How COVID-19 sets off ravaging inflammation in some people
By Roberta Attanasio
Back in March 2020, Jane Brody wrote in The New York Times “While most people focus, as they should, on social distancing, face coverings, hand washing and even self-isolation to protect against the deadly coronavirus now ravaging the country, too few are paying serious attention to two other factors critically important to the risk of developing a Covid-19 infection and its potential severity. Those factors are immunity, which should be boosted, and inflammation, which should be suppressed.” However, major efforts were already underway at that time not only to develop a SARS-CoV-2 vaccine, but also to understand how the virus triggers a blizzard of uncontrolled inflammatory immune responses. These uncontrolled inflammatory immune responses—usually called cytokine storms—eventually cause acute respiratory distress and multi-organ damage.
In the past two years, researchers have developed several COVID vaccines and, now, have discovered why SARS-CoV-2 sets off cytokine storms. A study published in the journal Nature at the beginning of April 2022 shows that SARS-CoV-2 can infect immune cells called monocytes and macrophages, causing their fiery death by a process dubbed pyroptosis. Judy Lieberman, one of the study authors, said: “We wanted to understand what distinguishes patients with mild versus severe COVID-19. We know that many inflammatory markers are elevated in people with severe disease, and that inflammation is at the root of disease severity, but we hadn’t known what triggers the inflammation.”
Monocytes and macrophages are immune cells that serve as “sentinels”, ready to detect invading microbes. Once SARS-CoV-2 infects them, both cells die by pyroptosis, which releases a barrage of powerful inflammatory alarm signals that cause fever and call more immune cells to the site of infection. The process is like a fire that, once started, cannot be stopped—there are no biological fire extinguishers that work against pyroptosis. “In the infected patients, about 6 percent of blood monocytes were dying an inflammatory death,” said Lieberman. “That’s a large number to find, because dying cells are rapidly eliminated from the body.” The researchers also found that about a quarter of the macrophages in the tissue were dying.
The investigators were surprised to find that monocytes and macrophages could be infected with SARS-CoV-2, as monocytes don’t carry the ACE2 receptor, the classic entry portal for the virus, and macrophages have low amounts of this receptor. However, they also found that although SARS-CoV-2 was able to infect monocytes and macrophages, it wasn’t able to produce new infectious viruses within them—likely because the cells die quickly from pyroptosis before new viruses could fully form. Lieberman said: “In some ways, uptake of the virus by these ‘sentinel’ cells is protective: it sops up the virus and recruits more immune cells. But the bad news is that all these inflammatory molecules get released. In people who are more prone to inflammation, such as the elderly, this can get out of control.”
The study also revealed that monocytes carrying a receptor called CD16 was especially likely to be infected. Interestingly, the number of these monocytes increased in patients with COVID-19 and were more likely to be infected with the virus. The CD16 receptor seems to bind antibodies that recognize the SARS-CoV-2 spike protein—these antibodies may actually facilitate infection of monocytes carrying the receptor. “The antibodies coat the virus, and cells with the CD16 receptor then take the virus up,” Lieberman said. Notably, healthy patients who had received mRNA vaccines against COVID-19 did not produce antibodies that facilitate infection. It is possible that vaccine-generated antibodies don’t bind as well to the CD16 receptor and, therefore, the cells don’t take the virus up.
The researchers believe that these findings may explain why COVID-19 treatments based on monoclonal antibodies work only when given early. Lieberman said: “It may be that later on, antibodies may help enhance inflammation. We may need to look at the properties of the antibodies.”
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Alizon Lopez Orozco
Dr. Attanasio mentioned two essential factors to the risk of getting a Covid-19 infection and how bad it could be. They include immunity and inflammation. I believe that to fully understand that, we would need to dive in a little deeper. To comprehend that, we need to know how the opposite sex reacts to immunity and inflammation. More and more evidence shows that coronavirus disease 2019 (COVID-19) is different for men and women. Takehiro Takahashi mentions, “however, it is not clear if men and women have different immune responses to SARS-CoV-2, or if this is why men are more likely to get COVID-19.” Although, based on the observations taken for males and females, they were tested based on viral loads, SARS-CoV-2-specific antibody levels, plasma cytokines, and blood cell phenotypes. According to the article, “male patients had higher plasma levels of innate immune cytokines like IL-8 and IL-18 and more robust induction of non-classical monocytes than women.” So, in addition to the monocytes carrying a receptor called CD16, it can be seen that this other factor can contribute to it. As for women, interestingly, Takehiro Takahashi found that “female patients had significantly more T cell activation than male patients when they were infected with SARS-CoV-2.” Each gender’s body has more abundance of antigens than the other. One contains more than the other or has less, based on how the body reacts to the virus.
