The immune system and COVID-19
Research on COVID-19 and the virus that causes it—SARS-CoV-2—is still in its infancy. As a result, study designs on COVID-19 have not been ideal and any conclusions drawn about how the virus causes injury and disease should be considered preliminary.
Before delving into what scientists have found about SARS-CoV-2 and the immune system, we first present some general and simplified information about the immune system.
The first line of defence against germs is the innate immune system. This part of the immune system recognizes patterns in the structure of germs and can activate an immune response when it senses a virus or other germ.
Another part of the immune system is called the adaptive immune system. This involves B-cells that produce antibodies and T-cells that help regulate the immune response and also fight viruses (and other germs).
The immune system is widely distributed—it’s found in lymph nodes and lymphoid organs such as the spleen, thymus and bone marrow. Cells of the immune system are also present in different organs and tissues, where they are on guard for invading germs.
The immune response
The immunological response to an invading germ involves first sensing the germ and then releasing chemical signals to attract other cells of the immune system to the site of infection or accumulation of the germ, such as in a lymph node or infected organ. These chemical signals can cause the production of interferon, which can protect cells against infection.
Organs such as the spleen and tissues such as lymph nodes can become swollen as they cause a massive expansion in the number of the immune system’s cells. Some cells that specialize in capturing invading germs bring the germs to lymph nodes and lymphoid organs, where other cells of the immune system can be educated about what to attack.
To increase the body’s ability to resist the invading germ, the immune system triggers a fever. The raised temperature helps to slow the growth of infected cells. However, the steps taken by the immune system to fight an infection can cause the symptoms of what many people associate with the flu or a severe cold—fatigue, bone and muscle pain, swollen lymph nodes and so on.
It is possible that, in some cases, the immune system may overreact to an invading germ and its ability to regulate itself becomes weakened. This could lead to the immune system inadvertently attacking itself or parts of the body. Some of the severe lung injury found in people who died from COVID-19 may be immunological in origin.
Findings in COVID-19
Scientists in China have been exploring the impact of SARS-CoV-2 on the immune system. Their findings should be treated as preliminary, as the studies generally have small numbers of people. However, they are what is available as this issue of TreatmentUpdate goes to press.
A study at Tongji Hospital in Wuhan, China, analyzed blood samples from 21 people (17 men, 4 women), all of whom had either severe (11 people) or moderate (10 people) symptoms of COVID-19.
People who had severe symptoms tended to be old and had elevated levels of many chemical messengers (cytokines), such as the following:
- IL-6 (interleukin-6)
- Il-10 (interleukin-10)
- TNF-alpha (tumour necrosis factor-alpha)
They also had elevated levels of high-sensitivity C-reactive protein (hsCRP) and D-dimer. All of these are suggestive of inflammation.
Nearly all patients had reduced levels of T-cells, including CD4+ and CD8+ cells. The normal range for CD4+ cell counts at the hospital’s laboratory is between 550 and 1400 cells/mm3 and the normal range for CD8+ cells is between 320 and 1250 cells/mm3. Here are the cell counts in two sub-groups of patients with COVID-19:
- CD4+ count – 328 cells/mm3
- CD8+ count – 254 cells/mm3
- CD4+ count – 178 cells/mm3
- CD8+ count – 89 cells/mm3
These values are well below the normal range.
When researchers assessed the functional capacity of cells of the immune system to produce an antiviral response (by producing interferon-gamma), this ability was generally weakened in CD4+ cells, particularly in people with severe symptoms. Immunological weakness was present but less pronounced in people with moderate symptoms.
About 27% of patients in this analysis had bacterial infections of the lungs and respiratory tract.
Doctors gave patients intravenous fluid to maintain hydration, the antibiotic moxifloxacin to treat respiratory tract infections, broad-spectrum antiviral drugs to treat any presumptive viral infections and the steroid methylprednisolone to try to reduce inflammation. Four people died, all of whom had severe symptoms.
There are many limitations to this and similar studies. It had a small number of people. Data were captured for one purpose and then reanalyzed at a later date for another purpose. Another limitation was that lymphocytes (T-cells) were analyzed from only blood samples. Most lymphocytes are in lymphoid organs and tissues such as lymph nodes. In the future, when conducting immunological research on SARS-CoV-2 infection, it may be more useful to extract cells from lymphoid organs and related tissues.
Another limitation is that data were captured at one point in time and assumed to be relevant to the whole course of illness with COVID-19. The immune system is dynamic; there are changes that occur over the course of an infection and these need to be documented and studied.
However, the doctors in China were dealing with a health emergency and the fact that any information was captured on the immune systems of patients is remarkable.
Why were there decreased numbers of immune cells and functional capacity? Some scientists have speculated on these findings and advanced the following theories:
- SARS-CoV-2 could have directly infected T-cells. These cells have a receptor called ACE2 on their surface. The virus uses this receptor to gain entry to other cells, so it is plausible that the virus could have used the same receptor to enter cells of the immune system.
- SARS-CoV-2 could attack important organs of the immune system, such as the bone marrow, spleen and thymus gland.
