Comparison of the Characteristics of Cytokine Storm and Immune Response Induced by SARS-CoV, MERS-CoV, and SARS-CoV-2 Infections

Figures & data

Figure 1 The infection and replication of SARS-CoV in epithelial cells and immune cells. SARS-CoV infect and replicate in epithelial cells. Monocyte-macrophage and DCs are infected by SARS-CoV to induced apoptosis of activated T cells. The cells in the dotted frame can secrete a variety of cytokines in the immune response, further forming a cytokine storm.

Figure 2 MERS-CoV can infect and replicate in the cells shown above, causing apoptosis in the dotted frame and releasing cytokines that cause cytokine storms. It is worth noting that whether it can replicate in human monocyte-derived macrophages and DCs is still not clear.

Figure 3 SARS-CoV-2 infect and replicate in epithelial cells and T cells and cause them to secrete a large number of cytokines, which can cause cytokine storms to cause the damage of heart, kidney and lungs. But it is not clear which other cells that SARS-CoV-2 can infect and replicate in them.

Table 1 Comparing Host Cells Infected with Different Types of Coronavirus and Changes in Immune Cells and Cytokines

Immune Response	SARS-CoV	MERS-CoV	SARS-CoV-2
Infected host cell	Alveolar epithelial cells^Citation20	Alveolar epithelial cells^Citation29	Respiratory epithelial cells^Citation36
	Monocyte–macrophage	Monocyte–macrophage
			T lymphocytes^Citation46
	Dendritic cells^Citation21,^Citation22	Dendritic cells
	Activated T cells	Activated T cells^Citation30^–^Citation32
Changes of immune cells	The accumulation of a large number of mononuclear macrophages and neutrophils in the body led to an increase in Th1 cells^Citation25 and a significant decrease in NK cells.^Citation47	CD4^+ T cells, Th1 cells, and Th2 cells were all downregulated.^Citation48	CD4^+ T cells and T regulatory cells (Treg) decreased. Th17 and Tfh cells increased, while Th1 cells decreased significantly.^Citation2 DCs, macrophages, CD4^+ T cells, and TGF-β^+CD28^− naïve CD8^+ T cells were higher in the mild group than in the critical patients.^Citation49,^Citation50
Cytokine changes	SARS-CoV stimulates the body to produce IL-6, IL-1, IFN-γ, TGF-β, IL-12, IL-8, CXCL9, CXCL10, and CCL2,^Citation23^–^Citation25 It induced the production of TNF-α, IFN-β, and IP-10, which was significantly higher than that of MERS-CoV,^Citation29 but the expression of cytokine IL-10 was low.^Citation23	MERS-CoV induces the body to produce IFN, IL-6, IL-2, IL-1β, CCL-3, CCL-2, IL-8, CCL-5.^Citation29^–^Citation31 IL-1, IL-6, and IL-8 in patients are higher than those in patients with SARS.^Citation29	COVID-19 induces the body IL-10, IL-7, IL-2, MCP1, IP10, G-CSF, MIP1α, and TNF-α.^Citation3 Unlike SARS-CoV infection, SARS-CoV-2 infection also triggered an increase in the secretion of Th2 cytokines that inhibit inflammation, such as IL-4 and IL-10.

Table 2 Comparing Protein Differences in Coronavirus

Types of Protein	SARS-CoV	MERS-CoV	SARS-CoV-2
Spike protein (S)	S protein can bind to ACE2 directly, and the binding sequence site is highly consistent with SARS-CoV-2.^Citation60	The core structure of the S2 gene of SARS-CoV is very similar, but the structure of the receptor-binding motif is quite different, so its receptor is dipeptidyl peptidase.^Citation57	Compared with SARS-CoV, the receptor-binding domain sequence homology of S protein is 76%.^Citation60 Its S protein also participates in the process of virus invasion by binding to the ACE2 receptor.^Citation61
Envelope protein (E)	E protein acts as an ion channel in the form of a pentamer.^Citation58	Control virion assembly, deletion mutants lose pathogenicity.^Citation58,^Citation62	Compared with SARS-CoV, the sequence homology of E protein is as high as 95%.^Citation60 It is suggested that the functional diversity of E protein in the process of coronavirus replication and pathogenesis.
Membrane protein (M)	M protein is only expressed in the endoplasmic reticulum and Golgi matrix. Its conserved domain participates in the process of virus assembly and budding through protein-protein interaction.^Citation53	Control virion assembly.^Citation63	Compared with SARS-CoV, the homology is as high as 91%.^Citation60 The specific function is not clear.
Nucleocapsid protein (N)	Serum cross-reaction can occur through N protein.^Citation64	It can fold the coronavirus genome into a spiral ribonucleoprotein (RNP). At the same time, it can also enhance the efficiency of virus transcription and assembly.^Citation65	Compared with SARS-CoV, the homology is as high as 94%.^Citation60 It is possible to recognize the N protein of SARS-CoV in the COVID-19 patient’s serum and this can be used for clinical detection of asymptomatic patients.
Open reading frames (ORFs) ORF3b	ORF3b protein is meaningless in the process of SARS-CoV replication.^Citation51 It can inhibit the IFN-β signal pathway and does not depend on protein nuclear localization.^Citation60	Nonstructural protein, no difference.	A specific protein with four helical structures was found in the fragment of ORF3b protein, and there was no homologous sequence with SARS-CoV.^Citation60
ORF8	ORF8 protein can activate intracellular stress signals and cause an NOD-like receptor protein 3 (NLRP3) inflammatory response.^Citation66	Nonstructural protein, no difference.	Compared with SARS-CoV, ORF8 has a 20% homology, which is the lowest homologous protein but can mediate the downregulation of host cell MHC-II.^Citation67

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