Immune-System Paralyzed in Severe COVID-19 Cases

Immune System Paralyzed Concept

A study by Stanford University of Medicine and other institutions suggests that immunological differences in the innate immune system may contribute to the varying severity of COVID-19 cases.

Some people get really sick from COVID-19, and others don’t. Nobody knows why.

Now, a study by investigators at the Stanford University of Medicine and other institutions has turned up immunological deviations and lapses that appear to spell the difference between severe and mild cases of COVID-19.

That difference may stem from how our evolutionarily ancient innate immune system responds to SARS-CoV-2, the virus that causes the disease. Found in all creatures from fruit flies to humans, the innate immune system rapidly senses viruses and other pathogens. As soon as it does, it launches an immediate though somewhat indiscriminate attack on them and mobilizes more precisely targeted, but slower-to-get-moving, “sharpshooter” cells belonging to a different branch of the body’s pathogen-defense forces, the adaptive immune system.

“These findings reveal how the immune system goes awry during coronavirus infections, leading to severe disease, and point to potential therapeutic targets,” said Bali Pulendran, PhD, professor of pathology and of microbiology and immunology and the senior author of the study, which will be published today (August 11, 2020) in Science. Lead authorship is shared by Stanford postdoctoral scholars Prabhu Arnunachalam, PhD, and Florian Wimmers, PhD; and Chris Ka Pun Mok, PhD, and Mahen Perera, PhD, both assistant professors of public health laboratory sciences at the University of Hong Kong.

Three molecular suspects

The researchers analyzed the immune response in 76 people with COVID-19 and in 69 healthy people. They found enhanced 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 lung inflammation in other diseases but had not been shown previously in COVID-19 infections.

“These three molecules and their receptors could represent attractive therapeutic targets in combating COVID-19,” said Pulendran, who is the Violetta L. Horton Professor. His lab is now testing the therapeutic potential of blocking these molecules in animal models of COVID-19.

Bacterial debris and immune paralysis

The scientists also found elevated levels of bacterial debris, such as bacterial DNA and cell-wall materials, in the blood of those COVID-19 patients with severe cases. The more debris, the sicker 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 ordinarily present only in places such as the gut, lungs and throat may make their way into the bloodstream, kick-starting enhanced inflammation that is conveyed to all points via the circulatory system.

But the study also revealed that, paradoxically, key cells of the innate immune system in the blood of COVID-19 patients became increasingly paralyzed as the disease got worse. Instead of being aroused by the presence of viruses or bacteria, these normally vigilant cells remained functionally sluggish.

If high blood levels of inflammation-promoting molecules set COVID-19 patients apart from those with milder cases, but blood cells are not producing these molecules, where do they come from? Pulendran believes they originate in tissues somewhere in the body — most likely patients’ lungs, the site of infection.

“One of the great mysteries of COVID-19 infections has been that some people develop severe disease, while others seem to recover quickly,” Pulendran said. “Now we have some insights into why that happens.”

Pulendran is a member of Stanford Bio-X and a faculty fellow of Stanford ChEM-H.

Reference: “Systems biological assessment of immunity to mild versus severe COVID-19 infection in humans” by Prabhu S. Arunachalam, Florian Wimmers, Chris Ka Pun Mok, Ranawaka A. P. M. Perera, Madeleine Scott, Thomas Hagan, Natalia Sigal, Yupeng Feng, Laurel Bristow, Owen Tak-Yin Tsang, Dhananjay Wagh, John Coller, Kathryn L. Pellegrini, Dmitri Kazmin, Ghina Alaaeddine, Wai Shing Leung, Jacky Man Chun Chan, Thomas Shiu Hong Chik, Chris Yau Chung Choi, Christopher Huerta, Michele Paine McCullough, Huibin Lv, Evan Anderson, Srilatha Edupuganti, Amit A. Upadhyay, Steve E. Bosinger, Holden Terry Maecker, Purvesh Khatri, Nadine Rouphael, Malik Peiris and Bali Pulendran, 4 September 2020, Science.
DOI: 10.1126/science.abc6261

Other Stanford study co-authors are MD/PhD [MSTP] student Madeleine Scott; postdoctoral scholars Thomas Hagan, PhD, and Yupeng Feng, PhD; basic life research 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 at 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 Parker Cancer Institute, the Soffer Endowment and the Violetta Horton Endowment. Stanford’s Departments of Pathology and of Microbiology and Immunology also supported the work.

4 Comments on "Immune-System Paralyzed in Severe COVID-19 Cases"

  1. Strangely, this virus is reproducing polio in everything but name. As with chicken pox and shingles, this is most likely a polio bite-back, for which we still have no defense. This explains the huge medical response, and the extraordinary efforts to avoid public response. As with polio, most experienced asymptomatic cases, but remained carriers. There are many info on the net dealing with this including WIKI.

  2. What about people with ME did not want to know about them! Still it is know excuse to shutdown the country or the world! And falsing people to wear a mask, which will make no difference! And shut down hospital! If you allow this to carry on you have got worse to come! And it won’t be the virus! The is a front for what the elite like Bill Gates are involved in this lockdown!! They have created this for there benefit!!! And to control everyone. NEW WORLD ORDER!!!

  3. But we have some understanding from post mortems, autopsies where it has shown to cause very numerous mini blood clots.
    They also showed that the coronavirus embeds itself on or under the endothelium in blood vessels and throughout the whole digestive system. This means the regular immune system secretions from under the endothelium become seriously compromised in the advanced spread.
    The blood clots also raise the question of how extensive they can be beyond the lungs and the possibility of crossing the blood brain barrier for strokes.
    The endothelium invasion in the digestive system is therefore very likely can knock out the work in the ileum which holds an important centre for immunity and whether there is a knock on to the lymphatic system and peyers patches too.
    Seems to me the virus is so powerfully invasive if the immunity is already compromised with regular inflammation and clearly hits the individual in their weakest area.

  4. I believe Sid is a troll. Hmm.

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