Johns Hopkins Scientists Discover Possible Key to Controlling COVID-19 Immune Response

They believe that by inhibiting factor D, it would reduce the inflammatory reactions that make COVID-19 so deadly.

Researchers at Johns Hopkins Medicine identified a protein, known as factor D, that appears essential to the inflammatory process of SARS-CoV-2, the virus that causes COVID-19. They believe that by inhibiting factor D, it would reduce the inflammatory reactions that make COVID-19 so deadly. They published their research in the journal Blood.

The researchers believe that there may already be drugs in development being tested for other indications that could block factor D.

The research into SARS-CoV-2 is clear that the virus attaches to cells using its spike (S) protein. It typically catches hold of heparan sulfate, a large, complex sugar molecule on the surface of cells in the lungs, blood vessels and smooth muscles. Once attached, the virus then leverages another protein on the surface of cells, angiotensin-converting enzyme 2 (ACE2), to move into the cell.

The Johns Hopkins investigators found that when the virus latches onto heparan sulfate, it prevents factor H from using the sugar molecule to bind with cells. Normally, factor H (as opposed to factor D) regulates the chemical signals that trigger inflammation and prevent the immune system from attacking healthy cells. But without this protection, lung, heart, kidney and organ cells can be destroyed by the inflammation and immune response.

“Previous research has suggested that along with tying up heparan sulfate, SARS-CoV-2 activates a cascading series of biological reactions—what we call the alternative pathway of complement, or APC—that can lead to inflammation and cell destruction if misdirected by the immune system at healthy organs,” said the study’s senior author, Robert Brodsky, director of the Johns Hopkins University School of Medicine hematology division. “The goal of our study was to discover how the virus activates this pathway and to find a way to inhibit it before the damage appears.”

There are three chain reaction pathways that involve splitting and combining more than 20 different proteins, dubbed complement proteins, that are activated when bacteria or viruses attack the body—and APC is one of those three. The final product of the complement cascade is a structure called membrane attack complex (MAC). MAC forms on the surface of the virus or bacteria and destroys it by either drilling holes in the bacterial membranes or disrupting a virus’ outer envelopment.

But MACs can also form on the membranes of healthy cells. Humans have several complement proteins, including factor H, that regulates the APC and keeps it from damaging normal cells.

Brodsky and his team leveraged human blood serum and three subunits of the SARS-CoV-2 S protein to determine exactly how the virus activates the APC, takes over the immune system and damages normal cells. They found that two of the subunits, S1 and S2, are components that bind the virus to heparan sulfate. This launches the APC cascade, blocking factor H from connecting with the sugar. This then disables the complement regulation where factor H prevents the immune system from attacking normal cells.

Getting back to factor D (not factor H), the researchers discovered that by blocking yet another complement protein, factor D, which works immediately upstream from factor H, they could stop the out-of-control immune reaction caused by SARS-CoV-2.

“When we added a small molecule that inhibits the function of factor D, the APC wasn’t activated by the virus spike proteins,” Brodsky says. “We believe that when the SARS-CoV-2 spike proteins bind to heparan sulfate, it triggers an increase in the complement-mediated killing of normal cells because factor H, a key regulator of the APC, can’t do its job.”

He describes APC as being like a moving car. Factor H is like the car’s biological brakes, while factor D is like the car’s gas pedal. The virus’ spike protein disables the brakes (factor H), which lets factor D accelerate the immune system. But if you inhibit factor D, the brakes can be reapplied and the immune system reboots.

Misdirected APC linked to factor H suppression is already associated with several complemented-related diseases, including age-related macular degeneration and atypical hemolytic uremic syndrome (aHUS), a rare disease causing blood clots to the kidneys.

“There are a number of these drugs that will be FDA-approved and in clinical practice within the next two years,” Brodsky said. “Perhaps one or more of these could be teamed with vaccines to help control the spread of COVID-19 and avoid future viral pandemics.”