This article translates a major scientific report from the European Academy of Allergy and Clinical Immunology (EAACI) into everyday language. The report, written by 36 experts from leading research institutions across Europe and North America, explains how the novel coronavirus SARS-CoV-2 enters human cells, why some people develop severe COVID-19 while others experience only mild symptoms, and what goes wrong in the immune system during the most dangerous forms of the disease. It highlights that the virus primarily uses a cellular "door" called ACE2 to infect the airways, but also reveals that dozens of other molecular pathways, including an alternative receptor called CD147, may be involved. Understanding these mechanisms will help researchers develop better treatments, faster diagnostics, and more effective prevention strategies.
When the World Health Organization (WHO) officially declared COVID-19 a pandemic on March 11, 2020, the world entered a new era of public health crisis. The virus, officially named Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), has infected millions of people worldwide, and the disease it causes, Coronavirus Disease-19 (COVID-19), has become one of the greatest medical and scientific challenges of our time.
The high infection rate and the severe disease course seen in many patients have forced governments to impose major safety and social restriction measures across the globe. But restrictions alone cannot solve the problem. There is an urgent need for unbiased, expert knowledge to guide the development of efficient treatment and prevention strategies.
This report, published by the European Academy of Allergy and Clinical Immunology (EAACI), was written by a group of experts in basic and clinical immunology who joined forces to provide a consensus document on the fundamental molecular and immune mechanisms associated with susceptibility to the virus, clinical presentations of the disease, and severity of COVID-19 outcomes. In other words, the authors wanted to answer one big question: why does the same virus cause a mild cold-like illness in one person and a life-threatening multi-organ failure in another?
The report summarizes current immunological data on the mechanisms associated with SARS-CoV-2 infection and COVID-19 development and progression to the most severe forms. It characterizes the critical differences between an adequate, healthy immune response in mild disease and the deep immune dysfunction observed in severe multi-organ disease. The similarities between the human immune response to SARS-CoV-2 and the earlier coronaviruses, SARS-CoV and MERS-CoV (Middle East Respiratory Syndrome Coronavirus), are also underlined.
Throughout the document, the authors identify key knowledge gaps and urgent research requirements, providing a roadmap for ongoing and future COVID-19 studies worldwide.
All human coronaviruses have animal origins, based on their genetic sequence similarity. The report explains that SARS-CoV, SARS-CoV-2, MERS-CoV, HCoV-NL63, and HCoV-229E are all considered to have originated from bats, while HCoV-OC43 and HKU1 likely came from rodents. SARS-CoV-2 has significant structural similarity to both SARS-CoV and MERS-CoV, as well as other human and animal coronaviruses, which has allowed scientists to make educated guesses about how it behaves.
Just as a key fits a lock, viruses need specific "keys" on their surface to open "locks" (called receptors) on the surface of your cells. Researchers quickly determined that SARS-CoV-2, similarly to SARS-CoV, uses a receptor called angiotensin-converting enzyme 2, or ACE2 for short, to enter human cells. This interaction happens through the virus's spike protein (the "S" protein) — the same spike you see sticking out of the virus in illustrations.
Once SARS-CoV-2 binds to ACE2, the receptor is internalized (pulled inside the cell), and its presence on the cell membrane decreases. This has important consequences: ACE2 is a key regulator of a substance called bradykinin, which affects blood vessel function. When ACE2 expression is reduced in the lung environment, local vascular leakage occurs, leading to a condition similar to angioedema (swelling caused by fluid leaking from blood vessels) in the affected lung tissue. This is one of the earliest steps that can lead to lung damage in COVID-19 patients.
However, ACE2 is not the only player. A host enzyme called TMPRSS2 (serine protease) acts as a "molecular scissors," cleaving the spike protein into two fragments, S1 and S2. This cleavage enables the virus to fuse with the cellular membrane, enter the cell, and begin the replication process.
In addition to TMPRSS2, other proteins are potentially capable of cutting the spike protein. These include:
These alternative scissors are important because they may allow the virus to enter cells through different routes, potentially explaining why the virus can infect various tissues and why some cells are more susceptible than others.
ACE2 is highly expressed in a number of organs that are commonly affected in COVID-19:
Importantly, ACE2 is not expressed on innate and adaptive immune cells — meaning the virus cannot primarily use this door to directly infect immune cells. This is where other receptors come into the picture.
As recently shown by research, SARS-CoV-2 can also use a receptor called CD147 (also referred to as basigin (BSG) or extracellular matrix metalloproteinase inducer (EMMPRIN)) to enter T-cell lines (a type of immune cell) and cells of epithelial origin (surface-lining cells). However, scientists are not yet certain whether the virus can efficiently replicate inside these cells, or whether it simply infects them and causes cell death.
