Section 4: Host response to SARS-CoV-2 (from DOI: 10.1016/j.clim.2020.108427)
From publication: "COVID-19 pathophysiology: A review" published as Clin. Immunol.; 2020 Apr 20 108427. DOI: https://doi.org/10.1016/j.clim.2020.108427
Section 4: Host response to SARS-CoV-2
The symptom of patients infected with SARS-CoV-2 ranges from minimal symptoms to severe respiratory failure with multiple organ failure. On Computerized tomography (CT) scan, the characteristic pulmonary ground glass opacification can be seen even in asymptomatic patients. Because ACE2 is highly expressed on the apical side of lung epithelial cells in the alveolar space, this virus can likely enter and destroy them. This matches with the fact that the early lung injury was often seen in the distal airway. Epithelial cells, alveolar macrophages and dendritic cells (DCs) are three main components for innate immunity in the airway. DCs reside underneath the epithelium. Macrophages are located at the apical side of the epithelium. DCs and macrophages serve as innate immune cells to fight against viruses till adaptive immunity is involved.
T cell mediated responses against coronaviruses have been previously reviewed. T cell responses are initiated by antigen presentation via DCs and macrophages. How does SARS-CoV-2 enter APCs? DCs and macrophages can phagocytize apoptotic cells infected by virus. For example, virus-infected apoptotic epithelial cells can be phagocytized by DCs and macrophages, which leads to antigen presentation to T cells. Or DCs and macrophages may be infected with virus primarily? Based on the Immunological Genome database (http://rstats.immgen.org), the expression of ACE2 on (splenic) dendritic cells and alveolar macrophages is present but limited (Fig. 1 ). Determining whether or not SARS-CoV-2 uses another protein to bind to APCs helps to answer this question. SARS-CoV can also bind to dendritic-cell specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) and DC-SIGN-related protein (DC-SIGNR, L-SIGN) in addition to ACE2. DC-SIGN is highly expressed on dendritic cells and macrophages. Another target for SARS-CoV-2, if any, can help the virus to directly infect DCs and alveolar macrophages. This needs future research. These antigen presenting cells move to the draining lymph nodes to present viral antigens to T cells. CD4+ and CD8+ T cells play a critical role. CD4+ T cells activate B cells to promote the production of virus-specific antibody, while CD8+ T cells can kill viral infected cells.
Immunological studies were mainly reported in severe COVID-19 patients. Patients with severe diseases showed lymphopenia, particularly the reduction in peripheral blood T cells. Patients with severe diseases were reported to have increased plasma concentrations of proinflammatory cytokines, including interleukin (IL)-6, IL-10, granulocyte-colony stimulating factor (G-CSF), monocyte chemoattractant protein 1 (MCP1), macrophage inflammatory protein (MIP)1alpha, and tumor necrosis factor (TNF)-alpha. The more severe conditions patients were in, the higher their IL-6 levels were. CD4+ and CD8+ T cells were activated in those patients as suggested by higher expression of CD69, CD38 and CD44. Higher percentage of checkpoint receptor Tm3+PD-1+ subsets in CD4+ and CD8+ T cells showed that T cells were also exhausted. NK group 2 member A (NKG2A), another marker for exhaustion was elevated on CD8+ T cells. Exhaustion of T cells could have led to the progression of the disease. Another interesting finding was that aberrant pathogenic CD4+ T cells with co-expressing interferon (IFN)-gamma and granulocyte-macrophage colony-stimulating factor (GM-CSF) were seen in COVID-19 patients with severe disease. GM-CSF production from T cells has been previously reported as a response to virus infection. GM-CSF can help to differentiate innate immune cells and augment T cell function, but it can initiate tissue damage at excess. GM-CSF+IFN-gamma+ CD4+ T cells were previously seen upon strong T cell receptor (TCR) responses in experimental autoimmune encephalomyelitis (EAE) models, where CD8+ T cells expressing GM-CSF were found at higher percentage and secreted IL-6. It is worth mentioning that these immunological studies were exclusively reported from adult patients. Immunological responses in pediatric population needs to be examined.
The study of SARS-CoV showed that virus infected lung epithelial cells produced IL-8 in addition to IL-6. IL-8 is a well-known chemoattractant for neutrophils and T cells. Infiltration of a large number of inflammatory cells were observed in the lungs from severe COVID-19 patients, and these cells presumably consist of a constellation of innate immune cells and adaptive immune cells. Among innate immune cells, we expect the majority to be neutrophils. Neutrophils can act as double-edged sword as neutrophils can induce lung injury. The majority of the observed infiltrating adaptive immune cells were likely T cells, considering that the significant reduction in circulating T cells was reported. CD8+ T cells are primary cytotoxic T cells. Severe patients also showed pathological cytotoxic T cells derived from CD4+ T cells. These cytotoxic T cells can kill virus but also contribute to lung injury. Circulating monocytes respond to GM-CSF released by these pathological T cells. CD14+CD16+ inflammatory monocyte subsets, which seldom exist in healthy controls and were also found at significantly higher percentage in COVID-19 patients. These inflammatory CD14+CD16+ monocytes had high expression of IL-6, which likely accelerated the progression of systemic inflammatory response.
An interesting note is that ACE2 was significantly expressed on innate lymphoid cells (ILC)2 and ILC3 (Fig. 1). NK cells are a member of ILC1, which constitute a large portion of ILCs in the lung (~95%). ILC2 and ILC3 work for mucous homeostasis. So far there is a very limited study of ILC2 and ILC3 in coronavirus infection.
In additionto respiratory symptoms, thrombosis and pulmonary embolism have been observed in severe diseases. This is in line with the finding that elevated d-dimer and fibrinogen levels were observed in severe diseases. The function of the endothelium includes promotion of vasodilation, fibrinolysis, and anti-aggregation. Because endothelium plays a significant role in thrombotic regulation, hypercoagulable profiles seen in severe diseases likely indicate significant endothelial injury. Endothelial cells also express ACE2. Of note, the endothelial cells represent the one third of lung cells. Microvascular permeability as a result of the endothelial injury can facilitate viral invasion.
