Section 3: The Role of Host Immune Response (from DOI: 10.1007/s11886-020-01292-3)
From publication: "Cardiovascular Complications in Patients with COVID-19: Consequences of Viral Toxicities and Host Immune Response" published as Curr Cardiol Rep; 2020 04 21 ; 22 (5) 32. DOI: https://doi.org/10.1007/s11886-020-01292-3
Section 3: The Role of Host Immune Response
The host immune response to viral entry is also important to discuss, as pathogenesis in the later stages of SARS-CoV and SARS-CoV-2 infection results not only from direct viral toxicity but also from immune dysregulation and hyperactivity. Progress in this field, however, has been hindered by the failure to replicate in mice, ferrats, or non-human primates the lethal human immune response in ARDS with the original SARS-CoV strain. This has led to the development of mouse- or rat-adapted strains of SARS-CoV that have been able to replicate the extensive and often lethal pulmonary disease. The majority of studies addressing the immune response to respiratory viral infections involve mice infected with a variety of natural and mouse-adapted pathogens.
The process of respiratory viral invasion into the body begins with infection of the airway epithelial cells and the activation of lung-resident dentritic cells (rDCs) via acquisition of the invading pathogen or antigens from infected epithelial cells. These rDCs then become activated, process antigen and migrate to the draining (mediastinal and cervical) lymph nodes (DLN). Naive circulating T cells in the DLNs then recognize antigens presented on the DCs in the form of MHC/peptide complexes. In combination with additional co-stimatory signals, T cells then become activated, proliferate, and migrate to the infected site. Upon arrival to the site of infection, T cells produce and release antiviral cytokines including interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-2; chemokines including CXC chemokine ligand (CXCL)-9, 10, and, 11, and cytotoxic molecules such as perforin and granzyme B. IFN-gamma and other effector cytokines directly inhibit viral replication and enhance antigen presentation, while the chemokines released by activated T cells recruit more innate and adaptive cells to combat the pathogen. Granzyme B and other cytotoxic molecules also directly kill infected cells to eliminate the pathogen.
Recent data from China on SARS-CoV-2 as well as prior data from SARS-CoV demonstrate a rapid reduction of T lymphocytes (both CD4+ and CD8+) in the peripheral blood of infected patients. This is in direct contrast to the proliferative lymphocyte responses seen with other viral infections such as Epstein-Barr Virus (EBV), human immunodeficiency virus (HIV)-1, or cytomegalovirus (CMV), but similar to what happens during other acute viral infections, such as influenza. The loss of lymphocytes precedes even the abnormal radiographic changes on chest X-ray . Despite reduction in T lymphocyte counts, peripheral blood analysis on a patient infected with SARS-CoV-2 demonstrated increased markers of T lymphocyte activation, as evidenced by high proportions of HLA-DR and CD38 double-positive fractions. Additionally, there was an increased percentage of highly proinflammatory CCR6+ Th17 among CD4+ T cells, and an increased concentration of cytotoxic granules in CD8+ T cells (31.6% perforin positive, 64.2% granulysin positive, and 30.5% granulysin/perforin double-positive). Interestingly, one group found that production of IFN-gamma by CD4+, T cells but not CD8+ T cells or NK cells tended to be lower in severe cases compared with moderate cases. CD4+ T cells, in particular, are felt to be especially important in the host-immune defense against SARS-CoV infections. In addition, disturbances in T regulatory cells (Tregs) were noted in severe cases:with a significantly lower proportion of C45RA+ naive Tregs (nTregs) and a slightly higher proportion of their memory counterparts CD45RO+ memory Tregs (mTregs). On recovery, there is a rapid and significant restoration of CD3+, CD4+, and CD8+ T cells along with B cell and NK cell counts 2-3 months after onset of disease. Memory CD4+ T cells returned to normal 1 year after onset, whereas other cell counts including total T lymphocytes, CD3+, CD4+ and naive CD4+ T cells were still lower than healthy controls . The mechanism of lymphocytopenia in peripheral blood is unclear but thought to be due to sequestration, with release of sequestered cells upon recovery. Taken together, these changes in lymphocyte populations suggest dramatic dysregulation, evidence of T cell "exhaustion" and shifts in the adaptive immune response to SARS-CoV and SARS-CoV-2 infections.
In addition to changes in lymphocyte populations, changes in innate immunity likely also contribute to viral pathogenesis, particularly as seen in severe lung and systemic inflammation secondary to cytokine storm. In ARDS, increased levels of cytokines such as TNF-alpha, IFN inducible protein 10 (IP10), IL-6, and IL-8 are thought to contribute to tissue destruction and poor outcomes, attributed to hyperactivation of macrophage/monocyte lineage cells. SARS-CoV-2-infected patients have high levels of IL-1 beta, IFN-gamma, IP-10, and monocyte chemoattractant protein-1 (MCP-1), which probably leads to activated T-helper-1 cell response. Compared with patients who did not require ICU admission, those requiring ICU admission had higher conentrations of granulocyte colony-stimulating factors (GCSF), IP-10, MCP-1, macrophage inflammatory protein-1 alpha (MIP-1-alpha), and TNF-alpha, suggesting that cytokine storm might affect disease severity. Additionally, increased levels of type I IFN and a dysregulated IFN-stimulated gene (ISG) response have been seen in patients with severe SARS.
Last but not least, SARS-specific IgG antibodies are produced in the late acute stage (about 2 weeks from symptom onset), gradually increase throughout the course of the disease and are felt to be associated with disease outcome. The development of anti-SARS-CoV-2 antibodies is highly relevant for both protecting against viral replication/expansion in the infected host as well as providing a source of anti-SARS-CoV-2 convalescent plasma to treat patients with severe disease, although supporting data for efficacy is currently lacking. This is being tested in COVID-19 positive patients under an expanded access program by the FDA.
