Covid-19 continues to spread globally, in many places unabated. From the first origins of the disease in Wuhan, Chinese scientists have been rushing to find an effective immune based treatment and vaccine. In order to do so the immune response of the virus must be fully understood. How does the human immune system Function normally? On a molecular level why does the clinical syndrome of SARS-CoV-2 range from asymptomatic to death? How do scientists determine the immune response of the virus and how can this be used to determine the severity of the virus? How can recent developments be used to adapt our treatments? What parts of the bodies response to the virus remain unknown?
The immune system is a complex defence network comprising several biological structures within the body that act to protect us against disease, it can loosely be split in two main groups: Innate and Adaptive. While immunity is gained via the adaptive immune system it is also necessary to have a brief understanding of the innate immune system. Pathogens that enter the body first encounter the mechanisms of the innate immune system when pattern recognition receptors recognise the antigens. Simply put proteins expressed by the leukocyte cells of the innate immune system recognise proteins expressed on the pathogen’s surface as foreign. These cells commonly known as white blood cells act as an independent, single celled organism that engulfs the pathogen, trapping it in an intercellular vesicle (a structure in which liquid is enclosed in a lipid) called a phagosome. This fuses with another vesicle – a lysosome which contains enzymes to break down biological molecules. It is then destroyed by a respiratory burst (a rapid release of some reactive oxygen species like hydrogen peroxide) which releases free radicals (a highly chemically reactive molecule that has an unpaired outer or valence electron) into the fused vesicles. There are many different subgroups of white blood cell, however every type acts generically, meaning every pathogen is countered in the same generic way and it does not confer any lasting Immunity to the virus in question. To do that we need to discuss the adaptive immune system.
There is a subgroup of leukocytes called dendritic cells which trigger the adaptive immune response by using enzymes to break a pathogen down in smaller pieces called antigens which it then displays on its surface. Depending on the LINK type of dendritic cell they are this then triggers either helper (CD4+) or killer (CD8+) T-cells. Helper T-cells cannot kill infected cells or clear pathogens, but “manage” the immune response, by directing other cells to perform tasks. They provide extra signals that “help” activate cytotoxic cells. Killer T-cells release cytotoxins that form pores in the target cell’s plasma membrane, allowing ions and water to flow into the infected cell, and causing it to burst. Once an infection has been beaten most cells die and are cleared away but a few become memory cells. On a later encounter with the same antigen, these memory cells quickly differentiate into effector cells. These produce antibodies which are proteins that have the specific structure to attach to the pathogen leading to the pathogen being destroyed or unable to enter cells thus dramatically shortening the time required to mount an effective response – i.e. the body is now immune to the disease. A fuller explanation of the adaptive immune system in terms of immune network theory and clonal selection theory can be found in references (3) and (4).
Severe Acute Respiratory Syndrome Coronavirus 2 (or SARS-CoV-2), which has caused the COVID-19 pandemic, enters the target cells through the interaction of its envelope Spike protein and then enters the cell membrane. Antibodies that can bind to this Spike protein have the potential to neutralize viral entry into cells and are thought to play an important role in the protective immune response to CoV-2 infection. To predict protection, it is critical we understand the quantity, quality, and duration of the antibody responses during different stages of COVID-19 and in the convalescent period. Defining the relationship between the disease severity, other individual-specific co-morbidities and the neutralizing antibody responses will be critical in our understanding of COVID-19 and in tailoring effective therapies.
A new paper by the British Society for Immunology (reference 6) analysed multiple immune cell populations in the blood of Chinese patients with COVID-19. Venous blood was withdrawn from each patient and was analysed. While the measured abnormally low lymphocytes are consistent with other reports, for severe patients with Covid both killer and helper T-Cells were comprehensively reduced. In patients with mild symptoms only CD8+ cells were significantly reduced. While this needs more work, it could provide a way to determine the severity of the virus. Surprisingly IFN-c, an important type of protein (called a cytokine) produced by both CD4+ and CD8+ T cells remained at low levels. The reason for this remains unknown and requires further study to enable effective vaccine design.
In another paper (reference 7) developed assays (a procedure to determine the amount of some target entity) to measure specific CoV-2 antibodies in patients and similarly found several useful results. First the clustering of antibody responses based on severity of the disease as hospitalized patients showed much higher antibody levels than outpatients or convalescent plasma donors. Most of the convalescent plasma donors had much lower level of neutralizing antibodies than hospitalized patients, who would be the suitable recipients for such plasma transfer therapy. This therefore raises the question of whether it is beneficial to actually transfer plasma to severely ill patients. It also means surviving COVID-19 may require non-antibody dependent factors or that producing too much antibody may even have deleterious effects.
For other infections it’s well-recognised that a massive immune response (known a cytokine storm) can be very dangerous and is what actually kills you. A further noteworthy observation is that further out from the infection, there appears to be less antibody response. While more observations must happen to better assess this finding, it may mean that the antibody response to the virus is short lived. Thus, understanding the mechanism of survival from COVID-19 and immune response dynamics will be critical, in better prediction of outcomes as well as for developing a protective response to potential vaccines.
1) – Caneway CA, Jr. Immunobiology (6th ed.). Garland Science (2005)
2) – Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walters P. Molecular Biology of the Cell (4th ed.). New York and London: Garland Science (2002)
3) – G. W. Hoffmann Immune Network Theory. (2008) http://www.physics.ubc.ca/~hoffmann/ni.html
4) – Rajewsky, Klaus. “Clonal selection and learning in the antibody system”. Nature. 381 (6585): 751–758 (1998)
5) – Dogan, M., Kozhaya, L., Placek, L., Gunter, C., Yigit, M., Hardy, R., Plassmeyer, M., Coatney, P., Lillard, K., Bukhari, Z. and Kleinberg, M. Novel SARS-CoV-2 specific antibody and neutralization assays reveal wide range of humoral immune response during COVID-19. medRxiv. (2020)
6) – Tan, M., Liu, Y., Zhou, R., Deng, X., Li, F., Liang, K. and Shi, Y. Immunopathological characteristics of coronavirus disease 2019 cases in Guangzhou, China. Immunology. (2020)