pathogen – The KGP Chronicle

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

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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Indian Express COVID Updates

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 virus. Is 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.

Clean India, Healthy India

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Does economic growth have a positive correlation with clean drinking water in India? Researchers at IIT Kharagpur seem to be not only agreeing with this idea but even found concrete proofs. In a recent study published in the Scientific Reports, the link between the influence of economic growth in reducing fecal pathogens in groundwater has been established. These are the pathogens that are considered to be one of the key causes of water-bourne diseases, across India.

Water-bourne diseases like diarrhea have been the cause of 15.5% of total deaths in India from 1990 – 2016. The study has made first-time observations on a significant reduction of fecal pathogen concentration in the spatially variable groundwater from 2002 to 2017. The study, however, reported elevated fecal coliform concentration in potable groundwater in rural regions across India than UNGA’s safe limit of zero pathogens. Download Paper

“Looking beyond the country globally, more than one-third of the total country’s population, living in economically stressed areas of Africa and South Asia still do not have access to basic sanitation, and more than 1 billion still opt for open defecation. Until recently, India has more than 500 million open-defecating population resulting unsafe disposal of fecal waste to nearby drinking water sources poses a serious environmental crisis and public health concern,” says Prof. Abhijit Mukherjee, faculty at the School of Environmental Science and Engineering and Dept. of Geology and Geophysics at IIT Kharagpur who led the research project.

In recent years, sanitation development to achieve goal-6 of UNGA’s Sustainable Development Goals (SDGs) has been encouraged across India by implementing Clean India (Swachh Bharat) Mission. But their effect on groundwater quality and human health are yet unquantified until now. The study, published on October 23 on the Nature group of journals, gives long term, high-spatial-resolution measurements of fecal coliform concentration (>1.7 million) and acute diarrheal cases for the first time. The study data covered almost the last three decades to delineate the long-term improvement trends of groundwater quality across India, as a consequence of development.

“A uniqueness in this study to determine economic development was instead of GDP or other economic growth data, we have used satellite-based nightlight (NL) information from NASA for the period 1992-2013 which was used to investigate the statistical trends and causal relationships. In most areas’ economic development, suggested by increasing satellite-based nightlight correlated to the reduction in faecal coliform concentration and alleviation of water quality. While, sanitation and economic development can improve human health, poor education level and improper human practices can potentially affect water-borne diseases loads and thus health in parts of India.” explained Srimanti Duttagupta, Ph.D. scholar at IIT Kharagpur, second author of the research paper which has come out recently based on this study.

Numerical and statistical analyses were performed on aforesaid culled datasets to understand the efficiency of development in alleviating the water quality and public health, and relationship with economic development. Enhanced alleviation of groundwater quality and human health have been observed since 2014 with the initiation of accelerated construction of sanitation infrastructure through Swachh Bharat Mission.

In the study it was observed that in more than 80% of the study region, night-time light demonstrated to be a strong predictor for observed changes in groundwater quality, sanitation development and water-borne disease cases.

However, the goal of completely fecal-pollution free, clean drinking water is yet to be achieved, Prof. Mukherjee remarked, however, needs more data to confirm.

“Nevertheless, in areas with inferior water quality, improper human practices outweigh economic development in affecting human health,” he added.

It has been further observed that very high population density deteriorates the quality of water in certain areas. The problem of overpopulation and slums is an intricate problem that is reflected in all life aspects in countries like India. Different statistical analyses conducted in this study showed about a 3.09 % decrease in fecal coliform concentration and a 2.69% decrease in acute diarrheal cases per year for the last three decades. Groundwater quality with respect to fecal coliform concentration and acute diarrheal cases generally reduced in most areas of India and has been mostly caused by sanitation development, urbanization and related land-use changes.

Since 2014 the government has built over 100 million toilets in six lakh villages and 6.3 million toilets in cities covering a total of 600 million people (almost 60% of India’s population) which is more than the total figure for toilets since 1947. Currently, 93% of village households have toilets with a usage rate of over 90%. On October 2, while celebrating the 150th birth anniversary of Mahatma Gandhi, Prime Minister Narendra Modi declared that India was open-defecation free. But there are facts beyond statistics primarily challenging the initiative at the level of societal and poor human practices.

The researchers opined that use and disuse and beliefs are mostly related to lower literacy rates. In turn, these results in a lack of awareness and encourage malpractice on sanitation, eventually leading to increased fecal waste into drinking water sourced from groundwater.