We also would have to see the perspective of aging since most of the affected people were the elderly. So which gender is more susceptible to the virus, males or females, based on age. Females have more robust immune responses than men on average: Females make more immunoglobulins (Igs), both IgM and IgG, and have a more robust antibody response after being vaccinated. So another contributing factor would have to do with whether they have been vaccinated.
COVID-19 is a disease caused by the virus SARS-CoV-2 which is very contagious and has quickly spread around the world. Monocytes and macrophages are white blood cells that serve as the frontline warriors of the immune system. They move inside the blood and tissues, searching for and destroying pathogens. However, this mechanism does not happen with patients infected with SARS-CoV-2. According to this article, SARS-CoV-2 can infect monocytes and macrophages cells that can lead to death by the pyroptosis process. Additionally, Dr. Roberta Attanasio also mentions that Covid-19 can trigger cytokine storms that cause acute respiratory distress and multi-organ damage.
So, is there any treatment that we can use to control and manage cytokine storms in Covid-19 patients? According to my research, using cytokine blockages targeting specific cytokines was proven successful in treating cytokine storms. IL-1 and IL-6 are two of the major pro-inflammatory cytokines. IL-1 inhibitor is comprised of IL-1α and IL-1β which exerts pro-inflammatory actions to recruit immune cells while IL-6 involve in iron metabolism which provides a microenvironment that prohibitive against infection. Furthermore, inhibition of the intracellular tyrosine kinase (JAK) pathway is also be used to treat cytokine storms. The ability to block cytokine signaling, reducing excessive inflammatory responses, as well as the entry of SARS-CoV-2, JAK inhibitors such as Ruxolitinib and Baricitinib are thought to be able to suppress cytokine storm.
Cytokines are diverse and have a key role in the immune system that bind to specific receptors on their target cells. But the excessive release of cytokines by the immune system when one or more agents enter the body leads to systemic inflammatory reactions. Even though cytokine inhibitors can be used to treat Covid-19 patients, I think cytokine storms can happen very quickly after patients got infected, so it is necessary to control it from the early stage to effectively reduce the risk of death for patients.
Before reading this article, I was unsure of the way in which SARS-CoV-2 caused inflammation. After reading this article, I have now learned that the inflammation of SARS-CoV-2 is due to the process of pryoptosis, which results in release of inflammatory markers into the body that will worsen the inflammation already taking place. This idea made me want to look more into the mechanism of COVID-19 inflammation, and how this harmful inflammation could be reduced to minimize disease in COVID-19-infected people.
In my search, I found a research article discussing research into blocking IL-1 to minimize respiratory failure in patients who have COVID-19. The immune system messenger IL-1 is a molecule that promotes inflammation, and so, if this molecule is blocked, then it cannot signal the body to create more inflammation. This would prove beneficial to treating patients who have COVID-19-associated respiratory failure, as the respiratory failure is induced by inflammation. The authors in the research article I found propose using the rheumatoid arthritis drug Anakinra to block IL-1 signaling. So, in a model infection, the SARS-CoV-2 virus would cause death of cells in our body, leading to the release of IL-1, but the drug Anakinra will block the IL-1 receptors on other cells, thus preventing the signal to increase inflammation, which will reduce autoinflammatory disease caused by SARS-CoV-2.
I believe that the research ongoing investigating blocking IL-1 in patients with COVID-19-associated respiratory failure is promising, as this will help the survival of most vulnerable populations like the elderly. Currently, the options for people with COVID-19 respiratory problems are slim, and typically involve intubation and breathing on a ventilator until the body can hopefully clear the infection, which is a miserable experience. I recall seeing beds lining the halls of my emergency department during the COVID-19 surge because there were too many people admitted to the hospital already with COVID-19-pneumonia or respiratory failure. If IL-1 blockage proves to be a successful in reducing respiratory failure in COVID-19 infection, then these patients will have a better quality of life, and the healthcare system will have less of a burden placed on it and its patients. Also, the anti-inflammatory mechanism of IL-1 blockage could hopefully be applied to other novel viruses if they have the same mechanism of disease as SARS-CoV-2.
