When COVID-19 struck, it seemed inconceivable that such a tiny virus could wreak such havoc in the body. But as it turns out, it is the body’s response to the infection—too forceful a burst of protective inflammation—that is the cause of the widespread disease seen in some patients.
“COVID-19 is a very good example of too much inflammation. People do not die of COVID directly, they die because their body generates too much inflammation,” said Professor Salvatore Albani, Director of the Translational Immunology Institute at the SingHealth-Duke-NUS Academic Medicine Centre.
Elaborating on what happens during COVID-19, Associate Professor Ashley St John from the Emerging & Infectious Diseases Programme at Duke-NUS explained how inflammation in the lungs can result in swelling and build-up of fluid.
“You can imagine how the lung tissue becomes very stretchy and, as you start recruiting all of these immune cells into the lungs, they make the tissue denser so that it’s more difficult for your lungs to inflate,” added St John on how chronic inflammation results in the laboured breathing experienced by some COVID-19 patients.
In a small percentage of patients who experience persistent inflammation because of COVID-19, the result is extensive damage to the surface of the lungs. This, in turn, causes more cells to be shed from the lining. This pooling of dead cells forms a thick layer, which makes it difficult for patients to cough or even breathe.
When the fires start to burn
But far from being the villain, inflammation is the immune system’s way of neutralising threats from pathogens like viruses as well as aberrant cells, such as cancer cells, with the goal of returning the body back to its normal state, explained Assistant Professor Lena Ho from the Cardiovascular & Metabolic Disorders Programme at Duke-NUS.
“Inflammation is like fire,” added Albani. In small measures, this fire keeps us warm and safe, but it also has the potential to harm us, if left uncontrolled.
Among the first to start the fire are mast cells.
“Mast cells are these really beautiful huge cells—they have lots of granules inside them. They’re kind of like an arsenal,” said St John.
These granules, which crowd inside the mast cell contain myriads of inflammatory mediators like histamines. And when the mast cell encounters an invading pathogen, the granules burst out of the cell.
“And then they explode and release these mediators,” she added.
Once released, these mediators work swiftly to clear the pathogens by calling other groups of immune cells to the site of inflammation. The process is complicated and coordination is key in ensuring that infections are cleared.
“Inflammation is the end product,” added Albani as he explained how the various immune cells mediate the process, either directly or indirectly by releasing antibodies or proteins into the blood.
As the immune system rains inflammatory fire on perceived threats, it often results in a certain extent of collateral damage among healthy cells and tissues.
This is why there are mechanisms in place to limit the extent of the damage.
“Inflammation is a spectrum—it’s always occurring, it’s constantly regulated,” explanied St John. “As soon as the inflammatory process begins, there are lots of other processes that begin to shut it down. You’re not supposed to experience chronic inflammation. Ideally, you experience just enough inflammation to clear infection and not to cause too much tissue damage,” she added.
From campfires to uncontrollable wildfires
“Usually your immune system is pretty good at deciding what kind of inflammatory response is needed,” said St John.
But when inflammation spirals out of control for the wrong reasons, the results can be disastrous. “I think of inflammation as being a problem in two ways: first when it should not have been initiated in the first place, or when it is not turning off at the right time,” added St John, who also holds an appointment with the SingHealth Duke-NUS Global Health Institute.
Using atherosclerosis as an example, blood vessel expert Lena Ho explained how vascular inflammation is triggered by seemingly harmless fats or lipids that are deposited along the walls of coronary vessels to form plaques. But these plaques can be deadly. As immune cells accumulate around the plaques to clear the lipids, inflammation results that does not switch off. And that can cause the plaques to rupture, forming a blood clot that may eventually trigger a heart attack or stroke.
“So having a plaque in your vessel is okay. But having an unstable plaque that ruptures is not and that’s what kills you—not the plaque itself,” said Ho.
The results can also be devastating if the immune system perceives a threat when there is none.
In an autoimmune inflammatory disease like rheumatoid arthritis that Albani is currently working on, the immune system goes berserk and attacks healthy cells in the body instead, causing inflammation at the joints that is often accompanied by painful swelling.
On the other hand, when inflammation is triggered by substances in the environment that should not trigger a response in the first place such as certain types of food or jewellery, allergies result.
“We’re supposed to be tolerant to our foods,” said St John, “but if your food somehow seems like a pathogen to your immune system, you can begin to develop a food allergy where your immune system starts fighting off that particular kind of food.”
How the embers can lead to cancer
Inflammation can also play a devastating role in cancer, which is the leading cause of death in Singapore.
“It is quite clear now that inflammation can initiate cancer,” said Duke-NUS Associate Professor Toh Han Chong, who is also Deputy Medical Director of Strategic Partnerships at the National Cancer Centre Singapore. “It was actually added to the updated Hallmarks of Cancer published in Cell in 2011, because it became apparent that a persistent inflammatory environment can cause cancer.”
According to Toh, the causes of inflammation in cancer are many, ranging from obesity, which is an inflammatory phenotype, to viral-induced inflammation that disrupts and damages normal cells and tissues in the body. He explained that patients who become chronic Hepatitis B carriers after infection by the Hepatitis B virus account for 70 to 80 per cent of liver cancer cases in Singapore.
