The deregulated immune reaction and cytokines release storm (CRS) in COVID-19 disease

Abstract

COVID-19 caused by the SARS-CoV-2 virus, accompanies an unprecedented spike in cytokines levels termed cytokines release syndrome (CRS), in critically ill patients. Clinicians claim that the surge demonstrates a deregulated immune defence in host, as infected cell expression analysis depicts a delay in type-I (interferon-I) and type-III IFNs expression, along with a limited Interferon-Stimulated Gene (ISG) response, which later resume and culminates in elicitation of several cytokines including- IL-6, IL-8, IL-12, TNFα, IL-17, MCP-1, IP-10 and IL-10 etc. Although cytokines are messenger molecules of the immune system, but their increased concentration results in inflammation, infiltration of macrophages, neutrophils and lung injury in patients. This inflammatory response results in the precarious pathogenesis of COVID-19; thus, a complete estimation of the immune response against SARS-CoV-2 is vital in designing a harmless and effective vaccine. In pathogenesis analysis, it emerges that a timely forceful type-I IFN production (18-24hrs post infection) promotes innate and acquired immune responses, while a delay in IFNs production (3-4 days post infection) actually renders both innate and acquired responses ineffective in fighting infection. Further, underlying conditions including hypertension, obesity, cardio-vascular disease etc may increase the chances of putting people in risk groups, which end up having critical form of infection. This review summarizes the events starting from viral entry, its struggle with the immune system and failure of host immunological parameters to obliterate the infections, which finally culminate into massive release of CRS and inflammation in gravely ill patients.

Keywords: ACE2; Acute Respiratory Distress Syndrome (ARDS); COVID-19; Corona virus; Cytokine Release Storm (CRS); Deregulated immune response; Immune cell homeostasis; SARS-CoV-2.

Fig. 1

Structure of Coronavirus: Coronavirus are enveloped with Ss RNA genome, which is non-segmented. Virion nucleocapsid along with Ss RNA also has phosphorylated protein (N) in phospholipid bilayer roofed by Spike (S) glycoprotein trimer. The layer protein (M) and envelope (E) protein are also located along with S proteins of the virus envelope.

Fig. 2

Life cycle of virus in an infected cell: After inhalation, virus reaches the respiratory system and internalization of SARS-CoV-2 virus starts with attachment of viral S (spike) protein on ACE2 receptor of humans, followed by TMPRSS2 mediated cleavage of S protein, which lead to internalization of virus. Viral uncoating in cytoplasm releases Ss positive sense genomic RNA (gRNA). The first step is translation of gRNA (+ve strand) into two polypeptides- pp1a and pp1ab, which is cleaved to many non-structural proteins (nsp), including RNA-dependent RNA polymerase, RdRp which is involved in viral genome replication in double membrane vesicles (DMVs). The negative strand, in another round, produces positive (+ve) strand genomic RNA and becomes the genome of the descendant viral cells. The transcribed sub-genomic RNAs is translated into various structural proteins (S, E, M and N) to create the viral progeny. S, E and M proteins enter the endoplasmic reticulum (ER), and the nucleocapsid protein, which joins with the genomic RNA (+ve strand) and combine into complete viral cell in the ER-Golgi compartment, and exocytosed out of the cell.

Fig. 3

Type-I IFNs synthesis happens through multiple cascades (discussed in main text) and is indispensable to induce immunity and its expression operates in various cell types, including DC and macrophages. Chiefly pDC plays a central role in the earliest production of IFN-α/β. In response to viral infection, TLR7 and TLR9 gets stimulated and trigger a robust MyD88-dependent and IRF-7 mediated type-I IFN signalling, involving production of large amounts of IFN-α and IFN-β (IFN-α/β). Stimulation of cytosolic radars RIG-1 and MDA-5, engages the mitochondrial antiviral-signalling MAVS adaptor protein, which results in IRF3-mediated signalling. cDCs and macrophages although not responsible for the IFN-α/β production during the early phase (24 hrs) of infection but generate protective immunity during the effector phase. The IFNs secreted works in an autocrine and paracrine manner via binding to its cognate receptor and initiating JAK-STAT signalling for IFN-γ and cytokines production including IL-6 and TNFα. Virus infected cells show increased inflammation due to activation of the multiprotein inflammasome complex, NLRP3. It activates caspase-I, which triggers the release of pro-inflammatory cytokines IL-1β and IL-18, involved in pyroptosis.

Fig. 4

The defensive function of Type-I IFNs in COVID-19. First panel (A) suggest that when viral load is faint, IFNs generated timely can absolve the virus effectively and patient recovers. Second panel (B) depicts a curve in patients where virus successfully evades the immune response, leading to elevated viral levels and deferred IFNs production could not control viral multiplication, leading to severity of infection.

Fig. 5

IL-6 cell signalling can occur three ways: (A) Classic pathway (or cis pathway) involves membrane bound IL-6R and gp-130 whereas; (B) Trans pathway involves IL-6 binding with soluble (sIL-6R) along with gp-130. Both classic and trans pathway mediate JAK/STAT signalling to mediate CRS (C) Trans presentation occurs via dendritic cells (DC) which trans-present IL-6 via their own IL-6R to cognately interact with T cells (termed IL-6 ‘cluster signalling’), resulting in their differentiation to Th17 cells via JAK-STAT signalling. The JAK/STAT signalling (by both cis and trans signalling) and RAS-RAF, SRC-YAP-NOTCH and AKT-P13K promote the transcription of multiple downstream genes associated with T-cell clonal amplification, B-cell differentiation, acute phase response production.