How COVID-19 causes inflammation in blood vessels
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Research led by Professor Kathy Lui Oi Lan (Croucher Fellowship 2009, Croucher Innovation Award 2017), Associate Professor of the Department of Chemical Pathology at the Faculty of Medicine at Chinese University of Hong Kong, has shed new light on how SARS-CoV-2 triggers potentially lethal cardiovascular inflammation among some patients.
Lui, whose expertise includes stem cells and regenerative biology, was prompted to focus on COVID-19 and its implications for the vascular system when the devastating consequences of the disease became apparent in the initial months of the pandemic, with many people succumbing to attacks on their cardio-vascular and respiratory systems.
“We thought it is very important to look into endothelial cells which form the inner-most layer of blood vessels, to see how they react to the virus,” she said.
She teamed up with virologist Professor Leo Poon Lit Man (Croucher Fellowship 1996, Croucher Senior Research Fellowship 2017) of the Faculty of Medicine of the University of Hong Kong, who was also perplexed why the virus could be so damaging for some patients but not others.
By the start of March 2022 as many as 5.96 million have died as a result of COVID-19, according to the World Health Organisation. Although vaccination can reduce the chance of having serious illness, COVID-19 is still a major health problem for unvaccinated individuals, such as elderly. COVID-19 so far has killed about one per cent of those it infects, Poon said, despite it being a “relatively less lethal virus” than H5N1 influenza virus and SARS-CoV-1 that he has also worked on. “It is not inducing large amounts of cytokines and many infected individuals only develop mild symptoms. This made me reflect on the causes [behind] why some people die,” he said.
Using biosafety level three laboratory facilities at the University of Hong Kong, Lui and Poon’s teams investigated the receptors that may or may not allow the virus to enter endothelial cells that line blood vessels and prompt the hyperinflammation, blood clotting and thrombosis observed in severe COVID-19 cases.
They came up with an unexpected finding that may have implications for future treatment. Their study, published in Stem Cell Reports, overturns conventional understanding that the receptor known as ACE2 is the entry point for the virus to these cells.
But ACE2, they found, is rarely expressed on the surface of endothelial cells. Instead, the team discovered that inflammation within the blood vessels is activated by a cell-surface receptor called TLR4 without the virus entering the host cell. TLR4, they explain, is an innate immune receptor that is best-known for recognising lipopolysaccharide derived from bacteria.
Study sheds light on role of T cells in limiting Omicron severity
Our T cells, whether generated by vaccination or infection, are playing a key role in the human body’s defence against the Omicron variant of the COVID-19 virus, despite the many mutations in the variant’s spike protein that has caused it to escape antibodies produced from these sources. Data scientists from Hong Kong University of Science and Technology and the University of Melbourne add to global evidence emerging on this immune response to the now dominant variant of the virus. Their study, published in Viruses, involved an analysis of more than 1,500 fragments of SARS-CoV-2’s viral proteins, called epitomes, found to be recognised by T cells after vaccination or in patients recovered from COVID-19. “Among these T cell epitopes that have Omicron mutations, our further analysis revealed that more than half are predicted to still be visible to T cells,” said study co-lead Professor Ahmed Abdul Quadeer, Research Assistant Professor at the Department of Electronic and Computer Engineering, Hong Kong University of Science and Technology. “This further diminishes the chance that Omicron may escape T cells’ defences.” While the study focused on the spike protein of the virus, when the team broadened their analysis to other SARS-CoV-2 proteins they found an overwhelming majority (more than 97 per cent) of the non-spike T cell epitopes did not encompass mutations associated with Omicron, suggesting that broad escape from T cells is unlikely. T cell responses elicited by vaccines and boosters would thus continue to help protect against Omicron and other variants of the virus, they conclude.
Their study shows that endothelial TLR4, when expressed, can also recognise SARS-CoV-2, contributing to vascular inflammation. By analysing the genome of circulating endothelial cells collected from mild and severe COVID-19 patients, at a single-cell resolution, they revealed that these cells displayed activated gene signatures of the TLR4 signaling pathway.
The hope now is that this response could be controlled by TLR4-specific inhibitors, Poon said. “The gene marker co-relates with the severity. So when we measure this marker it can tell us if this patient will have a better chance to survive,” he said. This, in turn, could inform the treatment of the patient, although why some people have this response is not yet understood.
A key feature of the research is that the team used human stem cells to generate the endothelial cells for the study, which they infected with live SARS-CoV-2.
Lui explained the advantages of this novel approach in research related to Covid-19. “By virtue of their capability of self-renewal, we can generate unlimited numbers of endothelial cells from human pluripotent stem cells for this study, and avoid invasive procedures that only allow us to get limited numbers of these cells from patients,” she said.
The cells were also less likely to have changed their characteristics than commercially available cells cultured over a longer time, thus revealing the lack of ACE2 on the cell surface, she explained.
The team now hopes to secure the resources needed to replicate the study in animal models – most likely mice and hamsters. This could inform a personalised approach to tackling COVID-19, using the expressed TLR4 gene receptor and its downstream gene targets as biomarkers for patient prognosis, and suppressing it with new or existing drugs.
Poon highlighted the importance of the collaboration, between universities and across different disciplines, in this and other breakthroughs in Hong Kong’s research related to the COVID-19 pandemic. His division now has a team of around 80 researchers – a ten-fold increase on the capacity when he joined the University of Hong Kong two decades ago. But that, he said, was not enough.
“We need experts from other disciplines to tackle the problem. Our team have worked with engineers, statisticians and other expertise to come up with new ideas and have an impact on the community.”
This collaboration, he said, was important in enabling Hong Kong’s relatively small research community to be the significant hub for research on emerging infectious diseases that it has become.
HKU research affirms virus risk to male fertility
Researchers at the University of Hong Kong have found that the SARS-CoV-2 virus damages the testicles and sex drive of hamsters, adding to the evidence of the wide-ranging health complications from COVID-19, including on male fertility. The study, led by Professor Yuen Kwok-yung (Croucher Senior Medical Research Fellowship 2006), Chair of Infectious Diseases in the University of Hong Kong’s Department of Microbiology, found that SARS-CoV-2 can cause acute testicular damage, chronic asymmetric testicular atrophy, and hormonal changes in hamsters despite the animals experiencing a light pneumonia. The research has been accepted for publication in the journal Clinical Infectious Diseases. Previous studies have reported testicular pain in COVID-19 patients. One autopsy study of men who died from COVID-19 showed orchitis, or inflammation of the testicles, and extensive testicular cell damage. The team investigated the testicular and hormonal changes of hamsters infected by the Omicron and Delta variants of the SARS-Cov-2 virus, compared with a control group infected with influenza A. The two coronavirus variants were found to cause an acute decrease in sperm count and serum testosterone four to seven days after infection, as well as testicular atrophy with reduced testicular size and weight. The serum sex hormone level was markedly reduced at 42 to 120 days after infection. Acute testicular inflammation, haemorrhage, and necrosis – or tissue death - of seminiferous tubules and disruption of spermatogenesis were seen in these animals. No damage was found in the control group. However, the damage, the team found, could be prevented with vaccination. “In managing convalescent COVID-19 males, it is important to be aware of possible low sex drive and subfertility,” Yuen said. “COVID-19 vaccination can prevent this complication.”