Before December of 2021, I only focused on the social distancing and hand washing Jane Brody mentioned. As a person who caught a moderate form of COVID-19, the cytokine storms are real. These cytokine storms do not always appear right after you test negative for COVID-19. Once the virus attacks your monocytes with CD16 and macrophages through pyroptosis there “double M’s” (monocytes and macrophages) are the main line of defense against certain microbes. If immune cells sense this discord, they will come to the rescue but it becomes too much leading to inflammation. A couple of months ago, I was diagnosed with costochondritis which arose from me having COVID-19 a month prior. The medicines they gave me for my symptoms did not include an anti-inflammatory; they were only anti-viral. According to my research, “antiviral treatment alone is not enough and should be combined with the appropriate anti-inflammatory treatment”. The reason for me having complications after came from the doctors treating the wrong symptoms of my COVID-19. This coincides with this article that treatments need to be given earlier.
COVID-19 has the ability to cause infections at different severity levels in different individuals. The SARS-CoV-2 virus can cause uncontrolled inflammatory responses, also known as cytokine storms, in certain individuals. The infection can result in acute respiratory disease and even multi organ damage.
Studies have shown that SARS-CoV-2 infects and causes death of monocytes and macrophages, otherwise known as pryoptosis. When SARS-CoV-2 infects monocytes and macrophages, the immune response releases inflammatory signals, which causes fever. It is known that the virus enters the cell through the ACE2 receptor; however, monocytes lack and macrophages have a small amount of this receptor. Although lacking the receptor, SARS-CoV-2 is still able to infect these cells, but it is not able to reproduce because it is destroyed by pyroptosis. Due to this response, more immune cells are recruited, and more inflammatory molecules are released. This is the likely cause of the inflammatory response.
Why does disease by COVID-19 severity vary among individuals? The reaction to the virus also varies upon different regions; however, reactions also vary in individuals within the same region. There are different factors that can contribute to the severity of disease from COVID-19, such as lifestyles, environmental, or genetic factors. An example of lifestyle factors could be reduced physical activity, overeating, and elevated alcohol and tobacco consumption. An obese individual has weaker local and systemic immune alterations due to metabolic stress. In adipose tissue, the anti-inflammatory immune cells (macrophages, regulatory T cells, T-helper cell) are replaced by increased numbers of pro-inflammatory primed immune cells, which secrete pro-inflammatory cytokines. This is characterized by elevated cytokine levels, which limit responses to viruses, such as SARS-CoV-2.
At the beginning of the article, Jane Brody mentioned that many people are not paying as much attention to the inflammation aspect that results from COVID-19 and the importance of getting immunized. I few like some people are not really paying to these two aspects due to the lack of correct information. Sometimes the media paints COVID-19 as not being as severe, and that it is mainly very similar to the flu. There are a lot of people who think they won’t be able to catch COVID or that if they do, they’ll only feel sick for a few days and be okay.
This article states that COVID-19 can cause uncontrolled inflammatory immune responses through the deaths of macrophages and neutrophils.
I know COVID-19 affects those with underlying medical conditions such as cardiovascular disorders, diabetes mellitus, or obesity more severely than those who don’t have an underlying medical condition. So, as I have someone in my family who is diabetic, I wonder … are diabetic patients more susceptible to COVID-19? How exactly does being diabetic lead to an individual being at a higher risk to develop severe cases of COVID?
So, individuals with diabetes are at a higher risk to develop severe cases of COVID, but they are not necessarily more prone to developing COVID in itself. One of the things I found interesting is that according to the article, “ COVID-19 and diabetes mellitus: from pathophysiology to clinical management”, is due to diabetic patients already having ongoing inflammation in their body, with the addition of SARS-COV-2, there will be more of an increase in the inflammation leading to the potential deadly event, cytokine storm. As type 2 diabetes is most common, these individuals are resistant to insulin which causes inflammation to occur. In addition, for those who are obese or overweight, inflammation is continuously occurring as well, but at a low rate.
When an individual is infected with SARS-COV-2, there is an increase in reactive oxygen species (ROS) and interleukin 6 (IL-6). These two events will lead to inflammation as IL-6 is pro-inflammatory. This will hence lead to higher insulin resistance and hyperglycemia, which puts the patient immune system more at risk and increases the inflammation that the body is undergoing. With a high glucose level, there is a direct correlation with the increase in the replication of SARS-COV-2 (Lim S., et al, 2020). In addition, hyperglycemia can also result in acute respiratory distress syndrome and damage to the lungs, which ultimately lead to mortality.
So, as someone whose grandma is old in age and has many underlying health problems such as obesity, diabetes, and more, I would make sure to check her blood glucose level and do anything in my power to make sure to reduce any risk that she may get sick with COVID.
