages, based on the alternation caused by Mtb in cells and the difference between normal and infected macrophages we concluded from a series of research articles-and eventually came up with an idea that if a cell-based therapy is applied, it can continuously damage Mtb and avoid its relapse due to long life cycle of cells.
Later in the hospital, we learned that drug resistance of tuberculosis is increasing year by year, since first-line drugs have been used for decades. Therefore, we put forward the idea of eliminating Mtb by activating human innate immunity in order to avoid the drug resistance issue in traditional therapy. For more details, please visit here!
How we will achieve our goals
We constructed a novel "immune-like cell", which possesses a Mtb sensor and can secrete anti-Mtb substances. Toll like receptor (TLR) 1/2 and CD14 are expressed on the membrane of designer cells to recognize Mtb. In another words, the TLR1/TLR2/CD14 cluster work as a Mtb sensor. After being stimulated, the "immune-like cell" can eliminate extracellular and intracellular Mtb separately by releasing granulysin and delivering miRNA containing exosomes into Mtb-infected macrophages. For more details, please visit here!
Why we thought our project was a useful application of synthetic biology
Mentioned above, we are committed to provide new ideas for the treatment (or adjuvant treatment) of tuberculosis according to the principle of synthetic biology. This is an unprecedented attempt, and we expect it would help more TB patients. In the future, by replacing TLRs and downstream effectors, our "immune-like cells" could target different pathogens. Thereby serving as a novel infectious disease treatment application in the post-antibiotic era.