Host genomics beyond the pandemic
8 July 2022
There is no denying the impact of the pandemic and the resourcefulness of researchers who have taken the opportunity to use a wide range of approaches to untangle the complex biology of COVID-19.
Host genomics has been a central player in this effort. Humans differ in their individual response to an infectious disease with evidence that genetics explains some of this difference. Insights from studying host genomics can lead to new tools and interventions to improve care of patients with infectious diseases.
At the PHG Foundation, we have been following this research as it continues to develop. COVID-19 triggered unprecedented investment in host genomics research to help build an evidence base for clinical decision making. Host genomics is not new, and yet, success for other pathogens has been more variable.
How has host genomics impacted on COVID-19?
When the COVID-19 pandemic was confirmed in March 2020, very little was known about this new infectious disease. The most immediate value of host genomics was helping researchers and clinicians to understand this biology. Host genomics research into COVID-19 has contributed to evidence from a range of sources around potential drug targets.
The role of type I interferon (IFN) in severe COVID is considered to be a major success of host genomics research. Interferons are proteins produced as part of the body’s immune responses to viral infections. Reduced type I IFN activation results in a weakened immune response early in COVID-19 infection. Type I IFN has been shown to be a key factor in why some people are more likely to become critically ill from COVID-19, and, now, a number of type I IFN therapies are being investigated in clinical trials. The challenge is that for type I IFN to be effective, it needs to be administered early following infection. Most patients will only receive an intervention once they are hospitalised, and success of any intervention driven by host genomics should consider this.
There has been more apparent success with the TYK2 gene. The TYK2 protein produced from this gene is another important mediator of immune and inflammatory responses, including to viral infections. High expression levels of TYK2 are associated with severe COVID-19 disease. While the early phase of severe COVID-19 is associated with poor immune activation, later stages of disease are associated with hyper-inflammation resulting in tissue damage. TYK2 plays an important role in this immune activation, suggesting that blocking this protein could have clinical benefit. Following trials, a TYK2 inhibitor, baricitinib, is now approved by the US regulator the FDA to treat COVID-19 in hospitalised patients. This illustrates the value of designing interventions around clinical need.
One important question is whether we can predict which patients are most at risk of severe COVID-19 disease. Host genomics could be used to identify these high risk patients earlier, enabling prompt interventions or early hospitalisation to prevent or reduce complications. It is not currently clear how genetic testing would be delivered to identify patients, or how it would fit into existing care pathways, but this sort of application of host genomics remains of considerable interest.
Host genomics before COVID
While current research has been heavily focused on COVID-19, there is a long history of host genomics research for a number of infections.
One well-known example is from research into HIV host genomics, which identified a deletion of 32 base pairs in the CCR5 gene as protective against HIV infection. The cell-surface protein produced from this gene, CCR5, plays an important role in allowing HIV to bind to and infect human immune cells. The CCR5 deletion variant results in low production of CCR5 proteins, reducing the chance that the virus can infect cells. A hypothesis that blocking the CCR5 protein could reduce HIV infection resulted in a novel treatment, Maraviroc, and has been used successfully to help manage HIV infection.
Linking evidence from host genomics to the design of new treatments is not easy, and for some pathogens untangling the biology of infection has been more challenging. Perhaps the best example of this comes from study of M. tuberculosis, the pathogen that causes tuberculosis (TB). Only a small proportion of individuals infected with M. tuberculosis progress to acute disease, with most individuals either clearing the infection or living with M. tuberculosis without symptoms, known as latent infection. Some individuals with high exposure to M. tuberculosis never become infected. This difference in response suggests that host genetics may be an important factor in response to infection. However, host genomics studies of M. tuberculosis have produced conflicting results in understanding why people have such different experiences in their infection. Ultimately, for this research to be successful, host genomics studies need to be performed in more diverse and representative populations, prioritising the people most at risk from this disease.
The future for host genomics
COVID-19 has highlighted the potential of host genomics research when it is performed at scale, and lessons learned should be used to improve our approach to other pathogens. In particular, COVID-19 has illustrated the importance of having clear definitions of disease and collecting accurate epidemiological data to maximise the potential of research.
Ultimately, understanding host genomics could prove to be critical in enabling health systems to efficiently protect people from the worst risks or effects of serious infection. However, many questions remain. In the coming months, the PHG Foundation will be exploring these issues further by examining host genomics for a number of different pathogens to understand how this research has or could be translated into healthcare applications to improve patient care and outcomes.