The SARS-CoV-2 strain is a virus that causes the corona virus disease in humans. Contracting this virus can lead to an uncontrollable immune response, to where there is an abnormal abundance of inflammatory immune response and the severity is unknown. The severity depends on the immunity levels of humans; immunosuppressed humans that come in contact with COVID-19 develop a greater risk of severe symptoms that can ultimately result in death. SARS-CoV-2 can cause acute respiratory distress that can spread to other organs of the body. Macrophages and monocytes, along with other immune cells are considered the body’s first line of defense. Macrophages have minimal ACE2 receptors and monocytes have CD16 receptors that lead to an increase SARS-CoV-2 to bind and cause a viral infection to occur.
Is there a way to block the CD16 receptors present in monocytes to bind to SARS-CoV-2 so that it is less likely to be infected with the virus? A possible molecule that can be used to block the binding of SARS-CoV-2 are sACE2-anti-CD16 VHH bi-speciﬁc molecule. “The sACE2-anti-CD16 VHH bi-speciﬁc molecule not only blocks SARS-CoV-2 from infecting cells but also mediates ADCC by NK cells.” There is a high affinity present so that it is easy for the binding to occur.
This article is easy to read and highly educational to anyone who seeks to learn about the difficulties some people experience from the disease Covid-19 caused by the virus SARS-CoV-2. This article focuses on the immune mechanism that caused vast inflammation in some people during the Covid-19 infection. It was noted that receptors called CD16 present in monocytes are likely to bind to antibodies that recognize the spike protein present in SARS-CoV-2. This causes the infection of CD16 carrying monocytes and leads to proptosis of infected cells. This further led to cytokine storms and eventually caused damage to organs.
Even though Covid-19 infection mainly causes respiratory inflammation, the study has indicated that it can also cause inflammation in the brain. One article titled “Brain Inflammation and Intracellular α-Synuclein Aggregates in Macaques after SARS-CoV-2 Infection” examines this relationship. Four cynomolgus and four macaques infected by SARS-CoV-2 were observed in the study. The result showed infiltration of T-cells in the pituitary gland of these animals. Some of the animals also showed elevated pituitary gland to brain size ratio. The overall study points out that the SARS-CoV-2 infection can cause lethal neuroinflammation.
After researching and reading articles regarding Covid-19 infection and the type of inflammations, it can cause. I think that the SAR-CoV-2 is shown to cause deadly respiratory inflammation due to an unrestrained inflammatory immune response. However, SAR-CoV-2 has been observed to cause lethal brain inflammation in mammals such as macaques. I believe that developing drugs that directly or indirectly inhibit the inflammation mechanism caused by Covid-19 infection is essential to combat the ongoing battle against SAR-CoV-2. I think that death due to inflammatory reasons will be more common due to the high mutation rate of SAR-CoV-2; therefore, I believe we should promote more research that aims to develop drugs that deal with inflammatory responses.
This blog highlights how two receptors found on two specific immune cells, monocytes and macrophages can do more damage than benefit. The cells are programmed to undergo cell death when compromised or at end of life stage and do so through pyroptosis. This leads to the potential harmful release of inflammatory molecules. Inflammation in an intergral part of the immune response, but can be deadly when trying to heal. Healing is one of the most unique attributes of a human, different for each individual, and based on a number of factors, such as diet, fitness, preexisting conditions, stress levels, immune levels, and sleep habits. Specifically, the eating and sleep habits of individuals during a pandemic are to be examined. The study “Eating habits and lifestyle changes during COVID-19 lockdown: an Italian survey” attempted to examine the lifestyle habits of a small nonrandom population during the peak period of the pandemic. The study highlighted how making lifestyle changes during the pandemic led to a fitter individual. Smoking and dietary habits were the two habits that offered the most benefit. Smoking carries no positive effects and a well balanced diet leads to fitter lifestyle. Regular exercise and sleep habits followed behind and needed to promote healing and recovery.
COVID-19 infection affects individuals in different ways. Some people experience mild symptoms, such as fatigue and headache, while others experience more severe symptoms. Some COVID-19 patients have experienced blood clots forming in their arteries and veins which caused many deaths.
In this article, Dr. Attanasio mentions how COVID-19 infection risks the development of uncontrollable inflammatory responses. COVID-19 can trigger cytokine storms, in which inflammatory proteins are flooded into the bloodstream. Cytokine storms are caused by cytokine release and hyperactivation of immune cells. In patients who are critically ill, these uncontrollable inflammatory responses can damage many bodily organs, and can become life threatening.
