SARS-CoV-2 Alters Lung Cell Metabolism – IIT Kharagpur Research Model Shows, Model Could Help Therapeutics

  • Model development by IIT Kharagpur researchers predicting alteration in metabolic reaction rates of lung cells post SARS-CoV-2 infection

  • The research would lead to a better understanding of metabolic reprogramming and aid the development of better therapeutics to deal with the viral pandemics

COVID-19 pandemic has been posing unprecedented threats to the whole world. Among its many perils is the cellular metabolic system of those who tested positive. Coronaviruses are known to hijack the metabolism of lung cells. This threat makes it absolutely imperative to understand the mechanism of metabolic reprogramming of host human cells by SARS-CoV-2.

Researchers at IIT Kharagpur have, for the first time, have reported a method to find an alteration in metabolic reaction rates inside lung cells when they are affected by virus/pathogens. As the method finds and reports critical aspects of physiology, which are affected by SARS-CoV-2 infection, it will enable the discovery of therapeutic targets.

“We have used the gene expression of normal human bronchial epithelial cells (NHBE) infected with SARS-CoV-2 along with the macromolecular make-up of the virus to create this integrated genome-scale metabolic model. The growth rate predicted by the model showed a very high agreement with experimentally and clinically reported effects of SARS-CoV-2,” said Dr. Amit Ghosh, Assistant Professor, School of Energy Science & Engineering, IIT Kharagpur.

Scientists have been trying to extract information from the human genome sequences for the past two decades to gather a better understanding of genetic disorders thus allowing us to penetrate deeper into the fabric of life and enable better therapeutics.

Talking about this new development researcher Piyush Nanda (B.Tech.-M.Tech Dual Degree, Biotechnology, 2020, currently a graduate student at Harvard University) explained, “In this model development, we have explored how metabolism works and how it is altered in diseases. Our work involved measuring how the tens of thousands or more complex chemical reactions change when biological cells are intruded on by an uninvited guest like SARS-CoV-2, which would help improve our understanding of diseases.” 

Using the power of genomics the researchers posed the operation of reactions as a set of mathematical equations and solved it to obtain which reactions are altered in the cells when SARS-CoV-2 infects a person.

“A better understanding of metabolic reprogramming would aid in the design of better therapeutics to deal with the COVID-19 pandemic,” remarked Piyush.

Further, the researchers have identified pathways like fatty acid synthesis and lipid metabolism that can be targeted by novel drugs. This model is based on genome-scale differential flux analysis (GS-DFA) in context-specific metabolic models.

“Analysis of the rates of all intercellular metabolic reactions in disease biology is opening up new avenues for therapeutic interventions. Numerous diseases lead to metabolic pathway alterations and it is becoming increasingly important to be able to quantify the difference under normal and diseased conditions. Using our method we have observed the alterations between diseased and normal metabolic states in the case of SARS-CoV-2 infection which have been proven using human patients data. The model will allow researchers to understand the wide spectrum of viruses that manipulate human metabolism and will help to design better therapeutics in COVID-19 treatment leveraging the power of systems biology,” added Dr. Ghosh.

In the case of SARS-CoV-2 infection, the researchers predict that lipid metabolism particularly fatty acid oxidation, cholesterol biosynthesis and beta-oxidation cycle along with arachidonic acid metabolism to be most affected which was confirmed with clinical metabolomics studies.

The research was published in the international journal PLOS Computational Biology 

Cite paper: Article Source: Genome Scale-Differential Flux Analysis reveals deregulation of lung cell metabolism on SARS-CoV-2 infection Nanda P, Ghosh A (2021) Genome Scale-Differential Flux Analysis reveals deregulation of lung cell metabolism on SARS-CoV-2 infection. PLOS Computational Biology 17(4): e1008860. https://doi.org/10.1371/journal.pcbi.1008860


For more information contact:

Dr. Amit Ghosh, Assistant Professor, School of Energy Science and Engineering, IIT Kharagpur,

E: amitghosh@iitkgp.ac.in; Mobile: +91-9635844538

Piyush Nanda, B.Tech.-M.Tech Dual Degree, 2020, Dept. of Biotechnology, IIT Kharagpur, Graduate Student, Harvard University,

