In the early 20th century, scientists noted that children managed surprisingly well against most microbes despite high child mortality and low life expectancy, which indicates that high mortality was not always due to the microbes’ ability to cause severe infections.
Over the past few decades, research has shown that some severe infections in children can arise due to congenital disabilities in the immune system. Specifically, genetic traits can affect the body’s response to the SARS-CoV-2 coronavirus and Epstein-Barr virus (EBV).
Some individuals have a genetic predisposition to severe infections, confirmed by cases where serious viral diseases are inherited. Among such diseases are severe forms of EBV and COVID-19.
The Role of Genetics in Epstein-Barr Virus Infections
Epstein-Barr is a herpes virus transmitted orally and primarily infects B lymphocytes, causing a lifelong latent infection. Under certain conditions, the virus can reactivate, leading to the infection of new cells. Some individuals with specific immune defects never suffer from EBV, as seen in X-linked agammaglobulinemia, a form of immunodeficiency characterized by a lack of mature B cells, suggesting that B lymphocytes are necessary for primary EBV infection.
EBV, or mild upper respiratory infection, is often asymptomatic in healthy young children. In some cases, EBV causes infectious mononucleosis and is associated with nasopharyngeal and gastric cancers, as well as Burkitt’s and Hodgkin’s lymphomas. Between 1.3% and 1.9% of cancer cases are associated with EBV. EBV can also contribute to the development of autoimmune diseases, including multiple sclerosis and systemic lupus erythematosus.
The severity of EBV can be genetically predisposed. At-risk groups include patients with immunodeficiencies and gene mutations that affect the interaction between B and T cells.
The Role of Genetics in Coronavirus Infections
Most patients experience mild coronavirus infections, but some develop severe pneumonia requiring hospitalization. Genetic predisposition plays a crucial role in the development of severe COVID-19. For example, genetic variants inherited from Neanderthals can increase or decrease the risk of severe COVID-19. Rare genetic mutations also make some individuals particularly vulnerable to the virus, significantly when the type I interferon (IFN) response is weakened.
In patients with a weakened IFN I response, the virus can silently spread in the respiratory tract and bloodstream until about the 10th day, after which leukocytes are attracted to the infected tissues, causing hyperinflammation, which was observed in four adult patients with interferon system defects: they seemed healthy for a long time. However, they were suddenly hospitalized with critical COVID-19 pneumonia.
Another case involves a 3-year-old girl with multisystem inflammatory syndrome (MIS) and critical COVID-19. While pneumonia typically occurs two weeks after coronavirus infection, MIS usually emerges about four weeks later. The girl hospitalized with MIS had a genetic deficiency in the receptor for type I interferons.
In some patients with critical COVID-19, autoantibodies that block the action of type I interferons are found. These autoantibodies may cause severe disease in about 15% of patients. Interestingly, IFN autoantibodies are present not only in patients with severe COVID-19 but also in some healthy individuals, particularly the elderly, which increases the risk of severe complications from coronavirus infection.
EBV and Coronavirus: Connections
Typically, patients with genetic mutations leading to severe EBV do not tend to suffer from severe COVID-19. However, exceptions exist. One example involves a child with EBV-induced B-cell proliferation and Hodgkin’s lymphoma caused by a CD27 protein deficiency. During the pandemic, the child was in lymphoma remission and contracted a mild SARS-CoV-2 infection but was hospitalized with MIS four weeks later. SARS-CoV-2 infection might have reactivated EBV in this child, leading to hyperinflammation.
Conclusion
Recent studies have highlighted stark differences in the mechanisms causing severe diseases from two different viruses: SARS-CoV-2 and EBV. Critical COVID-19 conditions are often associated with autoantibodies against type I interferons and genetic defects in the interferon system, which is not typical for EBV-related diseases, where critical conditions can arise from disruptions in the interaction between CD8+ T cells and B cells.
It was long thought that two branches of immune defense, interferons and CD8+ T cells, were necessary for protection against a wide range of viruses. However, these branches have proven to be largely redundant. Type I interferons play a minimal role in combating EBV but are critical for protection against severe COVID-19. Conversely, CD8+ T cells are not crucial for defense against coronavirus but are essential for fighting EBV.
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