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The importance of multi-omic studies in fighting COVID-19

The importance of multi-omic studies in fighting COVID-19

The importance of multi-omic studies in fighting COVID-19 - Dr. Susmita Bhattacharya

COVID-19 continues to pose an unprecedented challenge to healthcare systems around the world. The enormity of the challenge is manifest by its spread across 221 countries or territories with more than 135 million confirmed cases of infection and almost 3 million deaths so far.1 In India alone, more than 13 million cases have been reported with 168436 deaths so far.2 On the other hand, it is heartening that vaccines have been developed and deployed at unprecedented speed. However, it is understandable that it will take quite some time before enough people are vaccinated to achieve ‘herd immunity’. In fact, it is now even being debated if vaccination of 60-70% of the population would be enough to achieve herd-immunity.3 Meanwhile, it is alarming that the virus has already been mutating as recent results show that some vaccines may be quite ineffective against emerging variants.4 Moreover, cases of re-infection are also on the rise and some of the emerging variants such as the Brazil variant pose elevated risk of re-infection.5 The recent surge in infection has been attributed mostly to new variants. Emergence of variants refractory to antibodies raised by older strain or vaccine may significant derail the plan to bring the pandemic under control. The other approaches to get hold of the situation are to minimize transmission and to develop an effective therapeutic regimen against the disease. 

Development of effective therapeutic regimen warrants detailed understanding of how the virus infects and hijacks cellular machinery to propagate itself, how our immune system responds to the challenge as well as how the interaction between virus and target cells affects different organs. This remains a work in progress. One of the major foci of ongoing research has been the interaction between the virus and cells of the respiratory system. However, the virus has actually been detected in several organs beyond the respiratory system. In fact, it has been found to directly infect lung as well as liver, kidney, immune cells and cells of the central nervous system.6-9 Thus, understanding of the underlying pathogenesis would require local as well as system-wide effect of SARS-COV-2 infection. It is interesting to note that while pre-existing conditions like COPD, diabetes, hypertension, cardiovascular disease, has been found to be risk factors in COVID-19 affecting different organs, the disease course and outcome shows significant inter-individual differences. While many with these vulnerabilities did not develop severe disease, several others who are relatively young and with no such pre-existing conditions showed sudden deterioration and adverse outcome.10 The response to therapy also remains very heterogeneous. In fact, the existing tools like EWS score for patient stratification has often been found to be inadequate for prognostic evaluation and making therapeutic choices. The viral load has also not been found to predict with disease manifestation and outcome. The first thing that comes to mind in the context of inter-individual differences is genome. Inter-individual differences in our genome contribute not only towards our differences in appearance and behaviours, but also prime us towards differences in response to external perturbation such as infection. In fact, recent studies have revealed genetic factors including polymorphism in ACE2 receptor and ABO antigen type to be associated vulnerability to SARS-COV-2 infection.11, 12 It should be noted that there are several factors (epigenome, transcriptome, proteome, lipidome, metabolome and volatome) involved in the information cascade starting from genome to physiological function. In addition to genetic code, extrinsic factors including, food, drugs, life-style, habitat, psychosocial atmosphere as well as earlier exposure to same or other infectious agents can influence the biochemical machinery comprising these factors during response to SARS-COV-2 infection. Thus, only a simultaneous analysis of the system-wide changes in multi-omic signature can help to identify key molecular events and determinants of response to and outcome of SARS-COV-2 infection. While several studies have reported on individual -omic signatures, signatures associated SARS-COV-2 infection and outcome,11-15 no study has so far been reported on pan-omic investigation. This is essential not only to identify targets for therapeutic interventions, but also in making appropriate therapeutic choices for an individual.  Limiting transmission requires detailed understanding of modes of transmission. It is now widely accepted that the virus spreads mostly through airborne droplets generated during coughing, sneezing, laughing, talking and even breathing. Thus, a potent strategy to minimize transmission is universal use of mask and other COVID-appropriate practices including use of sanitizers and maintaining a minimum distance of two metres. The last thing is easier said than done and hardly ever adhered in a highly populated country like India, unless there is a near-total ban on mobility. So, use of mask and sanitizer are must. Unfortunately, there is significant tendency of laxity in their use when there is no ‘known’ COVID-positive person or someone with COVID-like symptoms is around. It is important to note that a large number of infected people may never develop any symptom and unless there is a known COVID-positive contact, people would undergo test only when they become symptomatic. It has been shown that even asymptomatic or pre-symptomatic people can spread infection.16, 17 Consequently; many studies have revealed that asymptomatic and pre-symptomatic people contribute significantly in SARS-COV-2 transmission. Thus, identification of COVID-positive individuals without symptoms is of key importance to isolate them and prevent transmission. However, it needs to be kept in mind that the putative application would involve screening of large number of subjects. It also needs to be rapid so that subjects can be quarantined swiftly. Studies have indicated that the novel SARS-COV-2 variant may arise in hospitalized immune-compromised patients. Under the pandemic situation, such variants may spread quickly through healthcare workers. A rapid high-throughput approach would help to detect such silently evolving infection cluster and escalate sequencing to identify the variant of concern. However, there are not many reliable methods currently available for identification of asymptomatic carriers, other than those based on RT-PCR,18 which is time consuming. Recent studies indicated that the breath volatile signature of COVID-19 patients may be distinct.19, 20 Breath sampling is non-invasive and can be done in real-time allowing rapid high-throughput diagnosis. However, the challenge with breath analysis is that our knowledge of biochemical origin of these volatile molecules remains limited as has been demonstrated by the recent work by Dr. Sukul et al. In addition, the mechanistic connection between changes in breath volatile and underlying pathology remain even more opaque. In fact, as mentioned above, understanding of the mechanism of pathogenesis of COVID-19 itself is far from complete. Thus, a tandem analysis of system-wide changes in biochemical landscape and breath volatiles would be required to identify breath biomarkers mechanistically connected to COVID-19 pathogenesis. This may then also be useful in repeated non-invasive assessment of therapeutic response in patients. Eventually, this could also lead to methods for stratification of patients for appropriate therapeutic intervention. It is a pleasure to share that we have developed partnership with scientists at Saha Institute of Nuclear Physics (Kolkata), Indian Statistical Institute (Kolkata), Regional Centre for Biotechnology (Faridabad) and the breath analysis team including Dr. Jochen Schubert and Dr. Pritam Sukul at the University of Rostock (Germany) to embark on a multi-omic study to develop deeper understanding of COVID-19 pathogenesis as well as to identify signatures that might help in diagnosis and monitoring of COVID-positive individuals irrespective of disease manifestation.

