The after effects: Investigating the role of immunogenetics in long COVID

The global battle against COVID-19 has shifted focus from acute infections to the lingering challenge posed by long COVID, a condition where signs and symptoms persist well beyond the initial infection. While most individuals experience a mild reaction to the virus, approximately 10% develop hypoxemic pneumonia, 3% progress to critical illness, and 28% go on to experience Long COVID.

Recent studies have suggested that long COVID could be influenced by several factors, including viral persistence, autoimmunity and how our immune systems respond to the virus. In this blog, we introduce immunogenetics and outline its potential to help us understand how and why certain individuals experience long COVID.

Immunogenetics in context

Immunogenetics, at its core, is the study of the genetic components associated with the immune system, a sophisticated network of cells, tissues, and organs that acts as the body's defence mechanism against infections and diseases. Immunogenetics helps us understand the interplay between our genes and the way our immune system responds, both in normal health and during various health challenges. Overall, this field of science aims to decode how our genetic makeup influences the way our bodies defend themselves against infections, diseases, and environmental triggers.

To comprehend immunogenetics, we first need to understand the basics of genetic polymorphisms – variations in our genes that make each person genetically unique. These polymorphisms, particularly in immune-related genes, are like individual markers that influence how our immune system operates. For biotech and pharmaceutical companies, understanding immunogenetics and polymorphisms helps to create better vaccines and treatments for diseases. It also provides more information on the differences in how people react to certain conditions, making it instrumental in developing personalised treatments tailored to an individual's genetic makeup.

In a recent study, the genetic elements controlling the immune system were highlighted as some of the most polymorphic loci in our genome. This means that the genes governing immune responses are highly diverse, and even slight variations can impact how our immune system functions. Because of this, there are assumptions that they might also affect how we respond to viral infections like COVID-19.

Immunogenetics and long COVID

In the context of COVID-19, both innate and adaptive immune responses come into play. The innate response provides the initial line of defence, detecting and reacting to the virus, while the adaptive response involves creating antibodies and immune cells targeting the virus.

COVID-19 can impact the immune system in a number of ways. Sometimes a hyperactive immunological reaction, known as a cytokine storm, can occur, where the immune system produces excessive cytokines, causing widespread inflammation and potentially fatal consequences. Alternatively, COVID-19 may inhibit the immune response, particularly in older adults and those with underlying health conditions, making it harder for the body to combat the infection.

At the moment, long COVID affects around 28% of people who get COVID, with over 200 symptoms impacting various organ systems. We're still very much in the learning phase when it comes to immunogenetics and the condition. However, research is taking place every day to try to help us understand the ways genetic variations in immune-related genes might contribute to the observed heterogeneity in long COVID.

• A study comparing patients with long COVID to uninfected individuals and those with COVID-19 without long-term symptoms revealed distinct immune differences at around 14 months post-infection. Notable changes included increases in non-classical monocytes, activated B cells and specific T cell subtypes, along with decreased conventional dendritic cells and exhausted T cells. Other studies have been looking into B-cell responses in long COVID-19 patients, revealing reduced frequencies of memory B cells and impaired antibody responses in those with persistent symptoms.
• The COVID-19 Host Genetics Initiative, through a genome-wide association study, identified a variant near the FOXP4 gene that was also associated with long COVID. This gene, expressed in the lungs and some immune cells, was previously linked to COVID-19 severity. The variant's stronger impact on long COVID suggests its role in the prolonged nature of the illness, particularly in symptoms like shortness of breath and persistent cough.
• Researchers have also discovered that deficiencies in type 1 IFN immunity elevate the risk of critical COVID-19 pneumonia and that polygenic risk scores linked to fatigue also suggest susceptibility to long COVID. Researchers at the University of Sheffield and Stanford University have pinpointed specific genetic signals, mainly in NK cells and T cells, accounting for 77% of the observed heritability associated with increased severity of COVID-19.
• Investigations into the genetic factors influencing COVID-19 susceptibility and severity have brought attention to variants in the ACE2 receptor and TMPRSS2 gene. These proteins are crucial for viral entry into human cells, with ACE2 serving as the receptor for the virus and TMPRSS2 facilitating the activation of viral particles. Despite the association of certain genetic variations with COVID-19 severity, research involving 293 previously hospitalised COVID-19 patients found no direct link between four genetic variants related to ACE2 and TMPRSS2 genes and Long COVID symptoms. This discrepancy underscores the complexity of the disease and the need for further research to understand the genetic basis of Long COVID.
• The Human Leukocyte Antigen (HLA) system, which is integral to the immune response against viral infections, also demonstrates significant variability in the context of COVID-19. Variants within the HLA genes can influence an individual's susceptibility to the virus and the severity of their response. For instance, the HLA*B15:03 allele has been associated with a higher likelihood of asymptomatic COVID-19 infections, suggesting a genetic basis for the variability in disease manifestation. This highlights the importance of the HLA system in understanding individual differences in immune responses to SARS-CoV-2 and points to potential areas of investigation for long COVID.
• A grant-funded observational study by our team at Sano is working to unveil the genetics of diverse long COVID patients, understand biological causes, establish diagnostic criteria, formulate treatments, and guide rehabilitation services. In an analysis of the data by PrecisionLife, 73 genes highly associated with long Covid populations were identified, including 42 genes that are potentially tractable for novel drug discovery approaches.

As research progresses, it is hoped that the insights gained from immunogenetics will not only enhance our understanding of long COVID but also pave the way for more personalised and comprehensive care strategies, ultimately improving the quality of life for those affected by this perplexing condition. 

Future directions in long COVID research

The research landscape surrounding long COVID is rapidly expanding, exploring the complexities of this condition to uncover why it manifests so variably among individuals. This variability underscores the critical role of genetics and the immune system in influencing the range of responses observed in long COVID patients. Currently, approximately 90 studies are underway, aiming to identify effective treatments for long COVID. These efforts, however, are in their nascent stages and will require time to yield clinically actionable insights.

The approach to managing long COVID, for now, remains symptomatically focused, adopting a holistic strategy that addresses the multifaceted nature of the condition. Treatments being explored include the use of compression stockings, physical therapy, activity pacing, flexibility and strength training, and specific medications tailored to alleviate symptoms.

Despite these advancements, the essence of treating long COVID will likely continue to necessitate a multidisciplinary, team-based approach. Such an approach integrates the expertise of various healthcare professionals to address not just the physical aspects of the condition, but also the psychological, social, and rehabilitative needs of patients. 

Conclusion

The exploration into long COVID, a persistent aftermath of the COVID-19 pandemic, underscores a critical frontier in medical research. Immunogenetics, with its potential to explain individual immune responses, will be crucial as we move towards a better understanding of long COVID. As we explore the genetic differences that dictate why some are more susceptible to prolonged symptoms, one truth rises to the top: the future of long COVID treatment is poised to transform from a one-size-fits-all approach to tailored therapies. This shift not only promises more effective management of long COVID but also a more profound understanding of the interaction between our genetics and the diseases we face.