V4 COVID and the Immune System: Determining the Parameters of the Immune Response in Covid-19
Ending COVID
A Review of the Interactions of Covid-19 with Elements of the Immune System
As greater understanding of the progression of Covid-19 is documented, the interactions between the virus and the immune system are being determined. One of the critical factors that resulted in the pandemic was the variability of symptom presentation regarding Covid-19. While in some individuals, the Covid-19 disease remained asymptomatic, other individuals presented severe complications, such as interstitial pneumonia and respiratory failure. Due to the large presence of asymptomatic individuals throughout the population, the vast majority of those infected remained unidentified until it was too late to contain the spread of the virus. Establishing the mechanisms of immune responses in COVID-19 will allow us to provide a deeper insight into the disease pathogenesis of the virus, and document the diverse clinical manifestations of the disease in the immune system of an infected individual.
When considering the immune system as a whole entity, it can be observed as two separate systems, one being the innate, the other the adaptive. Additional key features of the immune system include cells, organs, and responses. It is suggested that the innate immune responses and relevant cell types play a vital role in the clinical symptoms and severity of COVID-19 disease. The disease appears to predominantly infect airway/alveolar epithelial cells, vascular endothelial cells, and macrophages. These innate immune cells, specifically macrophages, may contribute, in some cases, to the disease progression of Covid-19. Macrophages have shown a significant production of IL-6, suggesting they may contribute to the excessive inflammation in COVID-19, which is a factor in determining its severity and length.
The first line of defense, the mucosal surfaces, are protected against the virus via mucosa associated lymphoid tissues (MALT). Since it has been determined that the SARS CoV-2 has been described to enter the human body through the respiratory tract, oral mucosa and conjunctival epithelium. Mucosal IgA protects these physical barriers and its presence can be critical. IgA is considered a major effector molecule to defend the physical barrier against virus. It has been revealed that a specific IgA response is detectable in 75% of the patients within the first week and appears to be stronger and more persistent than an IgM response, a feature in those that demised. Autopsies on patients who died of COVID-19, revealed a high infiltration of macrophages within the area of broncho-pneumonia. These macrophages showed a significant production of IL-6 suggesting they may contribute to the excessive inflammation in COVID. In additional it has already been discussed if a strong IL-6 mediated inflammatory response, which is normally responsible for the health regain after the viral infection, could deteriorate the recovery of COVID-19 patients via what is known as the macrophage activation syndrome.
Another factor to consider is, that the maturation and differentiation of the innate immune cells, including neutrophils, macrophages, natural killer cells, and dendritic cells, is modulated by estrogen and testosterone hormones. Therefore a question could be raised, whether the sex differences in the clinical manifestation of COVID-19 disease might be associated with the hormonal dependency of the innate immune responses, clearly resulting in a gender bias regarding both the infection and severity of the virus among both genders.
An additional general issue causally linked, is the higher winter incidence of the respiratory disease relevant to innate immunity is vitamin supplementation and availability. Namely, vitamin D could be the key factor with its multiple immuno-regulatory functions in the combination with sun exposure which might be more evident in geographical factors. The clinical manifestation clearly depend on multiple factors, such as genetic background (HLA, gene polymorphisms – such as for ACE2) and the individual variability in environmental/personal risk factors (age, smoking, diet, physical activity, vaccination scheme, contact history with other CoV viruses). In addition COVID-19 mortality and severity is not only age, but might also be gender based.
Regarding the adaptive immune system. As opposed to innate immune responses, in adaptive immune responses, it has been revealed that cytotoxic CD8+ T cells exhibit functional exhaustion patterns, such as the expression of NKG2A, PD-1, and TIM-3. Adaptive immune responses are essential for SARS-CoV-2 virus clearance. Since SARS-CoV-2 restrains antigen presentation by downregulating MHC class I and II molecules therefore, it inhibits the T-cell mediated immune responses. From the very onset the most common clinical symptom of COVID-19 was determined as fever, therefore the involvement of pro-inflammatory cytokines is evident. Increased serum levels of IL-6 were observed in more than 50 % of the patients.
When the disease first materialized had there been the immediate development of a suitable vaccine it might have been effective in reducing the spread among the population. The presence of neutralizing antibodies is a critical component of effective vaccines, and their levels might assist in the prevention of viral infections.
T-Neutralizing anti-SARS-CoV-2 antibodies may serve not only as passive antibody therapy but also as a marker of vaccine efficacy. Regarding the cellular immune responses as a whole, a recent study has already shown that SARS-CoV-2-unexposed individuals were able to in vitro develop a CD4+ T-cell response to SARS-CoV-2-derived peptides only in ~50 % of cases, and a CD8+ T-cell response was noted even only in ~20 % of cases (Grifoni et al. 2020). In the COVID-19 convalescent patients, the response rate was then much higher: ~100 % for CD4+ and ~70 % for CD8+ T-cells (Grifoni et al. 2020). This data showed that a great portion of the SARS-CoV-2-unexposed human population might fail to mobilize the adaptive immune responses after the virus contraction. Therefore, enhancing the immunity in the first phase and suppressing the immunity in the second phase may be the fundamental approach for COVID-19 therapeutic management. In conclusion, some factors to consider when devising a preliminary outline of the description of the clinical manifestation of Covid-19 responses of the immune system.
COVID-19 and the Immune System Jan PACES1*, Zuzana STRIZOVA2*, Daniel SMRZ2 , Jan CERNY1 1 Laboratory of Cell Immunology, Faculty of Science, Charles University, Prague, Czech Republic, 2 Department of Immunology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
