Immune dysregulation and system pathology in COVID-19

Abstract

The coronavirus disease 19 (COVID-19) caused by the novel coronavirus known as SARS-CoV-2 has caused a global public health crisis. As of 7 January 2021, 87,640,402 confirmed cases and 1,891,692 mortalities have been reported worldwide. Studies focusing on the epidemiological and clinical characteristics of COVID-19 patients have suggested a dysregulated immune response characterized by lymphopenia and cytokine storm in these patients. The exaggerated immune response induced by the cytokine storm causes septic shock, acute respiratory distress syndrome (ARDS), and/or multiple organs failure, which increases the fatality rate of patients with SARS-CoV-2 infection. Herein, we review the recent research progress on epidemiology, clinical features, and system pathology in COVID-19. Moreover, we summarized the recent therapeutic strategies, which are either approved, under clinical trial, and/or under investigation by the local or global health authorities. We assume that treatments should focus on the use of antiviral drugs in combination with immunomodulators as well as treatment of the underlying comorbidities.

Keywords: SARS-COV-2; ards and multiple organs failure; covid-19; cytokine release syndrome; lymphopenia; pathogenesis.

Figure 1.

Structure and genome organization of SARS-CoV-2 particle. (a) SARS-CoV-2 is a large pleomorphic, nonsegmented, enveloped, and spherical round virus with projections. The structure is composed up of a lipid bilayer in which M, E and S proteins are embedded. The lipid bilayer encloses nucleocapsid, which is made up of multiple copies of N protein binding wrapping around genomic RNA. (b) The genomic RNA is positive-sense and single-stranded, which is 29kb. Two-third of the genome contains open reading frames (ORF1a and ORF1b), which encode the non-structural proteins essential for viral replication and viral protein synthesis. The 5ʹ and 3ʹ ends of the genome contain a methylated cap and poly-A tail, respectively

Figure 2.

Pathogenic mechanism of SARS-CoV-2 and activation and alteration in immune cells post-infection. (a) DAMPs and PAMPs derived from virus results in the activation of macrophage. Followed by the downstream production of cytokines. IL-6 and IL-1b results in the recruitment of CD8 + T cells and neutrophils. Activated T-cell directs the release of cytokines and cellular cytotoxicity, which can contribute to tissue inflammation. Cytotoxic T cells result in the production of cytokines, which may cause lung injury. CCL3 and IL-8 can induce eosinophil and neutrophil recruitment leading to NETosis and microthrombosis, which may result in lung injury. NK cells might infiltrate from the blood via the CXCL9/10/11-CXCR3 pathway, CXCL9/10/11 is derived from monocyte. Inhibitory receptors such as NKG2A is also increased on NK cells and CD8 T cells, which inhibits cytotoxicity. Besides, elevated expression LAG3 and on NK cells in COVID-19 patients may also contribute to viral escape. In addition, high expression of IL-6 may also reduce NK cell numbers. Dendritic cell secretes Type 1 IFN and is supposed to play a role in control of viral infection. (b) A nonresponsive cell state is driven by the persistent antigenic T cells activation by the epithelial cells leading to T cell exhaustion, which is accompanied by lymphodepletion in severe patients. T cells overexpress markers of exhaustion including PD-1 and Tim-3. B cells-induced pulmonary pathology during SARS-CoV-2 infection may also contribute to lung injury

Figure 3.

Illustration of the SARS-CoV-2 pathogenesis. (a) Virus binds to ACE2 receptor and enters into the cell through membrane fusion or endocytosis and release its RNA genome. Viral infection results in the activation of monocytes, macrophages, and dendritic cell instigation to release several cytokines and among these cytokines, a key player IL-6 can activate signaling pathways. These pathways are associated with lymphatic cell changes characterized by the proliferation of B cells, induction of CTL cytotoxicity, and reduction of Treg development. In addition, increase recruitment of monocytes and neutrophils, increase vascular permeability, and hypertension are also caused by the Trans signaling pathway activated by IL-6. The subsequent elevated cytokine production aid to pathophysiology in COVID-19. (b) ACE2 expression in organs and systems contribute to COVID-19. ACE2 is highly expressed on the GI tract, kidneys, and testis. Notably, expression of ACE2 varies remarkably from cell to cell in the same organs, for example, ACE2 is poorly expressed on bronchial epithelial cells compared to the higher expression on alveolar epithelial cells. Hepatocytes, Kupffer cells endothelial cells lack ACE2 expression but cholangiocytes expressed at a detectable level