As part of a complex multi-step process, inflammation is known to promote the growth of blood vessels inside the cancer to feed its growth. “Certain immune cells surrounding the cancer contribute to the growth of these abnormal blood vessels that feed cancer growth,” he said.
However, “the mechanisms of inflammation can also be harnessed for good,” added Toh, who is trying to use aspects of inflammation to fight cancer.
In this aspect, Toh is working on cellular immunotherapy, where patients’ immune cells are extracted and “re-engineered” before they are put back into the body as an infusion to treat the cancer.
As the flames spread to COVID-19
Concerned by the plight of people who develop severe COVID-19, St John is delving deeper into the link between inflammation and COVID-19. And her team has recently discovered a strong correlation between mast cells and severe disease—a discovery that St John hopes to use to prevent or even reverse severe disease.
“COVID-19 is something that needs additional therapeutics, people are really suffering,” she said, referring to the limited treatment options available at the moment.
While steroids such as dexamethasone have been recommended as treatment options by the World Health Organisation (WHO) and the National Centre for Infectious Disease in Singapore, they are used with caution and restricted to patients suffering from severe COVID-19.
According to St John, when patients are given dexamethasone, it is akin to hitting the immune system with a sledgehammer as the drug blocks every immune cell type and suppresses basic activation of immune cells. Depending on when the steroid is given, it can also be dangerous in the context of a viral infection like COVID-19, since the infection can escape if not enough time is given for the immune system to clear the virus before dexamethasone shuts it down.
Tapping her affiliation with the Department of Pathology at Duke University, St John will join forces with Duke Associate Professor in Surgery, Alexander Limkakeng on a clinical trial to test the effectiveness of a mast cell stabilising drug. The drug specifically stops mast cells from releasing granules that promote inflammation and does not interfere with other components of the immune system.
“So we think it’s a little bit like helping the immune system put the brakes on inflammation early on,” said St John.
Mast cells degranulating in the trachea of a mouse infected with SARS-CoV-2 (right). The granules released are stained in purple, and can be seen spreading away from the centre of the cell // Credit: Ashley St John
Conversely, focusing on patients who have recovered from COVID-19 has provided Albani and his team with insights on why certain patients fare better after they are infected. In particular, they found a population of regulatory immune cells known as T cells that function like a dimmer, sending a signal to the immune system when there is too much inflammation to “tune this down” while making sure that the body responds with enough force to resolve the infection.
“If we learn how to play with the dimmer, then we will be able to restore the natural mechanisms in our cells, which are compromised in diseases,” said Albani.
Dousing the wildfires with therapeutics
With inflammation at the heart of many conditions, it is no surprise that many researchers are working on various therapeutics to limit the extent of the damage caused by inflammation.
“Typically, we look at the ability to manipulate the intensity of immune responses, using switches, on and off, and then apply this to therapy,” said Albani.
He has been working on a short peptide to control the extent of inflammation in arthritis patients by making use of the body’s own reserves of regulatory cells to clamp down on the excessive inflammation.
“It’s like a vaccine for arthritis and it works because it creates or induces the cells which are missing—the regulatory cells. So it’s like a cellular therapy, but in a pill,” said Albani, who is optimistic about the peptide, which has produced promising results in Phase One and Two studies.
Making use of peptides to regulate inflammation is also an area of research that Ho focuses on. “Small proteins [like peptides] are much easier to manipulate than large proteins,” said Ho about her decision to work with peptides.
Innovating to improve treatment outcomes
Other than working on therapeutics, Albani and his team have also developed a tool to aid them in understanding the mechanisms of immunity in inflammation and other diseases.
Known as EPIC—short for Extended Polydimensional Immunome Characterisation, it is a web-based platform that hosts a comprehensive immune atlas and uses artificial intelligence (AI) to build an image of the immunome. According to Albani, it allows an image of the body to be captured at the cellular level, enabling researchers to pinpoint exactly what is going right or wrong.
“EPIC enables us to literally dissect various parts of the inflammation, the ones which are beneficial and the ones which are uncontrolled or unresponsive,” said Albani.
He has combined this approach of studying the immunome using EPIC with his ongoing work on treating rheumatoid arthritis. Calling it a “completely new approach”, Albani explained how this strategy allows his team to look at the entire immunome of the patient—before and after therapy.
“So we learn, what are the foundational responses,” he said, highlighting how the knowledge gained can not only be used to improve the therapy but also to select for which patients to give the therapy to—encapsulating the very essence of precision medicine—tailoring therapy based on the probability of the patient’s response.
“Imagine being able to go faster in in developing new drugs—this is a major leap for patients worldwide,” added Albani on the potential of EPIC in advancing research for new therapeutics.
And when it comes to the way forward in tackling inflammation in diseases, Albani has these last words of advice: “As long as you work on modulating the response, rather than destroying what is wrong,” he said.
St John agrees: “There’s a very fine line that you must walk: that’s the way inflammation is. You’re always trying to have the least amount of inflammation to create a beneficial outcome and control infection.”