The human immune system has numerous ways to fight infections. However, pathogens have tricks as well including a signal to prevent immune cells from killing them, according to a recent study.
The study of the signal utilized by pathogens to halt an immune response was conducted by scientists at Stanford University, a private research university in the US. Their findings unveiled the CD47 molecule, a signal expressed by bacteria and viruses to stop immune cells from fighting an infection. This molecule was previously identified in cancer cells, which used it to evade the immune system. They published their findings in the journal mBio.
The Signal Exploited by Pathogens to Inhibit Immune Cells
When harmful microbes enter the human body, cells of the innate immune system automatically respond to the invaders. These cells initialize a complex network of processes to increase immune activity, enhance healing if necessary, and strengthen immune cells to withstand invaders. As such, inflammation and cellular proliferation, among many other things, occur at the same time to eliminate the threats. But if the first responders fail to contain the situation, the adaptive immune system makes a follow-up using more potent mechanisms, such as antibodies and killer T cells, to prevent threats from further escalating.
During an immune response, chemicals are utilized by different cells to properly coordinate a defense. These chemicals command immune cells to attack pathogens and infected cells, order healthy cells to make room for other defenders, and direct non-fighting cells to heal injuries or induce cellular reproductive for repair purposes. Unfortunately, the dependence of cells on these chemicals can sometimes be against them. Cancer cells are can exploit the chemicals, and since they originated from healthy cells, they are familiar with how things work. Thus, they can express signals to avoid the immune system and grow without hindrance.
At Stanford, a team of scientists found the same signal expressed by cancer cells in pathogens. In bacterial and viral infections, the CD47 signal was found successful in halting the response of immune cells. It gave pathogens sufficient time to reproduce because macrophages failed to devour infected cells. But if the suppression could be targeted, novel therapies might reverse the problem. These therapies might become viable for cancer treatments as well.
“We wondered whether the mechanism activated by all cancer cells to avoid being destroyed could also be used by persistent infections so that the microbes can hide inside cells to evade immune cells. Amazingly, we found that to be true, and blocking the CD47 signal helped the body get rid of more infected cells,” said Dr. Irving Weissman, a senior author of the study and director of the Institute for Stem Cell Biology and Regenerative Medicine at Stanford.
CD47 is a protein normally expressed by the human body. It is one of many proteins that work as a signal to prevent the immune system from killing the body. This is how friendly cells modulate the aggression of certain immune cells. In real-life, the failure to regulate immune-inducing chemicals is attributed to some deaths of patients with infections. Rather than dying from the pathogens, the immune system accidentally damaged vital organs up to the point of organ failure. Cytokine storm and septicemia are examples of complications from severe overreaction by the immune system to an infection.
When first responders of infection completed their task, the friendly cells produce CD47 protein to say "do not eat me." The protein is recognized by immune cells as a signal to stop attacking. Specifically, the signal works for macrophages or cells that devour pathogens and infected cells. CD47 counters signals of aggression issued by other sources.
Many human cells have CD47 protein but the quantity diminishes over time. For example, red blood cells begin with tons of CD47 on their surface. As they age, the number of CD47 protein on their surface drops. Thus, red blood cells are not enough to modulate macrophages. So, the human body keeps replenishing the blood with new red blood cells to keep macrophages in check, at least, without requiring the help of immunomodulators.
How Pathogens Managed to Express CD47
The protein is unique in cells and unlikely to be produced by bacteria and viruses. By default, pathogens cannot unleash CD47 protein to evade macrophages upon entering the human body. The only way for them to express this protein is by hijacking the cellular controls of host cells. Once they infected healthy cells, they can take over the parts and examine the properties. After they detect the function of CD47, they produce enormous amounts to let nearby macrophages know that everything is fine.
Scientists confirmed the high expression levels of CD47 in both bacterial and viral infections. The same levels of expression were determined in infected human and mouse cells. The novel coronavirus SARS-CoV-2 utilizes the same tactic in slowing down the immune system. Cells infected with SARS-CoV-2 were found with increased production of CD47.
The team pushed forward and investigated if suppressing CD47 could boost the immune response against viruses. They infected mice models with LCMV - a meningitis-causing virus. They administered an antibody-based therapy to block the protein into the mice. The animals administered with the therapy had lower viral loads across all experiments, compared to mice that did not receive it.
Next, they exposed another set of mice to the bacteria known to cause tuberculosis. The mice for this experiment had been altered to lack the gene for CD47 expression. Analyses done on tuberculosis-infected mice showed better resistance to the infection and higher survival, compared to control mice. Scientists concluded that certain infections might be easier to clear out if CD47 levels were lowered.
Select Data on Global Infectious Diseases
According to Statista, a German portal for statistics, the distribution of infectious diseases between men and women varied in some countries. As of 2019, the distribution of infectious diseases was 69% in women and 31% in men in the US, 63% in women and 37% in the EU-5 countries, 62% in women and 38% in men in Japan, 53% in women and 47% in men in Brazil and Russia, and 55% in men and 45% in women in China.
Meanwhile, alcoholic consumption was found with high prevalence in patients diagnosed with infectious diseases. In a 2019 survey performed on 249,008 respondents, 62% of those diagnosed in Brazil, 78% in China, 79% in the EU-5 countries, 64% in Japan, 80% in Russia, and 70% in the US drink alcoholic beverages.
The antibody for suppressing CD47 expression is being tested on certain cancer types, including leukemia, lymphoma, and myelodysplastic syndrome. The approach has been approved for cancer clinical trials because malignant cells often exhibit higher levels of the protein than pathogens. If proven, the approach may be expanded to treat select infections.