E: piyush.wcame@gmail.com

Media Contact: media@iitkgp.ac.in

Follow us on social media: Facebook / Twitter: @IITKgp    Instagram: @iit.kgp


About IIT Kharagpur: Indian Institute of Technology Kharagpur is a higher educational institute known globally for its graduate output and affordable technology innovations. Set up in 1951 in a detention camp as an Institute of National Importance, the Institute is ranked among the top five in India and has been awarded Institute of Eminence by the Govt. of India in 2019. The key areas of research of IIT Kharagpur are Affordable Healthcare Technologies, Advanced Manufacturing, Advanced Transportation, Precision Agriculture and Food Technology, Cyberphysical Systems, Ecology & Environment, Mining, Water Resources and Architecture. The Institute is engaged in several international and national mission projects and ranks significantly in research output including 50-100 IPR filed annually and about 2000 research publications in top journals and conferences. At present, the Institute has about 750 full-time equivalent faculty members, more than 14000 students and over 70000 Alumni. For more information visit: www.iitkgp.ac.in


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Pandemic Healthcare Technologies Underway @IITKGP

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IIT Kharagpur has set up research funding for R&D work related to COVID-19. The Institute submitted a list of projects to the IIT Council last week of which 8 projects have been selected.

Dr Ramesh Pokhriyal Nishank, Hon’ble Minister, Ministry of Human Resource Development, Govt. of India appreciated and acknowledged the initiative by the Institute on his social media handle congratulating the Director Prof. Virendra Kumar Tewari and his team of researchers.

Talking about the initiative Director Tewari said “It is our responsibility to improve the quality of life of the last person in the society. While we built some quick technologies to cater to the immediate needs of the essential service providers at the campus, we were simultaneously preparing project proposals and evaluating them keeping in mind the immediate need of the country, cost and product delivery period.”

The researchers would be working on several technologies including design and development of rapid diagnostic kit, real-time PCR machine, body suit for COVID-19 patients, personal protective equipment for healthcare workers and portable shredder integrated with sterilizer, Hazmat Suit with forced purified and cooled air circulation for medical professionals, bootstrapping ambu-bag as automated ventilator, telemedicine for fighting viral pandemic, large scale production of recombinant proteins for vaccine and testing.

An amount of Rs. 50 Lakh has been allotted for phase I of 8 projects towards development of prototypes. For most of these projects, the prototypes are expected to be ready within a duration of 3 – 4 weeks, while a couple of them would take about 6 months to deliver the results. The phase I is expected to start immediately after the lockdown is relaxed and the research staff are able to attend the laboratories. Meanwhile software related work would progress as usual.

“IIT Kharagpur has a proven track record towards development of indigenous health and hygiene technologies which are affordable, high-quality at par with globally accepted standards, and commercially viable. Our researchers are committed to deliver the prototypes within a constrained timeline considering the healthcare needs in the current situation,” added Prof. Tewari.

1 Development of smartphone-integrated paper-strip kit for rapid low-cost diagnostics of COVID-19 infection Prof. Arindam Mondal and Prof. Suman Chakraborty
2 Design and Development of an indigenous Real Time PCR Machine Prof. Anandaroop Bhattacharya, Prof. Prasanta K. Das, Prof. Suman Chakraborty (ME Dept), with inputs from Dept. of Biotechnology and Physics
3 Towards large scale Production of Recombinant Proteins for Vaccine and Testing of Novel COVID-19 Prof. Sudip K. Ghosh, Prof. Ananta K. Ghosh and Prof. Ramkrishna Sen
4 Bootstrapping the ambu-bag as automated ventilator Prof. Aditya Bandopadhyay + Faculty and Students from ME Dept
5 Design and Development of a Bodysuit for COVID-19 Patients to Prevent the Spread of Infection Prof. Nishant Chakravorty
6 Telemedicine for fighting viral pandemic such as COVID-19 Prof. Jayanta Mukhopadhyay
7 A Hazmat Suit with Forced Purified and Cooled Air Circulation for Medical Professionals Prof. Manoj Kumar Mondal
8 Personal Protective Equipment for Health Care Workers
Prof. Santanu Dhara and Prof. Sangeeta Das Bhattacharya
8.a. Portable shredder integrated with sterilizer

Novel coronavirus – Insights by Prof. Arindam Mondal

COVID-19 infections in India are nearing 15000 cases while claiming more than 100000 lives globally. Coronaviruses are a virus family causing various diseases, ranging from common cold to those like SARS and MERS which can have a high fatality rate. The novel coronavirus responsible for the COVID-19 pandemic is a new strain and has been named Severe Acute Respiratory Syndrome Coronavirus-2 abbreviated as 19-nCoV or SARS-CoV-2.

