Researchers find immune system pathway that may prevent COVID-19 infection

Researchers find immune system pathway that may prevent COVID-19 infection

Researchers from the Johns Hopkins Medicine has recently identified that blocking a complement protein in the immune system pathway during the SARS- CoV-2 infection could prevent immune reaction leading to organ damage. The study was published recently in the journal Blood.

The team found that upon entry into the host the spike proteins on the surface of the SARS-CoV-2 virus would bind to heparan sulfate molecule which is a large, complex sugar molecule found on the surface of cells in the lungs, blood vessels and smooth muscle making up most organs.

Facilitated by its initial binding with heparan sulfate, the virus uses another cell-surface component protein known as angiotensin-converting enzyme 2 (ACE2), that helps enter the infected cells.

The team noted that as the virus held on to the heparan sulfate molecule it prevented the binding of the molecule with complement control protein factor H. This prevented the normal function of factor H to regulate the chemical signals that trigger inflammation and keep the immune system from harming healthy cells. Without this protection, cells in the lungs, heart, kidneys and other organs can be destroyed by the defense mechanism intended to safeguard them, wrote the authors.

“Previous research has suggested that along with tying up heparan sulfate, SARS-CoV-2 activates a cascading series of biological reactions or the alternative pathway of complement (APC) that can lead to inflammation and cell destruction if misdirected by the immune system at healthy organs,” says study senior author Robert Brodsky, MD, director of the hematology division at the Johns Hopkins University School of Medicine.

The APC is one of three chain reaction processes involving the splitting and combining of more than 20 different complement proteins that usually gets activated when bacteria or viruses invade the body.

The end product of this complement cascade, a structure called membrane attack complex (MAC), forms on the surface of the invader and causes its destruction, either by creating holes in bacterial membranes or disrupting a virus’ outer envelope. However, MACs also can arise on the membranes of healthy cells. Fortunately, humans have a number of complement proteins, including factor H, that regulate the APC, that help to keep it in check and therefore, protect normal cells from damage by MACs.

In a series of experiments, Brodsky and his colleagues used normal human blood serum and three subunits of the SARS-CoV-2 spike protein to discover exactly how the virus activates the APC, hijacks the immune system and endangers normal cells.

They discovered that two of the subunits, called S1 and S2, are the components that bind the virus to heparan sulfate setting off the APC cascade and blocking factor H from connecting with the sugar and in turn, disabling the complement regulation by which factor H deters a misdirected immune response.

In turn, the researchers say, the resulting immune system response to chemicals released by the lysing of killed cells could be responsible for the organ damage and failures seen in severe cases of COVID-19.

Most notably, the research team found that by blocking another complement protein, known as factor D, they were able to stop the destructive chain of events triggered by SARS-CoV-2.

“When we added a small molecule that inhibited 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.”

There may already be drugs in development and testing for other diseases that can do the required blocking to prevent the infection, which needs to be studied, said the authors.