CD147 is not new to virologists. It is used as a receptor by other viruses, including SARS-CoV and HIV-1, and even by the malaria parasite to enter red blood cells. This makes CD147 a particularly interesting target for research and potential treatments.
CD147 is a transmembrane immunoglobulin-like receptor, meaning it sits across the cell membrane, and it also exists in a secreted (free-floating) form. At the cellular membrane, it is activated by several extracellular ligands, which are molecules that bind to it:
Its extracellular glycosylation sites (sugar attachment points) bind to complex proteoglycans (sugar-protein molecules) such as syndecan-1. CD147 often forms membrane complexes with CD44, one of the receptors for hyaluronan, a major component of the extracellular matrix (the structural framework surrounding your cells).
Intriguingly, coronaviruses incorporate host cyclophilins during their cellular replication cycle, which further enables them to bind to CD147. The virus essentially "borrows" the host's own molecules to improve its ability to infect cells.
CD147 is expressed in several locations that are highly relevant to COVID-19:
The fact that CD147 is found on immune cells, whereas ACE2 is not, could help explain some of the immune system damage seen in severe COVID-19.
The report also lists several other receptors that the virus may potentially use:
These additional receptors expand the possible routes of virus entry and may partly explain the wide range of symptoms and organ involvement seen in COVID-19 patients.
The airway epithelium (the layer of cells lining your respiratory tract) is the battlefield where COVID-19 begins. Understanding exactly how the virus gains entry here is essential for developing preventive treatments, such as nasal sprays or inhaled medications that could block infection at the source.
In the upper and lower airways, ACE2 and TMPRSS2 are highly co-expressed — meaning they are found together on the same cells. This co-expression is what allows the virus to enter efficiently. Interestingly, there is no expression of a molecule called SLC6A19 in these cells. This is significant because SLC6A19 normally blocks the access of TMPRSS2 to ACE2, reducing active infection. In other words, the absence of this protective blocker in the airways makes them more vulnerable.
In the nasal and pharyngeal epithelium (the lining of the nose and the throat), ACE2 is expressed at high levels in goblet cells (which produce mucus) and ciliated cells (which have tiny hair-like projections that sweep mucus along). These cells also co-express TMPRSS2. This makes the nose and throat the initial sites of viral replication and a main source of infectious particles. Put simply, when you breathe in the virus, it finds a highly welcoming environment in your nasal passages. This also explains why testing via nasal swabs (which sample these very cells) can detect the virus early in the course of infection, and why COVID-19 often begins with a sore throat or loss of smell.
The lower airways — the bronchial (breathing tube) epithelium and, critically, cells called type II pneumocytes (AT2 cells) — also highly express ACE2 and TMPRSS2. AT2 cells are responsible for producing surfactant, a substance that keeps the air sacs of the lungs (alveoli) from collapsing. When these cells are infected and damaged, the lungs lose their ability to exchange oxygen properly, which ultimately leads to COVID-19 pneumonia.
Moreover, CD147, CD26, ANPEP, and ENPEP are all expressed in the airway epithelium, as well as in many innate and adaptive immune cells. This has been shown both in bronchoalveolar lavage (BAL) samples — where fluid is used to wash cells out of the lungs — and in peripheral blood. This wide-ranging receptor distribution may help explain why the virus can cause damage far beyond the lungs.
Once the virus enters a host cell, it releases its RNA (genetic material) into the cytoplasm — the jelly-like substance inside the cell. It then hijacks the cell's own protein-making machinery to translate the viral genetic material into two large polyproteins, called pp1a and pp1b, which act as replicases (enzymes that copy genetic material). The virus also produces essential proteases (protein-cutting enzymes) called 3CLpro and PLpro.
These proteases cleave the polyprotein complex into several non-structural proteins, known as Nsp (non-structural proteins). Together with the viral RNA-dependent RNA polymerase (the enzyme that copies the viral RNA), these Nsp proteins form the replication complex. This complex creates both the negative strand of RNA (a template) and the messenger RNA (mRNA) needed to produce the virus's structural proteins:
After protein translation, the viral components traffic through the endoplasmic reticulum (ER) to the Golgi apparatus — the cell's "packaging and delivery center." Here, mature virions (complete virus particles) are assembled in budding vesicles (small bubble-like compartments) and are exocytosed (released) from the cell to infect neighboring cells.
Inside infected cells, several innate immune mechanisms are responsible for recognizing the virus at different stages of its replication. These defenses lead to the production of interferons type I (IFN-α and IFN-β), type III interferons, and proinflammatory cytokines. Interferons are your body's natural "alarm bells" — they tell neighboring cells that a virus is present and help them prepare defenses.
