Table 1.

Overview of innate immune reactions to SARS‐CoV‐2

Innate immune response	Reaction	Outcome	References
Macrophage	After SARS‐CoV‐2 infection, the renal, splenic, and alveolar macrophages are stimulated and then heightened the formation of proinflammatory cytokines such as IL‐6, IL‐10, and TNF‐α. In sum, the accumulating evidence indicated that in severe cases with COVID‐19, alveolar macrophages are likely to generate chemokines that select further neutrophils and monocytes to the lung, which contribute to the excessive formation of proinflammatory agents.	Induction of highly inflammatory response and potent chemokines, ARDS	47 , 57 , 58
Neutrophil	Neutrophils serve as hyperinflammation operators using increased cell degranulation and cytokine production in patients with COVID‐19. Notably, investigations explained that the exhibition of neutrophils from healthy subjects to cases infected with SARS‐CoV‐2 sera supports the NET activity, suggesting that NETs might act as a possible target in severe cases with COVID‐19.	Tissue injury due to potent inflammatory reactions	59 , 60 , 61
NK cell	The rate of CD56dimCD16+KIR+ NK cells was significantly decreased in the blood sample of COVID‐19 patients, implying either disrupted maturation or expanded recruitment of NK toward tissues infected with SARS‐CoV‐2. The recent finding demonstrated that COVID‐19 could modulate the cytotoxic activity of NK cells by provoking the upregulation of the NKG2A. The impaired cytotoxic activity and decreased number of NK cells in circulation were noticed in severe cases with COVID‐19, in mild patients, and in dead versus survivor cases, proposing that the functional impairment of NK cells activity points to enhanced cell activation innate immunity with an extensive production of proinflammatory cytokine.	The induction of massive production of proinflammatory cytokine due to increased activation of innate immunity cells	47 , 62 , 63 , 64
MDSC	Current reports have indicated a dysregulation in the myeloid cells in COVID‐19 severe cases, with heightened levels and activity of MDSC relating to disease severity. The enhanced ratio of MDSC to T CD8+ effector cells (memory) was found in severe COVID‐19 cases with ARDS compared to moderate pneumonia cases with COVID‐19; this finding showed that MDSC related to COVID‐19 augmentation is directly associated with lymphopenia and heightened arginase activity. The accumulating data proposed that G‐MDSCs and other myeloid cells signify unlimited negative feedback, eventually establishing pan‐immunosuppression and following dysregulation in adaptive immune responses.	Modulating immunity against SARS‐CoV‐2 (immunosuppressive properties) increases cytokine levels and other proinflammatory markers	65 , 66 , 67 , 68 , 69
Eosinophil	Comprehensive examination showed that COVID‐19 severity is correlated with intensified eosinophil‐mediated pulmonary inflammation. The recent finding showed that SARS‐CoV‐2 infection distinct innate immune responses, including inflammatory conditions related to eosinophil and following Th2 reactions, contributing to severe pneumonia associated with COVID‐19.	Pulmonary inflammation	57 , 70 , 71 , 72
DCs	The investigation revealed that isolated pDCs are stimulated through diversification into P1 and P2, as well as P3 subpopulations. It has been shown that BALFs from severe and critical COVID‐19 cases comprise fewer pDCs than moderate cases. The pDCs stimulated in COVID‐19 generate high concentrations of IFNs by the TLR‐7 pathway.	Impaired IFN‐α production	73 , 74 , 75

Abbreviations: ARDS, acute respiratory distress syndrome; BALF, bronchoalveolar lavage fluid; COVID‐19, coronavirus disease 2019; DC, dendritic cell; IFN, interferon; IL, interleukin; G‐MDSC, granulocyte‐myeloid‐derived suppressor cell; NET, neutrophil extracellular trap; NK, natural killer; NKG2A, NK group 2 member A; pDCs, plasmacytoid dendritic cells; SARS‐CoV‐2, severe acute respiratory syndrome coronavirus 2; TLR, Toll‐like receptor 8; TNF‐α, tumor necrosis factor‐α.