Dr. Powell and Colleagues Identify Three Key Inflammatory Proteins Potentially Related to Risk of Acquiring Severe COVID-19

Dr. Timothy Powell, serving as first author, and Drs. Douglas Nixon and Rodrigo Duarte (last authors), have published a paper in Clinical & Translational Immunology that has identified three key inflammatory proteins that may be involved in the risk of acquiring severe COVID-19.

Dr. Timothy Powell

Dr. Powell, a Visiting Assistant Professor of Genetics in Medicine in the WDOM’s Division of Infectious Diseases, joined Dr. Nixon’s laboratory in 2019. Dr. Powell, whose research expertise is in the application of multi-omics in the field of psychiatry and neuroscience, was recruited to the Nixon lab with the goal of utilizing his specialized niche of expertise in relation to focused traits in immunology. He arrived shortly after the COVID-19 pandemic ensued.

As fate would have it, Dr. Powell’s background in the use of multi-omics would play a unique role in helping to unravel key immune factors implicated in the COVID-19 inflammatory process. Both recruited from King’s College London (United Kingdom), Drs. Powell and Duarte had been working together on novel research methods for the study of psychiatric genetics over the past four years. These methods include the analysis of many thousands of genetic variants from across the genome that incrementally increase risk (in addition to environmental risk factors) for complex disorders, such as major depression and schizophrenia. Genetic risk scores, explains Dr. Powell, are now heavily used in the field of psychiatric genetics but have been utilized far less frequently in the field of immunology.

In a previous genetic-based study, Dr. Powell and colleagues published findings showing that common genetic variation explained 28-42% of the variance in risk for acquiring HIV-1 in a European population. This discovery marked the first time a research group found a substantial genetic component to acquiring an infectious disease such as HIV-1.

In their current study, “Genetic risk for severe COVID-19 correlates with lower inflammatory marker levels in a SARS-CoV-2-negative cohort,” published in Clinical & Translational Immunology, Dr. Powell and colleagues asked the question: Are levels of inflammation in blood different among individuals susceptible to severe COVID-19, before they were exposed to SARS-CoV-2? Although previous studies had found very high levels of inflammation in the blood of severe COVID-19 patients, compared to a healthy cohort, few studies had considered whether levels of inflammation differed among susceptible individuals, prior to infection with SARS-CoV-2.

It remains difficult to determine who will develop severe COVID-19. However, by examining recently identified host genetic factors involved in susceptibility to the severe form of the disease, Dr. Powell and team were able to generate genetic risk scores that rank who in a given population might be at highest or lowest risk. Taking it to the next step, they then studied this genetic predisposition and tested whether it correlated with blood levels of 35 inflammatory markers in >400 individuals from South East London, all of whom were SARS-CoV-2-negative. Those individuals at highest genetic risk had lower levels of interferon gamma (IFN-γ), vascular endothelial growth factor D (VEGF-D) and tumor necrosis factor alpha (TNF-α) in their blood. While these immune proteins have previously been shown to be higher among COVID-19 patients, relative to controls, the study suggests they may be lower among susceptible individuals prior to infection. This means that case-control studies might be underestimating the importance of some cytokines, as levels could be lower among cases at baseline (before infection). Therefore, the magnitude of change in levels of IFN-γ, TNF-α, and VEGF-D from pre- to post-infection, might be greater than had been originally expected among severe COVID-19 patients.

Based on their findings, the team has theorized that the severe symptoms experienced by some people with COVID-19 are a consequence of the body’s immune system experiencing a delayed reaction to the virus. This delayed reaction involves a sudden and rapid release of inflammatory proteins, also known as the “cytokine storm” or “inflammatory storm.” The researchers hypothesize that the excessive release of some inflammatory proteins from immune cells could explain why some individuals experience severe COVID-19 symptoms.

“Inflammatory cytokines are immune messengers that play many important roles, including helping our blood cells to identify threats and eliminate them,” says Dr. Powell. “However, there seems to be a Goldilocks effect in relation to cytokine levels - whilst very low levels probably predispose individuals to infection, very high levels have been linked to inflammatory disease states like rheumatoid arthritis. In the case of COVID-19, severe symptoms might be the result of levels going from low to high, very rapidly, as the immune system attempts to compensate for an insufficient first-line response to SARS-CoV-2 infection.”

Another aspect of Dr. Powell’s study, which was funded in part by the National Institute for Health Research (NIHR) Biomedical Research Centre (UK), and in part by the National Institute of Allergy And Infectious Diseases (USA), explored how genetic susceptibility interacts with previously established risk factors, including age and body mass index (BMI). In both instances, those at highest genetic risk were found to have lower levels of inflammatory proteins relative to their peers of a similar age or BMI.

In a previous study, Dr Powell demonstrated positive associations between age and inflammation, suggesting that it is a natural part of the ageing process. However, this age-associated rise in inflammation is not seen in individuals at genetic risk of severe COVID-19, suggesting their immune profiles increasingly differ from their peers as they age, which might explain their increased susceptibility to severe infection.

Dr. Powell adds, “Whilst the results from this study are still preliminary and require replication in larger, longitudinal cohorts, they point towards possible innate immune differences amongst those most susceptible to severe COVID-19. Further studies will be needed to better understand whether the identified immune correlations are causal, or whether other biological mechanisms are more important in explaining severe COVID-19 risk.”

Dr. Timothy Powell obtained his Ph.D. in Psychiatric Genetics at King’s College, London, where he received the King’s College London’s Gottesman-Shields Prize for “outstanding PhD thesis.” He subsequently joined Professor Gerome Breen’s lab as a Biomedical Research Council postdoctoral scientist, exploring the mechanism of action of antidepressants by testing their effects on neural stem cells. In 2016, he was awarded a Medical Research Council (MRC) fellowship for training in statistical genetics, and, during this time, he established an independent research group.

Dr. Rodrigo Duarte is a Visiting Instructor of Neuroscience in Medicine working in the Nixon laboratory. He obtained his Ph.D. from King's College London and holds an M.Sc. from the University of São Paulo, Brazil.

Based at the Belfer Research Building, Dr. Douglas Nixon is a Professor of Immunology in Medicine in the WDOM. He obtained his D.Phil. and an M.A. from Oxford University, UK. He received his M.B.,B.S., from the Imperial College London Faculty of Medicine, UK. Dr. Nixon is a member of The American Society for Clinical Investigation.

All other authors on the paper in Clinical & Translational Immunology are from King’s College, London, where the population data was originally collected. They include Drs. Matthew Hotopf, Stephani L Hatch, and Gerome Breen.