Dr. Arindam Mondal, Assistant Professor at IIT Kharagpur’s School of Bioscience speaks with The Kgp Chronicle regarding frequently asked questions about novel coronavirus. Dr. Mondal leads the Molecular Virology Laboratory in the School of Bioscience where they study human RNA virus replication and host pathogen interaction on molecular detail to develop novel strategies for therapeutic or prophylactic measures. Currently, his lab focuses upon influenza viruses as a model that causes mild to severe respiratory illness.

1) What is novel coronavirus?

Corona viruses are relatively large viruses ranging from 80-200nm in diameter and having RNA as their genetic material. The outer surface of these viruses contain three surface proteins, namely spike protein (S), membrane protein (M) and Envelope protein (E), while the inner core is constituted of the long genomic RNA enwrapped with multiple copies of viral Nucleoprotein (N). Under the electron microscope, virus particles with spike proteins projecting outwards  form a crown-like appearance, leading to its name Corona (corona in Latin is crown). Recently, during December 2019 several cases of pneumonia like illness with unknown cause was reported from the Wuhan province of China. Later it was found that the disease is caused by a virus belonging to the coronavirus family (Coronaviridae). As this specific type of coronavirus has never been found to infect humans, named as novel coronavirus. 

2) How common are coronaviruses in causing epidemic in the human history?

Human infecting coronaviruses have been known since the 1960s. Coronaviruses like HCoV-229E and HCoV-OC43, HCoV-NL63 and HCoV-HKU1 cause common cold, mild respiratory infections and flu-like illness. First epidemic outbreak of coronavirus was reported  during 2002-2003 caused by Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV). The epidemic originated from the Guangdong Province of China and speeded across 26 countries causing approximately 8000 infections. Subsequently another Coronavirus was reported causing severe respiratory infections in Saudi Arabia and other countries of the Middle east during 2012, named as Middle eastern respiratory syndrome coronavirus or MERS-CoV. For COVID-19, initial cases of “pneumonia of unknown cause” were reported to WHO on December 31st , 2019, from Wuhan in the central Hubei province of China. On January 30th , 2020, the WHO declared the outbreak to be a “Public Health Emergency of International Concern” and recognized it as a pandemic on March 11th , 2020.

3) How is 19-nCoV different from SARS, Ebola, bird and swine flu etc.?

All of these viruses have drawn public attention due to pandemic or epidemics caused in the recent past, such as the 1918 Spanish flu, the 2009 Swine Flu, the 2014 West African Ebola Virus Disease Epidemic and the 2003 SARS epidemic. While bird and swine flu were caused by different subtypes of influenza viruses, Ebola virus causes hemorrhagic fever. The novel coronavirus, recently identified to have been originated from Wuhan province of China, is closely related to the SARS-CoV (Severe Acute Respiratory Syndrome Coronavirus) that caused the 2002-2003 epidemic, and has thus been alternatively designated as SARS-CoV2. Like the SARS-CoV that originated from bats and got transmitted to humans via an intermediate mammalian host (civets), the SARS-CoV2 seems to have jumped host species from bats to humans, although the existence or identity of the intermediate host is yet to be elucidated. Recent reports have identified pangolins as the possible intermediate host.