Genes encoding these interferons form what researchers call the type-1 (E1) epithelial response profile. Interestingly, ACE2 itself is a typical E1 gene — meaning your body tries to protect itself by, among other things, regulating the very receptor that the virus uses to enter cells. This response also includes mechanisms such as the expression of helicases (enzymes that unwind viral RNA) and cytidine deaminases (enzymes that introduce mutations into viral RNA, crippling the virus).
Viruses, however, are not passive victims. They use various strategies to evade these immune mechanisms. While little is known specifically about SARS-CoV-2's evasion tactics, researchers can extrapolate much from the knowledge built up about SARS-CoV and MERS-CoV.
The report details that viral single-stranded RNA (ssRNA), double-stranded RNA (dsRNA), and proteins are recognized by cytosolic pattern recognition receptors (PRRs) — the "sensors" that detect viral invaders inside the cell. The main sensors involved are:
This recognition leads to the recruitment of key signaling proteins, including MAVS, MyD88, and/or TRIF, depending on which sensor was triggered. Eventually, transcription factors called IRF3 and IRF7 are activated, leading to the production of type I interferons (IFN-α and IFN-β). Meanwhile, other transcription factors called NF-κB and AP-1 lead to the production of proinflammatory cytokines — the molecules that orchestrate inflammation and call other immune cells to the scene.
In mild disease, this coordinated response efficiently clears the virus. In severe disease, however, the response goes awry — often resulting in an overproduction of inflammatory molecules (the dreaded "cytokine storm") and a simultaneous failure of the antiviral defenses, leaving patients vulnerable to both viral damage and secondary infections.
One of the central messages of the EAACI report is that the immune system is a double-edged sword in COVID-19. The key difference between patients who recover quickly and those who develop severe multi-organ disease lies in the quality, timing, and balance of the immune response.
In mild COVID-19, the immune system mounts a well-orchestrated, balanced defense. The airway epithelium detects the virus through the pattern recognition receptors described above and produces interferons, which inhibit viral replication. Innate immune cells (like macrophages and dendritic cells) present viral fragments to adaptive immune cells, triggering the production of virus-specific antibodies (by B cells) and virus-killing T cells. This coordinated "innate and adaptive immune response" results in the virus being cleared before it can cause extensive tissue damage.
In severe COVID-19, the picture is very different. The report describes a deep immune dysfunction characterized by:
This combination of a blind antiviral alert system and a blaring inflammatory alarm is what drives the progression to severe multi-organ disease, including acute respiratory distress syndrome (ARDS), cardiovascular complications, kidney failure, and neurological symptoms.
The report emphasizes that the human immune response to SARS-CoV-2 shares many similarities with the responses to SARS-CoV and MERS-CoV. This is good news for researchers, because it means that some of the knowledge gained from studying the earlier coronaviruses can potentially be applied to treating COVID-19. However, there are also important differences, including the fact that SARS-CoV-2 spreads more easily and has a larger proportion of asymptomatic or mildly symptomatic carriers, which has made controlling the pandemic much more difficult.
The authors also highlight key knowledge gaps regarding the involvement of comorbidities (other pre-existing health conditions), gender, and age in the development of severe COVID-19. The report notes that multi-morbidity — having multiple pre-existing health conditions at once — is a major risk factor for poor outcomes. Older age is also consistently associated with more severe disease. These risk factors are discussed in the full report from various angles, including how the immune system ages (a process called immunosenescence) and how chronic inflammation ("inflamm-aging") might increase vulnerability to severe COVID-19.
The findings summarized in this report have several important implications for patients and healthcare providers.
The high expression of ACE2 and TMPRSS2 in the nasal and pharyngeal epithelium — the cells that line your nose and throat — explains why nasal swabs are an effective way to detect the virus. These cells are the initial replication sites for the virus, and they shed substantial amounts of infectious particles, especially in the first days of infection. This is also why COVID-19 is so contagious: the virus is actively reproducing in the upper airways, where it can be easily expelled through coughing, sneezing, talking, and even breathing.
The high expression of ACE2 in the small intestine offers a plausible explanation for why some COVID-19 patients experience diarrhea, nausea, and abdominal pain. The virus may directly infect the intestinal lining, although further research is needed to confirm this and to determine whether the virus can be transmitted through the fecal-oral route.
