Results & Discussion
We have performed in silico analysis of meta-data for transcriptomic and proteomic expression of SARS-CoV-2 host cell entry related factors (ACE2, TMPRSS2, CTSL, and FURIN). SARS-CoV-2 host cell entry receptor ACE2 was not-detected in bulk-transcriptomic and proteomic expression analysis in any of the studied immune cell components (bone marrow and lymphoid tissue) (Table 1, Fig. 1). ACE2 was also not-detected in single cell transcriptomic analysis of blood cell lineages (Table 2, Fig. 2). ‘Not-detected’ to ‘enriched’ transcriptomic expression, were observed in bulk (bone marrow and lymphoid tissue) as well as in single cell analysis (blood cell lineages), and ‘not-detected’ to ‘medium level’ proteomic expression (bone marrow and lymphoid tissue) expression were observed, for SARS-CoV-2 host cell entry associated proteases TMPRSS2, CTSL, and FURIN (Table 1-2, Fig. 1-2).
The observations made in this study are important and provide insights regarding immunopathogenesis in COVID-19. We findings, the non-detectable level of expressions of viral host cell entry receptor ACE2, and non-detectable to medium range expression of host cell entry associated proteases TMPRSS2, CTSL, and FURIN across immune system components of healthy individuals (Table 1-2, Fig. 1-2) are in line with recent sporadic studies reporting expression of a single or a set of these factors across human tissues.4,8,9 The non-detectable expressions of ACE2 across immune system components including blood (immune) cells indicate their non-susceptibility for SARS-CoV-2 infection. However, recent studies have provided indications of immune cell lesion in COVID-19.12–15Lymphocytopenia in COVID-19 cases is marked by selective killing of T cells.12 Moreover, SARS-CoV-2 mediated atrophy and lesion of the human lymphoid tissue— like spleen and lymph nodes—, also have been observed in a recent study.16 The viral mediated manipulations of the host immune-cell receptor signaling is well established fact; however, any such evidence specific to SARS-CoV-2 is currently scarce in literature.17 In absence of significant cell-surface expression of ACE2 in immune system components, the alternative mechanisms which are exploited by the COVID-19 virus to induce immunopathology, need to be ascertained. Therefore, our finding warrants for a systematic review of existing literature indicated for the set of plausible mechanisms which may explain immunological dysregulation in COVID-19 without the involvement of ACE2 signaling. The available data suggets that either, (i) selective killing of T cells may be a resultant of high productions of cytokines and pro-inflammatory markers,15,18 (ii) direct viral protein toxicity,16 (iii) or presence of an additional SARS-CoV-2 cell entry receptor which is expressed in immune system components.19 Recently, a study proposed Neuropilin-1 (NRP1) as an alternative receptor for SARS-CoV-2 cell entry, which has significant expression in immune cells.19,20 However, further in situ/in vivo studies will be necessary to prove that NRP1 can mediate SARS-CoV-2 infection of immune cells.