The SARS-CoV-2 strain is similar to the 2009 Swine Flu virus (Influenza A- H1N1) or the seasonal flu virus only in a few aspects, such as transmission via close contact, bodily secretions, respiratory droplets during coughing, sneezing or talking, and fomites and the general symptoms similar to common cold like fever, headache, joint and muscle pain, sore throat, runny nose, a typical dry cough. Early evidence shows that although it is more contagious than the seasonal flu or the Ebola Virus or SARS-CoV that caused epidemics, it is less deadly. While SARS-CoV-2 has a variable case fatality rate of 2% depending on age, geographic location, extent and criteria for testing, the Ebola virus and the SARS-CoV has case fatality rates of 40% and 10% respectively. Several infected individuals developing only mild symptoms or even being asymptomatic at times. Also, the major target age groups for the 2009 swine flu were children between 5 and 20 years of age, for the COVID-19 it is mostly older individuals above 60 years of age and immunocompromised people or people with other complications such as cardiovascular diseases, hypertension or diabetes, much like the SARS-CoV.

https://www.healthline.com/health-news/how-deadly-is-the-coronavirus-compared-to-past-outbreaks

4) What is the activity cycle of the novel coronavirus?

Coronavirus life cycle initiates with the interaction of surface spike proteins with the receptors on host cells. The spike protein of novel SARS-Coronavirus-2  recognizes host ACE2 (Angiotensin Converting Enzyme 2). The spike protein of this virus has significant similarity with two coronavirus strains that infects bats. Hence, it is assumed that the current strain of the novel coronavirus got adapted to infect humans through adaptation in its spike protein. Usually, these kind of novel viral strains, as they are unknown to the humans immune system, may cause severe infection, as happening currently.

Interaction of viral spike protein with the host cell receptors leads to entry of the novel coronavirus into the host cell, followed by uncoating of the outer envelope to release of viral genomic RNA. The viral RNA then utilizes host machinery to synthesize viral proteins. Some of these newly synthesized viral proteins (RNA polymerase/ replicase) then carry out genome replication to produce more copies of progeny viral genomes. Another set of viral proteins then assembles with these progeny viral genomes to generate a large number of progeny virion particles. 

5) For how long can this virus remain active on an inorganic surface?

According to recent reports, the new COVID-19 coronavirus can remain stable in aerosols and on various surfaces for several hours, indicating plausibility of aerosol and fomite-borne transmissions. The SARS-CoV2 can remain viable in aerosols for up to 3 hours, up to 4 hours on copper, up to 24 hours on cardboard and for the longest duration of up to 72 hours on plastic and stainless steel, although its infectivity reduces with time. This further highlights the importance of frequent hand sanitization and not touching the face or mouth after touching surfaces.

https://www.nejm.org/doi/pdf/10.1056/NEJMc2004973?articleTools=true

6) Social media is buzzing with the news that the virus would weaken with rise in temperature? Is there any scientific truth in this statement?

In 2002-03 during the SARS epidemic, it was observed that rising temperature and relative humidity did affect the spread of the virus by rapidly declining its viability. In case of COVID-19 pandemic, it has been observed that the virus spread is more rampant in regions of lower temperature (5-11°C) and moderate humidity (50-70%). Experts also noted that the duration of sunlight, which determines the duration of UV exposure to the virus, could be a determining factor as it is UV-sensitive. Some studies under review also suggest, laboratory grown strains of 19-nCoV could be sensitive to extreme heat, but that will not suffice to explain its expected behavior in a pandemic setting, influenced by unpredictable human factors. However the jury is still out on whether the temperature rise and monsoon will be able to significantly subdue the outbreak.

https://www.accuweather.com/en/health-wellness/higher-temperatures-affect-survival-of-new-coronavirus-pathologist-says/700800

7) Recently India has been getting orders for hydroxychloroquine by countries severely affected by the virusIs it the ultimate antiviral remedy for novel coronavirus?

Several antivirals have been identified that could combat the virus by interfering with different stages of the viral life cycle, for example, uncoating inhibitors chloroquine and hydroxychloroquine, replication inhibitor Remdesvir, RNA polymerase inhibitor Favipiravir and so on. Although, specific mechanisms of these antiviral drugs are still under investigation.

Dr Arindam Mondal’s group in collaboration with Prof. Suman Chakraborty’s laboratory at the Mechanical Engineering Department, IIT KGP, is currently trying to develop of a paper-strip kit for rapid low-cost diagnostics of COVID-19 infection. This is a portable rapid diagnostic kit, which in combination with a smartphone app, can be deployed at community level in order to carry out extensive detections for the SARS-CoV-2, the causative agent of COVID19.

Prof. Arindam Mondal can be reached at arindam.mondal@iitkgp.ac.in.