Microbiome included Integrative Organ on-a-Chip
Another course-related work is presented here (I am not expert in this field, so, please read this as a blog post, not a scientific paper/project. If you are further interested in, I strongly recommend you to read main articles referred in the text.).
Abstract
COVID19 is a disease caused by a novel coronovirus. There has been different strategies developed to fight against the pandemic caused by COVID19. Several factors has been described including metabolic diseases, which increases the susceptibility. Most of these diseases have characteristics of disregulated microbioata. Recently the studies have been started to focus on inflammation and its metabolic effects caused by the infection. In fact, it is also known that microbiata and immune system work together to defend the host body. Furthermore front line fighters of immune system might be regulated by the cross-talk between intestine and lung microbiata. However, no such model described to study these interactions all together so far. In this project, scalable, easy to manipulate on-a-chip microfludic approach is descried to develop preventive/supportive strategies against COVID19 via manipulating the complex microbiota.
Background
COVID19
It is now also known as SARS-CoV-2 is a disease caused by family of coronovirus emerged at 2019, in Wuhan-live wild animal trading center, China. Although, zoonotic transmission host issue is still debatable (whether bat or pangolin or another species), human-to-human transmission is present. Therefore, it has spreaded rapidly among different countries across different continents despite all the precautions not/taken (Fig. 1a), and declared as pandemic by World Health Organization (WHO) at the last quarter of March, 2020[i]. The disease is characterized mainly by dry cough, fever, pneumonia[ii] [iii]. The report shared by WHO as of April 29 2020, showed that more than 3 million people around worldwide have been infected and more than 200.000 have died because of it[iv]. Co-morbidity of COVID19 deaths mainly are lung diseases, hypertension, cardiovascular diseases and diabetes[v] (Fig 1b).
Microbiota
The human body not only consist of human cells, but also 10 more times, trillion number of small other organisms called microbiota including many bacteria, fungi and virus species[viii] [ix]. The diversity of microbiome varies among individuals, different health conditions for same individual, and different regions in the body[x] (Fig. 2a and b).
Microbiota contributes the well being of an individual. The balance of the community is important to sustain a healthy lifestyle. Gut microbiome, mainly in intestine, is the major location of commensal bacteria. However, microbiome is located in lung and other tissues/organs as well. In fact, the imbalance or lack of the diversity of microbiome is linked to wide range of diseases including diabetes, inflammatory bowel disease, depression, obesity, hypertension, cardiovascular disease and even stroke[xi] [xii](Fig. 2c).
Not posted here due to copyright permissions…
Figure 2: The human body is made up of human cells and microbiome. a) In fact microbiome outnumbers the human cells.[xiii] b) Diversity of microbiome in th respiratory track depending on the conditions of the tissue (i.e. pH, temperature)[xiv]. c) Microbiome and cardiovascular diseases[xv].
Immune System
Immune system is the defense mechanism of the human body against internal or external pathogens. Commensal microbiata not only contributes the development of immune system postnatally but also promotes the regulation of immunity in later stages. Thus microbiota has a role in mediating immunity and inflammation[xvi] [xvii] (Fig. 2c).
COVID19 and Immune System
Viral pathogens activate the host defense. After passing the mechanical barrier (i.e. skin layers), innate immune system takes over the mission of fighting against the virus. Interferons are members of cytokine family which is part of anti-viral innate defense system. Although the role of Type I interferons against pathogens are complicated[xviii], these interferons are the ones which combats to viral pathogens in the front line[xix] [xx] [xxi] [xxii]. In fact, commensal microbiome in gut is known to calibrate the antiviral response and Type I interferons[xxiii] [xxiv], ACE2 -the receptor which the virus spike-in protein binds- expression is linked to Type I interferons[xxv] [xxvi], and Type I interferons regulate lung inflammation as well[xxvii].
Microfludics
Microfluidics is the field that investigates the fluid dynamics at macro scales. Although the behavior of the fluid in such small scale does not completely reflect the real life, it is still valid since ease of the controllability of the system (thanks to Reynold numbers) and providing smaller space to test the real-life experiments in smaller scales.
On-a-chip Models
To understand the relationship of microbiome-gut crosstalk requires effective models such as models in microfluidic systems. Recently researchers established a on-a-chip model for complex microbiome and intestine (Fig. 3a, b, c).
Not posted here because of copyright concerns…
Figure 3: On-a-chip models. a) Intestine b) complex microbiome and intestine on a-chip model c) different level of oxygen across different regions on the chip to maintain complex microbiome species d) lung organoid model. Image credit for a, b, and c: Nature Biomedical Engineering, 2019[xxviii]; d: Development Review, 2019[xxix].
Aim and Novelty
Current Intervention Strategies for COVID19
Current interventions are focused on either re-purposing of some of the available drugs in the market or developing novel drugs to inhibit virus replication, which have side effects, and entrance or vaccination strategies, which takes at least one year to develop or more recently filtration and injection of the plasma including neutralizing antibody against COVID19 of the recovered patients, which is not always applicable (Fig. 4).
Not posted here due to copyright concerns…
Figure 4: Potential intervention strategies against COVID19. Image courtesy: Nature Reviews Immunology, 2020 [xxx]
COVID19 and organoid models
Previously, researchers showed that microbiota driven interferon synthesis in lung protect against influenza virus[xxxi]. Although, there is current debate continues gut-lung crosstalk for COVID19[xxxii] [xxxiii], one of the recent papers suggested the idea of regulating gut microbiota as therapeutic option for COVID19 patients to improve the survival[xxxiv]. However, there is not enough evidence available neither to accept/reject this hypothesis nor how to implement microbiome to regulate this crosstalk, if any. Besides there is no such model to study intestine-lung microbiome crosstalk via secreted molecules and its effect on COVID19 to further develop therapeutic alternatives against COVID19. Therefore, our interactive intestine-lung on a chip with the complex microbiota will provide newer resolutions in this area.
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