References: 

  1. https://www.worldometers.info/coronavirus/
  2. https://www.mohfw.gov.in/
  3. Aschwanden C. Five reasons why COVID herd immunity is probably impossible. Nature. 2021 Mar;591(7851):520-522.
  4. Madhi SA, et al. Efficacy of the ChAdOx1 nCoV-19 Covid-19 Vaccine against the B.1.351 Variant. N Engl J Med. 2021 Mar 16;NEJMoa2102214.
  5. Sabino EC, et al. Resurgence of COVID-19 in Manaus, Brazil, despite high seroprevalence. Lancet. 2021 Feb 6;397(10273):452-455.
  6. Wang Y, et al. SARS-CoV-2 infection of the liver directly contributes to hepatic impairment in patients with COVID-19. J Hepatol. 2020 Oct; 73(4): 807–816.
  7. Khan S, et al. Does SARS-CoV-2 Infect the Kidney? J Am Soc Nephrol. 2020.
  8. Brosa M and Mazet JM. Attacking the defence: SARS-CoV-2 can infect immune cells. Nat Rev Immunol. 2020 Oct;20(10):592.
  9. Crunfli F, et al. SARS-CoV-2 infects brain astrocytes of COVID-19 patients and impairs neuronal viability. biorXiv 2021. doi: https://doi.org/10.1101/2020.10.09.20207464
  10. https://www.mohfw.gov.in/pdf/AIIMSeICUsFAQs01SEP.pdf
  11. Hou Y, et al.  New insights into genetic susceptibility of COVID-19: an ACE2 and TMPRSS2 polymorphism analysis. BMC Med. 2020;18(1):216.
  12. Ellinghaus D, et al.  Genomewide Association Study of Severe Covid-19 with Respiratory Failure . N Engl J Med. 2020;NEJMoa2020283.
  13. Daamen AR, et al. Comprehensive transcriptomic analysis of COVID-19 blood, lung, and airway. Sci Rep. 2021 Mar 29;11(1):7052.
  14. Shen B et al. Proteomic and Metabolomic Characterization of COVID-19 Patient Sera. Cell. 2020 Jul 9;182(1):59-72.e15
  15. Thomas T, et al. COVID-19 infection alters kynurenine and fatty acid metabolism, correlating with IL-6 levels and renal status. JCI Insight. 2020 Jul 23;5(14):e140327.
  16. Johansson MA, et al. SARS-CoV-2 Transmission From People Without COVID-19 Symptoms. JAMA Netw Open. 2021 Jan 4;4(1):e2035057. 
  17. Rivett L, et al. Screening of healthcare workers forSARS-CoV-2 highlights the role ofasymptomatic carriage in COVID-19transmission. Elife. 2020 May 11;9:e58728
  18. Shental M, et al. Efficient high-throughput SARS-CoV-2 testing to detect asymptomatic carriers. Sci Adv. 2020 Sep 11;6(37):eabc5961.
  19. Grassin-Delyle S et al. Metabolomics of exhaled breath in critically ill COVID-19 patients: A pilot study. EBioMedicine. 2021 Jan;63:103154.
  20. Berna AZ , et al. Breath biomarkers of pediatric SARS-CoV-2 infection: a pilot study. medRxiv 2020. doi: https://doi.org/10.1101/2020.12.04.20230755

Bio:-

Professor Susmita Bhattacharya is the Head of the Department of Microbiology in the College of Medicine and Sagore Dutta Hospital, which is a designated COVID-19 hospital of West Bengal Government. She received her MBBS and MD (Microbiology) from Calcutta University. She also received her Ph.D. from the “The West Bengal University of Health Sciences” in Bacteriology. She has published several papers in peer-reviewed journals on infectious diseases. She is spearheading RTPCR-based COVID-19 diagnosis at the hospital and is involved in a number of studies on risk and outcome of COVID-19.  She is also actively involved in teaching and thesis supervision.

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