Team:WHU-China/Description
SARS-CoV-2 overwhelmed the world since the beginning of 2020, with our city Wuhan as the firstly-reported epicenter. With the rapid development of COVID-19 pandemic and ensuing destructive influences, our team members were deeply impressed by the heroic stories of medical staff and researchers battling the dangerous virus, and felt responsible for discovering hidden but life-threatening problems and harnessing synthetic biology approaches to address these challenges.
Through investigations, we deemed that nosocomial infections, or hospital-acquired infections (HAIs), were troublesome issues in the epidemic but usually ignored by the public. According to the definition in encyclopedia, nosocomial infections refer to infections during the stay in hospital, including those caused by technical measures of surgery, therapy, diagnosis and prophylaxis, such as IDVC, injection, transfusion, inhalation, and burn treatment. The advanced diagnostic methods have revealed the astonishing data of nosocomial infections, as a preprint manuscript showed the specimens collected from Renmin Hospital of Wuhan University between November 2018 and November 2019 [1]. Having consulted the researchers participating in the battles against coronavirus, we found that nosocomial infections in the epidemic were even more pervasive than usual, in a degree worsen by the attack of coronavirus, and multi-resistant gram-negative pathogen bacteria were quite considerable threats.
Ventilator was indeed a hot-spot word across the globe during the spread of this contagious pulmonary disease, for its capability to assist the patients to breathe. However, when medical staff struggling to cope with the surging positive cases, the massive use of ventilators might lead to unexpected troubles. Ventilator-Associated Pneumonia (VAP) is a severe health problem among immunocompromised patients caused by inhaling pathogen bacteria during ventilation, which subsequently contribute to high-density biofilm formation in respiratory tract and even lead to death [2]. Although noninvasive mechanical ventilation could to a degree prevent VAP, the mass use of invasive ventilators was inevitable, resulted from high requirements of air pressure in numerous cases. Given broad and massive applications, VAP included a large proportion of nosocomial infections in the COVID-19 pandemic, and we aimed to solve this problem.
Current interests towards the effects of probiotics on human respiratory tract and their interactions with immune systems are increasing, and therapies of intaking probiotics, such as Lactobacillus spp., Bifidobacterium spp., Bacteroides spp. and Escherichia coli Nissle 1917, by nasal or oral approaches to protect the hosts from respiratory infections are proven effective in animal models [3]. The relevant mechanisms remained largely unelucidated, while several researchers guessed that probiotics secreted chemicals to stimulate and activate the immune systems. Interestingly, probiotics are considered as next-generation chassis in biomedical fields and have been engineered to facilitate emerging therapies, on the basis of their original beneficial functions [4]. Synlogic, the leading enterprise renowned for synthetic biotic medicines, has already promoted engineered probiotic therapies in clinical trials to address metabolic diseases, inflammations and tumors [5]. Besides reinforcing immune systems, engineered probiotics were also harnessed to directly solve pathogen infections in animal models [6].
It is known that many gram-negative pathogen bacteria coordinate their virulence behaviors in a cell density-dependent manner known as Quorum Sensing (QS). In this communication process, pathogen bacteria exchange autoinducers (AIs) to regulate the expression of virulence genes [7]. When the concentration of AIs increases, the pathogen bacteria will express virulence synchronously, such as forming biofilms and secreting toxins. The interaction between pathogen bacteria and hosts is considered an arms race, with self-evolving strategies implemented respectively (e.g. biofilm formation for bacteria, and pathogen-killing immune cells recruitment for hosts) [8]. We can imagine immune cells as police squads, pathogen bacteria as criminals and autoinducers as communication tools, and in most cases the immune system of a healthy individual will eradicate the intruders. However, considering those immunocompromised patients that have suffered from the coronavirus, the balance is broken due to their impaired immune system, and criminals might easily dominate the battleground with the help of their quorum sensing systems.
Thus, we came up with an idea: how about creating negotiators (engineered probiotics) to parley with criminals (pathogen bacteria) while give instructions secretly to police squads (immune cells)? The idea later turned into an iGEM project, which our team named "The Negotiator" to salute a classic gangster movie released in 1998.
1. Wang M, Fu A et al., Same-Day Simultaneous Diagnosis of Bacterial and Fungal Infections in Clinical Practice by Nanopore Targeted Sequencing, medRxiv 2020.04.08.20057604.
2. Povoa H et al., COVID-19: An Alert to Ventilator-Associated Bacterial Pneumonia. Infectious Diseases and Therapy, 9 (2020): 417-420.
3. Wypych TP, Wickramasinghe LC, Marsland BJ, The influence of the microbiome on respiratory health. Nature Reviews Immunology, 20 (2019): 1279-1290.
4. Bober JR, Beisei CL, Nair NU, Synthetic biology approaches to engineer probiotics and members of the human microbiota for biomedical applications. Annual Review of Biomedical Engineering, 20 (2018): 277–300.
5. Synlogic, https://www.synlogictx.com/.
6. Hwang IY et al., Engineered probiotic Escherichia coli can eliminate and prevent Pseudomonas aeruginosa gut infection in animal models. Nature Communications, 8 (2017).
7. Lee J and Zhang L, The hierarchy quorum sensing network in Pseudomonas aeruginosa. Protein Cell, 6 (2015): 26-41.
8. Moura-Alves et al., Host monitoring of quorum sensing during Pseudomonas aeruginosa infection. Science, 366 (2019).
