Age-related gene expression alterations by SARS-CoV-2 infection contribute to poor prognosis in elderly

Journal of Genetics (2020)99:80 https://doi.org/10.1007/s12041-020-01233-7 Ó Indian Academy of Sciences (0123456789().,-volV) (0123456789().,-volV) RESEARCH ARTICLE Age-related gene expression alterations by SARS-CoV-2 infection contribute to poor prognosis in elderly UPASANA BHATTACHARYYA and B. K. THELMA* Department of Genetics, University of Delhi South Campus, New Delhi 110 021, India *For correspondence. E-mail: . Received 16 July 2020; accepted 20 July 2020 Abstract. The ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected millions of people worldwide and with notable heterogeneity in its clinical presentation. Probability of contracting this highly contagious infection is similar across age groups but disease severity and fatality among aged patients with or without comorbidities are reportedly higher. Previous studies suggest that age associated transcriptional changes in lung and immune system results in a proinflammatory state and increased susceptibility to infectious lung diseases. Similarly, SARS-CoV-2 infection could augment ageing-related gene expression alterations resulting in severe outcomes in elderly patients. To identify genes that can potentially increase covid-19 disease severity in ageing people, we compared age associated gene expression changes with disease-associated expression changes in lung/BALF and whole blood obtained from publicly available data. We observed (i) a significant overlap of gene expression profiles of patients’ BALF and blood with lung and blood of the healthy group, respectively; (ii) a more pronounced overlap in blood compared to lung; and (iii) a similar overlap between host genes interacting with SARS-CoV-2 and ageing blood transcriptome. Pathway enrichment analysis of overlapping gene sets suggest that infection alters expression of genes already dysregulated in the elderly, which together may lead to poor prognosis. eQTLs in these genes may also confer poor outcome in young patients worsening with age and comorbidities. Further, the pronounced overlap observed in blood may explain clinical symptoms including blood clots, strokes, heart attack, multi-organ failure etc. in severe cases. This model based on a limited patient dataset seems robust and holds promise for testing larger tissue specific datasets from patients with varied severity and across populations. Keywords. covid-19; SARS-CoV-2; biomarker; transcriptional changes; eQTL variants; SARS-CoV-2 poor prognosis; ageing. Introduction Since December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), that causes COVID-19 in humans (Siordia 2020) has spread rapidly across the world and is classified as a global pandemic by the World Health Organization (coronavirus (COVID-19) events as they happen; https://www.who.int/emergencies/diseases/novelcoronavirus-2019/events-as-they-happen). As of 2 July 2020, there have been 10.6 million confirmed COVID-19 cases with 519,766 deaths reported worldwide (https:// BKT and UB designed the study; UB performed all the data analysis; UB and BKT wrote the first draft of manuscript; and both approved the final manuscript. ourworldindata.org), with continuing trend of sharp rise in both these categories in many countries/regions. The disease is highly heterogenous in its clinical presentation with most common symptoms being fever, cough, shortness of breath and fatigue. In addition, myalgia, neurological symptoms, ischaemic and haemorrhagic strokes, muscle injury and gastrointestinal symptoms are also reported in a subset of patients (Harapan et al. 2020). Several clinical trials are ongoing but as of date, no drugs or other therapeutics have been approved by the U.S. Food and Drug Administration (FDA) to prevent or treat COVID-19 (Sanders et al. 2020) and thus clinical management includes infection prevention and supportive care (Sanders et al. 2020). Efforts to combat COVID-19 are severely hampered by grossly inadequate knowledge of several important aspects of the illness ranging Electronic supplementary material: The online version of this article (https://doi.org/10.1007/s12041-020-01233-7) contains supplementary material, which is available to authorized users. 80 Page 2 of 9 U. Bhattacharyya and B. K. Thelma from pathogen biology to host response, disease biology, target tissues and consequently treatment options. Therefore, there is an urgent need for a deeper understanding of the host–pathogen interaction biology of SARS-CoV-2, which in turn may offer important insights into general/personalized treatment strategies and management of the disease as well as development of new therapies. Probability of contracting this highly contagious infection has been reported to be similar across age groups but severe clinical manifestations and increased mortality has been reported in elderly patients (Cohen et al. 2020; Hauser et al. 2020; Meyerowitz-Katz and Merone 2020; Wu et al. 2020). These observations suggest that there may be a comparatively stronger association between age and poor prognosis of COVID-19, but this may well be multifactorial. Therefore, the uncovering mechanism(s) underlying poor prognosis to SARS-CoV-2 infection among the affected elderly might be insightful for effective patient management and treatment. Several reports suggest that with the ageing, elderly population becomes more susceptible to various infectious disorders (Meyer 2001; Gavazzi and Krause 2002; López-Otı́n et al. 2003; Meiners et al. 2015). With ageing, transcriptional dysregulation occurs in genes involved in cellular oxidant/antioxidant systems, proinflammatory mediators (C-reactive protein, tumour necrosis factor a (TNF-a), interleukins (IL) 6, 1b), and cell regenerations that might overlap with viral mediated dysregulation (Franceschi and Campisi 2014; Meiners et al. 2015; de Almeida et al. 2020; Fulop et al. 2018). Similarly in severe COVID-19 patients, a ‘cytokine storm’ comprised of TNF-a, IL 6, 1b, 8, 12, interferon-gamma inducible protein (IP10), macrophage inflammatory protein 1A (MIP1A), and monocyte chemoattractant protein 1 (MCP1) (Cascella et al. 2020) and hypercoagulable state with increased risk of venous thromboembolism (Cevik et al. 2020) has been observed. Based on this limited understanding, we hypothesize that SARS-CoV-2 mediated transcriptional alterations may overlap with age mediated expression changes. Thus, expression of genes that changes during ageing, might get further augmented on SARS-CoV-2 infection, leading to severe outcome in elderly patients. We attempted to explore this possibility by performing comparative transcriptomics using available data from two target tissues, namely lung and blood in healthy ageing group and COVID-19 patients. We also compared transcriptomic profile of ageing lung and blood with host genes interacting with SARS-CoV-2 protein. We observed a significant overlap between gene expression profile in both lung and blood of h (...truncated)