The COVID-19 pandemic, caused by the novel SARS-CoV-2 coronavirus, has massive global ramifications. As of 1st April 2020, the pandemic has produced 858,785 cases with 42,151 deaths. The pandemic has stretched hospitals and public health systems in developed countries such as Italy and the United States and also affected local and global economies with travel restrictions, falling stock prices and rising unemployment. Researchers around the world are studying the SARS-CoV-2 virus and COVID-19 infection to develop treatments and vaccines that can stop the pandemic. In particular, researchers are looking into how the immune system responds to COVID-19 infection.

Recently, researchers at the Peter Doherty Institute for Infection and Immunity in Melbourne, Australia published an article which described, for the first time, how the immune system responds to COVID-19 infection. In this study, researchers tracked the immune response of a patient who was hospitalised with COVID-19 infection but later recovered. They found that the patient was able to mount an effective immune response to the SARS-CoV-2 virus that persisted even after the virus was eliminated.

I like this article because it describes very simply how the immune system responds to COVID-19 infection. In addition, the article is quite short and contains results that, with further explanation, anyone can interpret and understand. In this blog post, I will explain how the immune system works and how this relates to what researchers found in their study. I hope this blog post will ignite your interest in the immune system and how it responds to COVID-19 infection. Who knows, you might even start reading and understanding some academic articles on COVID-19 infection!

The patient

The patient was a 47-year-old woman from Wuhan, China, who arrived in Melbourne, Australia. Seven days after arriving, she developed symptoms of fever, tiredness, sore throat, coughing, chest pains and shortness of breath. She was hospitalised four days later, where cell samples taken from inside the nose (nasopharyngeal swabs) confirmed the presence of SARS-CoV-2 virus. The virus was also present in sputum and faeces but could not be detected in any sample seven days after symptoms appeared. The patient successfully recovered from infection with symptoms disappearing 13 days after they appeared and the patient was still well seven days later.

A background on the immune system

The immune system is a collection of organs and cells around the body that aims to protect the human body against infection. It does this by recognising and eliminating pathogens, microorganisms such as bacteria and viruses that can cause disease. The immune system is split into two arms:

• Innate immune system: this arm, which consists of white blood cells such as neutrophils and macrophages and factors such as complement, immediately responds to pathogens entering the body. Their job is to restrict the spread and severity of infection which buys time for the body to set-up and mount a stronger immune response.
• Adaptive immune system: this arm, which consists of B and T cells, responds later in infection. However, it is able to mount a specific immune response that eliminates the pathogen from the body. In addition, it also produces memory cells that “remember” the infection so that it can mount a faster, stronger immune response if the same pathogen enters the body. The adaptive immune system can be further split into two types:
  • Humoral-mediated immune responses which involve antibodies; and
  • Cell-mediated immune responses which are mediated by T cells.

Humoral-mediated immune responses

Background

Humoral-mediated immune responses involve antibodies that are produced by plasma cells (which are derived from B cells). Antibodies bind to proteins on the surface of the SARS-CoV-2 virus to prevent them from infecting cells. Antibodies also mark these viruses for engulfment and degradation by white blood cells such as neutrophils and macrophages.

In the early stages of infection, IgM antibodies are produced. As infection progresses; though, IgG antibodies are produced which bind more strongly to the virus than IgM. The switch in antibody production from IgM to IgG is mediated by follicular helper T (Tfh) cells which provide factors and signals to keep activated B cells alive as they develop in the lymph nodes.

Results

Initially, researchers collected blood samples from the patient. The blood was separated into different components and plasma samples (liquid component of blood where antibodies are found) were collected. Plasma samples were diluted and added to a group of SARS-CoV-2-infected cells to measure levels of IgG and IgM antibodies. As shown in Table 1, researchers were able to detect both IgG and IgM antibodies against the SARS-CoV-2 virus. IgG antibodies emerged sooner in the plasma than IgM antibodies, but the levels of both antibodies increased as time passed. This table highlights that antibody responses became stronger over time even as the virus was in the process of being eliminated (from seven days after symptoms appeared).

In addition to measuring antibody responses, researchers also counted the numbers of follicular helper T (Tfh) and plasma cells (labelled antibody-secreting cells in the study) in the blood. Both Tfh and plasma cell numbers in the blood increased over time as the patient started to recover from infection. After the patient fully recovered from infection, their Tfh and plasma cell numbers in the blood were still higher than those of healthy people.

Collectively, these results highlight the strengthening and persistence of the patient’s antibody responses to the SARS-CoV-2 virus.

Cell-mediated immune responses

Background

Cell-mediated immune responses involve T cells that are activated in the presence of pathogens, particularly viruses. Their job is to coordinate immune responses to infection as well as kill cells infected by viruses. T cells can be split into two subsets:

• CD4⁺ T cells are T cells that possess the co-receptor CD4. When activated, they become helper T cells. Helper T cells secrete factors and interact with immune cells to enhance immune activity, increasing the immune system’s effectiveness to respond to infection.
• CD8⁺ T cells are T cells that possess the co-receptor CD8. When activated, they become killer T cells. Killer T cells find and kill cells that are infected by viruses. They do this by secreting two factors: perforin which form pores on the cell and granzyme which go inside to kill cells.

Results

In addition to counting cells that are involved in humoral-mediated immune responses, researchers also analysed T cell populations in the blood. They found that COVID-19 infection was associated with increased numbers of activated CD4⁺ and CD8⁺ T cells in the blood (as measured by activation markers CD38 and HLA-DR). Even after the patient fully recovered from infection (20 days after symptoms appeared), their CD4⁺ and CD8⁺ T cell counts in the blood were still higher than those of healthy people. This indicates the persistence of cell-mediated immune responses even after the SARS-CoV-2 virus disappeared from the patient.

Furthermore, researchers measured the amounts of perforin and granzyme inside CD4⁺ and CD8⁺ T cells to measure their cell-killing capabilities. Activated CD8⁺ T cells had increased amounts of granzymes A and B as well as perforin. This highlights the increased capabilities of CD8⁺ T cells and by extension killer T cells in killing virus-infected cells during COVID-19 infection.

Conclusion

This simple study showed for the first time that both arms of the adaptive immune system are activated during COVID-19 infection to eliminate the SARS-CoV-2 virus as well as virally-infected cells. These results provide an initial picture of how the body responds to COVID-19 infection. However, a few unanswered questions remain:

• How would the innate immune system respond to COVID-19 infection? This could not be measured in the study as immune responses were only tracked from seven days after symptoms appeared (where the innate immune system plays less of a role). Further studies could look at how the immune system responds in the early stages of COVID-19 infection.
• Does the immune response differ between mild, severe and fatal cases of COVID-19 infection? While this study looked at the immune response of a patient who managed to recover from infection, other studies found that some patients died from COVID-19 infection. It would be interesting; therefore, to compare immune responses among mild, severe and fatal cases of COVID-19 infection.
• Does a previously-infected patient develop memory to the SARS-CoV-2 virus to mount a stronger, faster immune response? This could be investigated by detecting memory cells that emerge during COVID-19 infection.

Nevertheless, this study is really good for describing the immune response to COVID-19 infection, allowing researchers to discuss how best to harness the immune system to respond better to COVID-19 infection. Furthermore, this study provides the basis for developing vaccines that would activate both humoral- and cell-mediated immune responses to SARS-CoV-2 virus. This would lead to the development of memory cells that allow humans to respond better to COVID-19 infection so that the virus is less likely to infect humans, ending the pandemic.