- Excessive levels of cytokines, such as TNF-alpha, could cause cells of the immune system to invoke a self-destruct mechanism (apoptosis). This mechanism is commonly triggered by many viral infections and helps to destroy infected cells. However, apoptosis can also be triggered in uninfected cells during major infections.
Similar immunological dysfunction—excessive immune activation and inflammation, apoptosis—occurs in untreated HIV infection. The number of documented cases of SARS-CoV-2 in HIV-positive people is very small. As a result, at this time, there are no extensive reports of what happens to the immune systems of people with HIV who become co-infected with SARS-CoV-2.
Reviews and other studies
In reviewing the findings from Wuhan, scientists at Yale University stated that in some people with severe COVID-19, infection with SARS-CoV-2 appears to deplete the immune system of CD4+ and CD8+ cells in the blood. Furthermore, there was excessive production of cytokines. The Yale scientists stated that these cytokines are likely produced by cells of the immune system called macrophages. Not much research has been reported on macrophages from people with COVID-19.
Another team of scientists at Anhui Medical University in China compared blood samples from three groups of people:
- healthy controls – 25 people
- those with mild symptoms of COVID-19 – 55 people
- those with severe symptoms of COVID-19 – 13 people
They found broadly similar immunological issues as the scientists in Wuhan. In addition to low CD4+ and CD8+ cell counts, the Anhui scientists found that levels of a group of cells that can fight viruses, natural killer (NK+) cells, were less than normal.
The Anhui scientists also found that CD8+ and NK+ cells seemed less capable of carrying out antiviral functions in people with SARS-CoV-2, regardless of the degree of their symptoms. Analysis of blood samples from people who recovered from COVID-19 suggested that levels of T-cells and NK+ cells eventually returned to normal.
Another team of scientists at the Kunming Institute of Zoology, also in China, analyzed blood samples from 16 people with COVID-19. Ten of the people had mild symptoms and six had severe symptoms. For comparison, blood samples were taken from six healthy people.
In general, the scientists found a higher level of activated CD8+ cells in people with severe disease compared to people with mild disease or healthy people. What’s more, the CD8+ cells from people with severe COVID-19 seemed immunologically exhausted.
All of the teams of scientists have uncovered that infection with SARS-CoV-2 can harm the immune system. Perhaps the harm arises from excessive immunological activation, excessive inflammation, and exhaustion of CD8+, NK+ and CD4+ cells. However, it is important to note that many people who become infected with SARS-CoV-2 have mild symptoms or even no symptoms. Studying the immune systems of such people will become important to find clues about how they resist severe immunological injury.
—Sean R. Hosein
- Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579(7798):270–273.
- Perlman S, Dandekar AA. Immunopathogenesis of coronavirus infections: implications for SARS. Nature Reviews Immunology. 2005;5(12):917–927.
- Weiss SR. Forty years with coronaviruses. Journal of Experimental Medicine. 2020;217(5):e20200537.
- Cui J, Li F, Shi ZL. Origin and evolution of pathogenic coronaviruses. Nature Reviews Microbiology. 2019;17(3):181–192.
- Wang JT, Chang SC. Severe acute respiratory syndrome. Current Opinion in Infectious Diseases. 2004;17(2):143–148.
- Xu Z, Shi L, Wang Y, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respiratory Medicine. 2020; in press.
- Chen G, Wu D, Guo W, et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. Journal of Clinical Investigation. 2020; in press.
- Tan L, Wang Q, Zhang D, et al. Lymphopenia predicts disease severity of COVID-19: a descriptive and predictive study. Signal Transduction and Targeted Therapy. 2020;5(1):33.
- Zheng HY, Zhang M, Yang CX, et al. Elevated exhaustion levels and reduced functional diversity of T cells in peripheral blood may predict severe progression in COVID-19 patients. Cellular and Molecular Immunology. 2020; in press.
- Zheng M, Gao Y, Wang G, et al. Functional exhaustion of antiviral lymphocytes in COVID-19 patients. Cellular and Molecular Immunology. 2020; in press.
- Gu J, Gong E, Zhang B, et al. Multiple organ infection and the pathogenesis of SARS. Journal of Experimental Medicine. 2005;202(3):415–424.
- Wang X, Xu W, Hu G, et al. SARS-CoV-2 infects T lymphocytes through its spike protein-mediated membrane fusion. Cellular and Molecular Immunology. 2020; in press.
- Ong EZ, Chan YFZ, Leong WY, et al. A dynamic immune response shapes COVID-19 progression. Cell Host and Microbe. 2020; in press.
- Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. Journal of Pathology. 2004;203(2):631–637.
- Harmer D, Gilbert M, Borman R, Clark KL. Quantitative mRNA expression profiling of ACE 2, a novel homologue of angiotensin converting enzyme. FEBS Letters. 2002;532(1-2):107–110.
- Turner AJ, Hiscox JA, Hooper NM. ACE2: from vasopeptidase to SARS virus receptor. Trends in Pharmacological Sciences. 2004;25(6):291–294.
- Wang F, Nie J, Wang H, et al. Characteristics of peripheral lymphocyte subset alteration in COVID-19 pneumonia. Journal of Infectious Diseases. 2020; in press.