Since its debut as a respiratory virus, it’s become clear that SARS-CoV-2 affects more than just the lungs. Its symptoms can be felt all over the body, causing neurological, cardiovascular, renal, gastrointestinal, and muscular problems too. Scientists have been working to figure out how the virus affects all these systems, and think that bradykinin might have something to do with it.
“Everybody was struggling with this bizarre set of symptoms. How do we explain that?” said Daniel Jacobson, a computational systems biologist at Oak Ridge National Laboratory.
A team of researchers led by Jacobson combined genetic analyses and supercomputing to come up with a hypothesis explaining the wide constellation of Covid-19 symptoms. Published in eLife in July, their findings reveal a potential mechanism that suggests bradykinin storms could be causing the coronavirus’s diverse effects.
“It makes a lot of sense,” said Miriam Merad, director of the Precision Immunology Institute at the Icahn School of Medicine at Mount Sinai, who was not involved in the research. Although, she pointed out, Covid-19 is likely a complex disease. “There are probably many mechanistic pathways that we have not completely unraveled. It’s not going to be one pathway that’s responsible for everything.”
Before Jacobson’s group, other researchers had already noticed potential connections between Covid-19 and pathways involving bradykinin. For one, bradykinin is important for blood pressure regulation and inflammatory responses. People with high blood pressure are at risk for more severe cases and Covid-19 can lead to inflammation in several body systems. On top of that, ACE2, the coronavirus’ point of entry into cells, produces a bradykinin-boosting hormone.
Jacobson’s group came up with their bradykinin hypothesis by feeding cellular gene expression data into Oak Ridge’s Summit supercomputer. They wanted to find out which genes were expressed, and at what levels, in Covid-19 patients.
This genetic data came from nine bronchoalveolar lavage samples of lung cells from Covid-19 patients admitted to the intensive care unit at a Wuhan hospital early in the pandemic. The researchers compared that dataset to gene expression data in 40 samples from individuals without Covid-19, collected in a 2018 study of asthmatic adults.
After about a week with the data, the supercomputer had an answer.
Summit revealed that a dysregulated renin-angiotensin system (RAS), which is important for blood pressure regulation, and disruption in the pathway that produces bradykinin, which is also involved in RAS, could explain clinical outcomes in Covid-19 patients. SARS-CoV-2 could throw off the careful balance of gene expression normally involved in the healthy functioning of these pathways.
“All your normal checks and balances, both from the RAS and the bradykinin side, have been taken away so you’re going to have this flood of bradykinin and an inability to control it,” said Jacobson. These effects converge into a bradykinin storm.
Bradykinin Storms And Covid-19
If proven true, the bradykinin hypothesis explains a lot. “The results in the expression data give you a nice overview of how it could actually happen,” said Christopher Bradburne, senior scientist in the Johns Hopkins Applied Physics Laboratory and associate professor in the department of genetic medicine, who was not involved in the study.
The flood of bradykinin makes blood vessels prone to leakage, which means blood can spill into the lungs. The abnormal bradykinin and RAS activity also leads to overproduction of hyaluronic acid in the lungs. That extremely absorbent acid then gels with blood leaking from the lungs’ capillaries.
“That’s going to look like a gelatin building up in the alveoli in your lungs,” said Jacobson. “And that’s really not good news.”
This aligns with what clinicians are seeing in Covid-19 patients. “It helps explain why once people are severely ill and intubated for ventilation, we have these horrific mortality statistics,” said Jacobson. “It doesn’t matter how much oxygen you pump in there. You can’t exchange CO2 for O2 through Jell-O.”
The model also explains why people can experience neurological symptoms. When blood vessels leak fluid into the brain, that leads to swelling, and MRI studies have shown that this can happen in Covid-19 patients. Some patients also report sore muscles and joints, a common symptom in other conditions associated with too much bradykinin. High bradykinin levels can also drive gastrointestinal symptoms, like diarrhea, cramping in nausea, which happen to occur in Covid-19 patients too.
Vitamin D deficiencies have also been associated with severe Covid-19 cases, and it just so happens that the Vitamin D receptor is involved in both the RAS and bradykinin pathways. The model showed that the Vitamin D receptor gene was expressed at lower than normal levels in the Covid-19 samples. Meanwhile, the genes for enzymes that chew up Vitamin D are expressed at higher levels, which further throws these pathways off balance.
The model also provided a possible explanation for why men are dying from Covid-19 at higher rates than women. A gene called TMSB4X that’s involved in RAS was downregulated in the Covid-19 samples. But this gene is located on the X chromosome. Women typically have two X chromosomes while men usually have one, meaning that women have double the amount of this protein and potential protection against downregulation of the gene.
“Everywhere we looked we kept seeing this alignment,” Jacobson said.
Merad agreed that this model is promising. “But I’d like to have more data,” she said. The study only analyzed nine samples from severely ill patients that were obtained early in the pandemic, before the virus started circulating and gradually accruing slight genetic changes. The current model is also based on gene expression only, and not measurements of the proteins encoded by those genes.
By just measuring gene expression, “you’re not measuring a functional unit,” said Merad. This study also doesn’t show whether the dysregulated gene expression in RAS and bradykinin pathways causes Covid-19’s damage, or if that dysregulation is a reaction to inflammation, she said.
“What it does do,” said Bradburne, “is give you a hypothesis that seems to fit a lot of the clinical and physiologic data.”
To test this hypothesis, Jacobson and his colleagues are working with other researchers to run studies in animals looking at multiple facets of RAS and bradykinin dysregulation. In animal studies, they’ll be able to see how SARS-CoV-2 infection affects not just gene expression, but protein expression, products of cellular metabolism, and the microbiome.
A Target For Treatment
One reason the bradykinin hypothesis is so appealing is because effective drugs might already exist. “There are 11 or more existing pharmaceuticals in common clinical practice that that can target different parts of this mechanism,” said Jacobson.
Several clinical trials of drugs that target bradykinin production or signaling are currently underway. In the United States, for example, a multicenter randomized clinical trial is testing whether the hereditary angioedema medication, icatibant, can improve outcomes in severely ill Covid-19 patients.
But with all the bodily systems disrupted by the virus, it’s unlikely one medication would treat all symptoms. “The analogy I use is if you’re sailing your boat over a reef and you punch five holes in your boat, you hope you have more than one cork,” said Jacobson.
For now, Jacobson is optimistic about their model and the opportunities to further refine it. “The early clinical results that are consistent with what the model predicts are really encouraging.”