**2. Innate immune response to SARS-CoV-2**

Upon infection by SARS-CoV-2 several chemokines (CCL2, CCL3, CCL4, CCL5, CXCL8, CXCL9, and CXL10) and pro-inflammatory cytokines (IFN-γ, TNF, IL-1, IL-6, IL-12) are released, these molecules will induce cell activation, migration, and infiltration of the infected tissue by innate immune cells like monocytes and neutrophils and further activate local cells such as resident macrophages [19]. These cells will further increase the local production of pro-inflammatory mediators, which could result in tissue damage, such as alveolar damage, formation of edema, and reduced lung capacity. In addition, cytokines can generate a systemic effect, resulting in damage to other organs (kidney, liver, spleen, among others) [20]. An increase in circulating pro-inflammatory monocytes and nonclassical monocytes are commonly observed in COVID-19 patients [21, 22].

Concomitantly, the number of neutrophils in the blood increases, and the infiltration of neutrophils to the infected tissue. Upon infiltration, neutrophils release inflammatory mediators, cytokines, and neutrophil extracellular traps (NETs) which can further increase tissue injury and cellular death [23, 24]. The local production of pro-inflammatory factors, viral particles, and cellular death induces the activation of macrophage and dendritic cells (DCs), which will further increase the production of cytokines and chemokines and antigen presentation [20, 25] DCSs are commonly referred to as professional antigen-presenting cells (APCs) and integrate innate and adaptive immune response. In COVID-19 they can uptake SARS-CoV-2 viral particles, be activated, migrate to lymphatic tissue, initiate antigen presentation, and trigger adaptive immune response. Nevertheless, DCs can also be infected by SARS-CoV-2 [26], reducing quantitatively, generating functional impairment, and lower lymphocyte immune response [27].

The complement system has also been implicated in the pathogenesis of COVID-19. The activation of C3 and C5 complement components are correlated with disease severity and lung biopsy from severe COVID-19 patients presented high C3-fragment content [28]. C3-deficient mice are partially protected from respiratory dysfunction after SARS-CoV-1 infection, exhibiting less inflammatory infiltrate in the lungs, reduced production of cytokines and chemokines, but similar viral load in the lung tissue as Wild Type mice [29]. Importantly, treatment with anti-C5a antibodies resulted in clinical improvement in COVID-19 patients [28]. Indicating a possible use of complement-inhibitor to ameliorate lung injury in COVID-19 patients.

The role of eosinophils and basophils in COVID-19 is yet to be fully comprehended. To the moment, a negative correlation is established between circulating eosinophil and basophil count and COVID-19 severity, with patients exhibiting an increase in those cells upon SARS-CoV-2 clearance [30, 31]. Mast cells (MCs) may also play a role in COVID-19, since they can be activated by viral products and release chemokines, cytokines, and inflammatory mediators, increasing vascular permeability and cellular infiltrate [32]. A few reports have indicated that COVID-19 inflammatory syndrome is in many aspects similar to Mast cell activation disease [32, 33].

The frequency of mononuclear and polymorphonuclear myeloid-derived suppressor cells also increases in the blood, but not in the lungs, of COVID-19 patients according to the severity [15, 34]. Importantly, these cells do maintain their immunosuppressive functions in COVID-19 patients [35].

The hyperinflammatory state is also accompanied by a dysregulated antiinflammatory state, with an increased early IL-10 production, which could curb the anti-viral immune response [36], and impaired T cells (CD4+ and CD8+) and T regulatory cells function [37].