My question is, since COVID-19 triggers the release of cytokines into the bloodstream, could they be the reason in forming blood clots in COVID-19 patients? I found a research article which states that interleukins (IL)-1β and IL-6, which are cytokines produced by macrophages and monocytes in the lung, can induce thrombocytosis. Thrombocytosis is a disorder in which the body produces too many platelets. The formation of many platelets can lead to certain conditions such as blood clots, stroke, and heart attacks. The article also states that pulmonary embolism has been identified as an extreme consequence of COVID-19 infection. Pulmonary embolism is a blood clot that travels to the lung and blocks blood from flowing. I found this information very interesting because I always wondered why some COVID-19 patients experience blood clots. With these findings, I believe that cytokines (IL)-1β and IL-6 play an important role in blood clot formation in COVID-19 patients. When COVID-19 infection occurs, cytokine storms are triggered in which cytokines in the lung indirectly cause blood clots when inducing thrombocytosis.
In this article we are introduced to how COVID-19 spreads throughout the body. According to the article one major factor that needs to be taken into consideration is how to suppress inflammation. SARS-CoV-2 infects our immune cells, particularly monocytes and macrophages, causing them to die by pyroptosis. Pyroptosis is a form of programmed cell death. This triggers an inflammatory response causing a fever and a rush of immune cells to the infected site. Mast cells that are infected with the virus become activated. They release early inflammatory molecules (histamine and protease), which triggers the production of proinflammatory IL-1 (recruit’s inflammatory cells to site), IL-6 (production of neutrophils), and IL-33 (functions as a traditional cytokine). So, the question I am wondering is how can we suppress or stop inflammation?
One article I found suggest that Botox (botulinum toxin type A) injections eliminates inflammation in the affected area within 2 weeks. The neurotoxin can be retargeted to inhibit factors that induce cytokines which in return inhibit inflammation. Another way is the use of antiviral drugs like Ribavirin, Remdesivir, and Tenofovir. They contain anti-inflammatory properties that decrease inflammation seen in patients with SARS-CoV-2. Also, researchers are studying immunomodulatory and anti-inflammatory therapies that help reduce inflammation. In these therapies biological agents are used to target cytokine expressions and specific cytokine antagonists which in return reduces inflammation pathways.
Jenny Nguyen Do
According to Dr. Attanasio, once the SARS-CoV-2 virus infiltrates an individual’s body, it sets off a cytokine storm. The cytokine storm is the leading cause of uncontrollable acute inflammation in COVID-19 patients. Many factors contribute to the cytokine storm in the patient’s body: T cell activation and cytokine release, activation of transcription factors, mast cells, etc.
At the beginning of the pandemic, it was hard to figure out a treatment that would cure COVID-19 patients. Since researchers determined that the onset of the uncontrollable inflammation in the body was the reason why SARS-CoV-2 is so deadly, would it be possible to treat the disease by inhibiting a part of the cytokine storm mechanism?
I believe that if we are able to minimize the function of mast cells, not completely inhibit their function, we would be able to reduce the inflammation and prevent the development of pneumonia or lung failure.
There is another possibility where we should induce the function of mast cells in the early onset of SARS-CoV-2 infection. According to Zabetakis et al., the late activation of mast cells “triggers the production of proinflammatory IL-1 family member.” Their study found that there were elevated levels of inflammatory factors, including IL-1RA, IL-1B, IL-7, IL-8, IL-9, and IL-10. Perhaps, if we are able to induce early activation of mast cells, we would be able to reduce inflammatory factors that would cause organ failure.
Cytokine storms due to COVID-19 are thought to be caused by monocyte CD16 receptors. It is believed that host antibodies produced against COVID bind to CD16 receptors which leads to monocytes/macrophages taking them up and eventually leading to pyroptosis. Pyroptosis causes a powerful inflammatory response that brings more immune cells and repeats itself until the host dies. Although most severe COVID cases are genetic and age-related, the article states how healthier individuals are less prone to this cytokine storm due to their CD16 receptors not being able to bind effectively to COVID virus particles. This made me think about the mental implications of COVID and regular exercise. There is an inverse relationship between our immune health and stress: immune health/effectiveness tends to decrease and stress increases. With regular exercise, stress tends to decrease. The article “Physical exercise effects on the brain during COVID-19 pandemic: links between mental and cardiovascular health” states how this stress can eventually snowball into more severe disorders like obesity, heart issues, and mood disorders which are not all that beneficial to your immunity against novel pathogens. Furthermore, those who would commit to some type of movement fared better than those who were sedentary: however, there was a curvilinear relationship between how much exercise was being done and the negative impacts of COVID. Those who did moderate exercise faired the best, whereas those who did little and too much exercise fared worse against COVID. This perfectly displays how moderation is key, and should show us how things are neither black nor white, but can instead be gray.