Innate Immune Response
The innate immune system is the first line of defense against pathogens through the activation of PRR in macrophages, neutrophils, and dendritic cells by the interaction with PAMPs. An effective innate immune response against viruses like SARS-CoV-2 is essential not only to initiate the response but also to structure the basis for the production of a robust and more specific adaptive response (162). Changes in this process, commonly observed in viral infections, can cause an immune imbalance and susceptibility of the host (163).
Patients who develop severe COVID-19 exhibited a marked increase in neutrophil and reduced lymphocytes counts compared with patients with mild signs of the disease (10). A general increase in the number of circulating neutrophils and the reduction of lymphocytes enhance the neutrophil/lymphocyte ratio, which has been used as a predictor of the infection severity and development of pneumonia. In addition to being a predictor of a worse prognosis, an increase in this ratio also indicates a serious immune imbalance in these patients (153).
In addition to having high levels of cell-free DNA, myeloperoxidase-DNA, and citrullinated histone H3 – important markers of neutrophil extracellular traps (NETs) –, the serum of COVID-19-positive patients was able to strongly trigger NETosis in healthy neutrophils in vitro (164). Despite representing important strategies to eliminate pathogens by neutrophils, NETs damage healthy tissue and induce inflammation (165), in addition to featuring a variety of oxidizing agents and being involved in several vascular diseases, as well as pathogen-induced acute lung injury. The release of NETs by neutrophils can be triggered by several factors, such as virus-damaged epithelial cells, activated platelets, activated endothelial cells, and inflammatory cytokines, such as IL-1β, IL-8, and G-CSF, among others (95, 166–169). In this context, it is fundamental to conduct studies assessing the role of neutrophils and NETs to better understand COVID-19 pathogenesis.
Concerning monocytes, COVID-19 patients have shown an abundant circulation of CD14+ CD16+ cells, with a sharper increase in patients who developed severe respiratory syndrome. This subtype of monocytes can over-secrete TNF-α, IL-1β, and IL-6 and expand quickly in systemic infections, implying that they must play an important role in the rapid defense against pathogens. Controversially, these cells are the main producers of IL-10, which makes their exact function in immune responses elusive (170, 171). Additionally, Dutertre et al. (172) demonstrated that CD14+ CD16+ monocytes are responsible for TNF overproduction in HIV infections and might be considered the major actor in immune hyperactivation in disease (172).
A study assessing bronchoalveolar lavage of SARS-CoV-2-positive individuals found an abundance of monocytes-derived inflammatory macrophages in critically ill patients. In addition, the authors observed through single-cell analysis that these macrophages can contribute to local inflammation by recruiting inflammatory monocytes and neutrophils through CCR1 and CXCR2 chemokine receptors. However, in patients who presented a moderate form of the disease, macrophages produced chemo-attractants for the recruitment of T cells, such as CXCR3 and CXCR6. Such a difference in response might be the key to understanding the pathogenesis of respiratory failure in COVID-19 (173).
Furthermore, critically ill patients have also manifested rapid proliferation of another subpopulation of monocytes characterized by GM-CSF+ IL-6+, which may be related to inflammatory risk and impairment of the lungs when migrating in large quantities (170). GM-CSF has been described as an active part of the pathogenesis of autoimmune and inflammatory diseases, mainly in the involvement of myeloid cells, such as monocytes, which can initiate tissue damage in a dependent manner on this marker (174, 175). In addition, high levels of mediators, such as IL-6, TNF-, and IL-10, found in these patients are likely to have been produced by these monocytes and to be highly involved in cytokine storm and pathogenesis of SARS-CoV-2, since as the disease progresses these mediators reduce, which is correlated to the restoration of the immune function of CD4+ and CD8+ T lymphocytes, which is further discussed later (154).
Critical COVID-19 patients have shown excessive activation of circulating HLA-DR- monocytes, which has been associated with the onset of respiratory failure, suggesting its role as a predictive factor. The lack of expression of HLA-DR in monocytes may indicate a modulatory capacity of the virus, which prevents the antigen presentation and hampers the formation of an adaptive immune response (176, 177).
During an in vitro experiment, Yang et al. (178) found that, despite being permissive to infection by SARS-CoV-2, human monocyte-derived macrophages and dendritic cells are not able to effectively produce viral replicates. Despite their central role in pathogenesis, this may indicate that these cells are not important reservoirs for viruses. In addition, neither of the cell types developed a response based on type II IFN, but macrophages had lower production of type I and III IFN than the control, indicating that the virus can inhibit a response mediated by these types of IFNs. Additionally, macrophages were able to trigger an exacerbated inflammatory response with higher TNF-α, IL-8, IP10, MIP1α, and IL-1β. Dendritic cells had not been reported to show such inflammatory phenomenon, which is due to the ability of SARS-CoV-2 to inhibit STAT1 phosphorylation. Such important attenuation of dendritic cell response caused by the virus may have important implications for humans to develop effective immunity, therefore, further studies should seek to better elucidate such a relevant relationship.
Similarly, in the presence of IFN-α and GM-CSF, circulating monocytes should quickly differentiate into monocyte-derived dendritic cells (mDC), which are important antigen-presenting cells capable of phagocyting viruses and initiating the adaptive immune response process, as well as activating CD4+ T cells, generating immune memory in the process, and refining the body’s defense against infections (179, 180).
The number of mDCs has not increased in patients infected with SARS-CoV-2 compared with healthy controls, even in the most severe cases of the disease. Interestingly, the levels of GM-CSF in the serum of these patients are highly elevated, which should lead these cells to increase, demonstrating that the virus may have a mechanism to control the production of IFN-α and consequent differentiation of mDCs (9, 26). In the same way, individuals infected and not infected with SARS-CoV-2 have similar levels of IL-12, an important cytokine produced by mDC that is involved in the differentiation of naïve T cells (9, 181).
Thus, we hypothesize that the lack of mDC generation and consequent inability of the infected individual to produce IL-12 may be among the main factors of innate immunity-related pathogenesis of COVID-19. As further discussed, the increase in naïve T cells, reduced cell functionality of CD4+, CD8+, and natural killers (NK), and delay in the appearance of humoral response found in these patients indicates a failure in the generation and function of mDC. Therefore, it is urgent to carry out studies aimed at analyzing the effect of SARS-CoV-2 on dendritic cells.