Why does COVID-19 affect people differently?


COVID-19 infection can have varying affects an individual’s health. So, in the wake of the pandemic, how can we better determine why some people experience severe illness when contracting COVID-19, and others don’t?


A research team based at Yale University, USA, have identified a particular gene that may explain the significant variation of the disease, showing great promise for improved outcomes for those who contract COVID-19.


Read the Research Features article here


Read the original research here: https://pubmed.ncbi.nlm.nih.gov/35262710/


Image source: Adobe Stock Images





Hello and welcome to Research Pod! Thank you for listening and joining us today.


As most people are aware, COVID-19 infection affects people very differently, even when factors such as age, sex and ethnicity are accounted for. In this episode, we look at the research of Professor Richard Bucala at Yale University, USA, who has found that a particular gene can explain the significant variation in COVID-19 disease. The research suggests that a simple genetic test could identify those at highest risk of getting severe disease that requires hospitalization, as well as improve outcomes and suggest new and effective treatments.  


Estimates from the World Health Organization reveal that there have been 750 million confirmed cases of COVID-19 since the pandemic began in 2020, causing millions of deaths. However, there’s also been an enormous variety in the symptoms experienced by people infected with SARS-CoV-2 – the virus that causes COVID-19. Some people experience serious illness, while others are asymptomatic. Why is this? Professor Richard Bucala at Yale University, USA, is leading research efforts to uncover the reasons behind this. Could it be to do with a naturally occurring genetic susceptibility to COVID-19? 


Vaccination status, age, underlying health conditions, and the variant of the virus can all contribute to different outcomes for patients infected with COVID-19. However, some people’s genetic code also makes them more susceptible to developing a more severe form of COVID-19.  


It’s already known that higher levels of inflammation are associated with worse outcomes for COVID-19 – and that using medicines that suppress the body’s overactive inflammatory response can be beneficial. To explore this further, an international research team led by Bucala investigated the links between COVID-19 and genes that are known to be involved with key inflammatory mechanisms within the body.  


The team started by looking at levels of a signalling molecule called macrophage migration inhibitory factor (MIF) in patients with COVID-19 in the Yale New Haven Health System. MIF is closely involved with the immune system and can cause increased and prolonged levels of inflammation. MIF is already known to play a role in other illnesses, such as rheumatoid arthritis and sepsis, as well as being involved in the body’s first-line defence mechanisms against bacteria. A higher level of inflammation can actually be beneficial at times, as it’s essential to help the body fight off invaders during infection. 


Bucala’s group observed that patients with severe COVID-19 illness had higher levels of MIF in the blood than those with mild symptoms. Interestingly, this also was in line with studies in the lab which showed that higher levels of MIF led to more deaths in COVID-19-infected mice. 


The scientists suspected that common genetic variation in MIF would influence the severity of COVID-19, so they analysed the structure of the MIF gene in patients diagnosed with COVID-19. They then compared this structure to data from a large control group, collected from before the virus appeared. The retrospective study included 1,171 patients recruited from three medical centres in the United States, Spain, and Hungary. 


The frequencies of MIF genes with different structures, called gene variants, were compared between the two studied groups; this included high-expression (or high-inflammatory) gene variants and low-expression variants. The high-expression form of the gene causes the body to produce higher levels of MIF, increasing MIF levels and inflammation during infection. The researchers further looked for links between these gene variants and the stage and severity of the COVID-19 infection among the patients in the study group. 


The research group found that those with a high-inflammatory variant of the MIF gene were less likely to be diagnosed with COVID-19. Bucala and colleagues suggest that this could be because MIF first works with the immune system to prevent infection, possibly by helping the body to quickly clear the virus.  


However, the story is different for those who do ultimately become infected with the virus and are subsequently diagnosed with COVID-19. In these patients, the researchers showed that individuals with higher levels of the high-inflammatory MIF gene variant were nearly three times more likely to be admitted to hospital. This indicates that once people do get COVID-19, higher levels of MIF can promote excessive levels of inflammation that can make the clinical picture much worse.  


The data show that around 19% of individuals have the high inflammatory form of the MIF gene, which increases the risk of severe COVID-19 disease and hospitalisation (regardless of age, sex, or other factors). While having a high-inflammatory variant of the MIF gene can help prevent infection, the same variant can be deadly for those who do become infected with the SARS-CoV-2 virus. 


Proactively identifying patients with COVID-19 who also have the high-inflammatory MIF gene variant would mean that medical staff could monitor these individuals more closely, and therefore intervene sooner when severe symptoms begin to set in. They might also decide to treat the illness more aggressively and recommend hospital admission sooner to prevent the serious complications which are more likely to occur in these patients.  


Drugs that stop the action of MIF could be helpful for treating patients with COVID-19. Bucala highlights research studies that already suggest the effectiveness of these types of medicines. In one study using this family of pharmaceuticals, patients’ clinical condition was significantly improved – and the length of hospital stay was substantially reduced. Bucala also notes plans to undertake the study of MIF blockers in Long COVID, which may result from a low level of persistent inflammation in some patients.  


It also means that the populations which are most likely to carry a risk version of the MIF gene could be prioritised for protective measures in future pandemics, for instance through early vaccination, as they are more likely to develop severe or fatal diseases due to excessive inflammation. This type of clinical risk stratification would also allow the earlier application of anti-inflammatory medications to genetically at-risk individuals. Such an approach could be a vital and highly effective public health measure, especially during the early stages of a pandemic and in countries with limited healthcare resources. 


Treating patients in this way is a form of personalised medicine, where treatment is optimised to a single individual’s needs based on biologically relevant genetic markers. This means doctors can avoid using a ‘one size fits all’ approach, which in turn means the best outcome for the patient and the most effective use of medical and public health resources. 


Bucala’s work shows that genetic variation in the population influences susceptibility and severity of COVID-19. He explains that further studies are still needed to explore the precise links between COVID-19, MIF, and other genes, especially in the context of other risk factors for severe infection, such as age and metabolic and cardiovascular disorders.  


Research into COVID-19 is still in its infancy; therefore, longerterm studies are already being planned, such as those by Canada’s University Health Network in targeting MIF in Long COVID. Understanding why different people respond differently to the same infection is vital for exploring the epidemiology of infections – and ensuring the most effective prevention and treatment strategies are used. 


That’s all for this episode – thanks for listening, and stay subscribed to Research Pod for more of the latest science. See you again soon. 

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