The presence of ACE2 and other potential receptors in the heart, kidneys, and central nervous system helps explain why COVID-19 is far more than a respiratory disease. Cardiac complications, kidney failure, and neurological symptoms such as loss of smell, headache, and confusion are increasingly recognized as part of the COVID-19 spectrum. Patients with pre-existing cardiovascular disease, hypertension, or chronic kidney disease may be particularly vulnerable because their organs already have reduced reserve to withstand viral damage.
Understanding the molecular entry mechanisms opens up several potential treatment strategies:
The report also addresses the challenges of current approaches to diagnosing SARS-CoV-2 infection immunologically. The authors note that antibody tests need to be carefully validated, as cross-reactivity with other coronaviruses (including the common cold coronaviruses HCoV-OC43, HCoV-229E, HCoV-NL63, and HKU1) can produce false-positive results. Understanding the precise immune response — including which antibodies are protective and which may be harmful — is essential for developing reliable serological tests and, ultimately, vaccines.
The authors of the EAACI report are careful to acknowledge the limitations of current knowledge. At the time of writing (early in the pandemic), many aspects of SARS-CoV-2 immunology remained unknown:
Because this is a review and position paper, rather than a clinical trial, it cannot prove that any specific treatment works. It provides a framework for understanding the disease and identifies the most promising avenues for future research.
Based on the scientific understanding summarized in this report, here are key practical takeaways:
The virus uses its spike protein to attach to a receptor called ACE2 on the surface of your cells, like a key in a lock. It also needs a molecular 'scissors' called TMPRSS2 to cut the spike protein, allowing the virus to fuse with your cell and start replicating. Other receptors and scissors may also be involved.
In mild disease, the immune system responds in a balanced way with interferons and immune cells clearing the virus. In severe disease, this response is dysfunctional: there is too little early antiviral action, too much inflammation (cytokine storm), low lymphocyte counts, and exhausted T cells. This combination leads to severe multi-organ damage.
The nose and throat lining cells (goblet and ciliated cells) have high levels of ACE2 and TMPRSS2, making them the initial sites where the virus replicates. These cells shed large amounts of virus, especially early in infection. That is why nasal swabs can detect the virus effectively and why COVID-19 is so contagious.
Yes. ACE2 is found in the small intestine, kidneys, and heart, and other receptors like CD147 are on immune cells. This helps explain gastrointestinal symptoms, kidney failure, and heart damage. The virus can affect many organs, not just the respiratory system. Inform your doctor if you have symptoms in these areas.
People with multiple pre-existing health conditions (multi-morbidity), older adults, and those with cardiovascular disease, hypertension, diabetes, or chronic lung disease are at higher risk. The immune system changes with age and chronic inflammation may increase vulnerability. If you fall into these categories, seek medical advice early if you develop symptoms.
According to the EAACI report, having an allergy does not automatically increase your risk of severe COVID-19. Continue taking your regular medications, including inhaled corticosteroids for asthma. If you have concerns, consult your allergist. The report is from the European Academy of Allergy and Clinical Immunology.
Antibody tests need careful validation because cross-reactivity with other coronaviruses, including common cold coronaviruses, can cause false-positive results. This is a known challenge in coronavirus serology. If you receive an antibody test, understand that results can be affected by this cross-reactivity, which is not unique to any one test manufacturer.
This patient-friendly article is based on peer-reviewed research originally published as:
Original Article Title: DR. MILENA SOKOLOWSKA (Orcid ID : 0000-0001-9710-6685)
DOI: 10.1111/ALL.14462
Authors: Sokolowska M, Lukasik Z, Agache I, Akdis CA, Akdis D, Akdis M, Barcik W, Brough H, Eiwegger T, Eliaszewicz A, Eyerich S, Feleszko W, Gomez Casado C, Hoffmann-Sommergruber K, Janda J, Jiménez-Saiz R, Jutel M, Knol E, Kortekaas Krohn I, Kothari A, Makowska J, Moniuszko M, Morita H, O'Mahony L, Nadeau K, Ozdemir C, Pali-Schöll I, Palomares O, Papaleo F, Prunicki M, Schmidt-Weber CB, Sediva A, Schwarze J, Shamji MH, Tramper-Stranders G, van de Veen W, Untersmayr E
Publication: Allergy (European Journal of Allergy and Clinical Immunology), 2020. DOI: 10.1111/ALL.14462
Article Type: EAACI Position Paper (peer-reviewed, accepted for publication, in press version)
Note: This patient-friendly article is based on peer-reviewed research and was created to make the scientific findings accessible to a general audience. It does not constitute medical advice. For personal medical questions, always consult a qualified healthcare professional. The original research was supported by the European Academy of Allergy and Clinical Immunology (EAACI), Swiss National Science Foundation, and other funding bodies acknowledged in the original publication.
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