Some people get really sick of it COVID-19, and others do not. Nobody knows why.
Now, a study by researchers at Stanford University of Medicine and other institutions has revealed immunological abnormalities and degenerations that appear to spell the difference between severe and mild cases of COVID-19.
That difference may stem from how our evolutionary ancient domestic immune system responds SARS-CoV-2, the virus that causes the disease. Found in all creatures from fruit flies to humans, the infected immune system quickly senses viruses and other pathogens. Once it does, it launches a direct, albeit somewhat shameless, attack on them and mobilizes more precisely targeted, but slower, “sniper” cells that belong to another branch of the pathogen-defensive forces of the body, the adaptive immune system.
“These findings show how the immune system malfunctions during coronavirus infections, leading to serious illness, and pointing to potential therapeutic targets,” said Bali Pulendran, PhD, professor of pathology and microbiology and immunology and senior author of the study, which will be published today (August 11, 2020) in Science. Lead authorship is shared by Stanford postdoctoral scientists Prabhu Arnunachalam, PhD, and Florian Wimmers, PhD; and Chris Ka Pun Mok, PhD, and Mahen Perera, PhD, both assistant professors of laboratory sciences for public health at the University of Hong Kong.
Three molecular suspicions
The researchers analyzed the immune response in 76 people with COVID-19 and in 69 healthy people. They found improved levels of molecules that promote inflammation in the blood of severely ill COVID-19 patients. Three of the molecules they identified have been shown to be associated with pneumonia in other diseases, but were not previously shown in COVID-19 infections.
“These three molecules and their receptors could represent attractive therapeutic targets in combating COVID-19,” said Pulendran, who is Professor Violetta L. Horton. His lab is now testing the therapeutic potential of blocking these molecules in animal models of COVID-19.
Bacterial waste and immune paralysis
The scientists also found elevated levels of bacterial waste, such as bacterial DNA and cell wall materials, in the blood of those COVID-19 patients with severe cases. The more waste, the safer the patient – and the more pro-inflammatory substances circulating in his or her blood.
The findings suggest that in cases of severe COVID-19, bacterial products commonly present in places such as the intestines, lungs and throat, may find their way into the bloodstream, kick-starting improved inflammation that is transmitted to all points via all circulation .
But the study also found that, paradoxically, important cells of the infectious immune system in the blood of COVID-19 patients became increasingly lame as the disease diminished. Instead of being awakened by the presence of viruses or bacteria, these normally growing cells remained functionally slow.
If high blood levels of inflammatory promoter molecules differentiate COVID-19 patients separately from those with milder cases, but blood cells do not produce these molecules, where do they come from? Pulendran is thought to originate in tissue somewhere in the body – probably the lungs of patients, the site of infection.
“One of the great mysteries of COVID-19 infections was that some people develop serious illness while others seem to recover,” Pulendran said. “Now we have some insight into why that happens.”
Pulendran is a member of Stanford Bio-X and a faculty member of Stanford ChEM-H.
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Reference: August 11, 2020, Science.
Other authors of Stanford study are MD / PhD [MSTP] student Madeleine Scott; postdoctoral scientists Thomas Hagan, PhD, and Yupeng Feng, PhD; basic science scientist Natalia Sigal, PhD; senior research scientist Dhananjay Wagh, PhD; John Coller, PhD, Director of Stanford Functional Genomics Facility; Holden Terry Maecker, PhD, Professor of Microbiology and Immunology; and Purvesh Khatri, PhD, associate professor of biomedical informatics and of biomedical data science.
Researchers from Emory University, the University of Hong Kong and the Hospital Authority of Hong Kong also participated in the work.
The study was sponsored by the National Institutes of Health (grants U19AI090023, U19AI057266, UH2AI132345, U24AI120134, T32AI07290, P51OD011132 and S10OD026799 and contract HHSN272201400006C), the Sean Immunology and Pathology Institute, the Psychology Institute support the work as well.
