Unveiling the crucial roles of two often-overlooked immune cells in the pathogenesis of SARS-CoV-2 infection
When SARS-CoV-2 invades the human body, most of us think of antibodies and T-cells as the key players in the immune drama that follows. But behind the scenes, two often-overlooked cell types—basophils and mast cells—orchestrate crucial aspects of our defense that can mean the difference between mild illness and severe disease. These rare but powerful cells, once considered merely allergy mediators, have emerged as unexpected protagonists in the COVID-19 story, influencing everything from initial symptoms to long-term complications.
The fascination of scientists with these cells isn't coincidental. Research has revealed that basophil levels plummet during acute COVID-19, with the degree of depletion serving as a prognostic indicator of disease severity 1 4 . Meanwhile, mast cells present in nasal and lung tissues participate in the first immune response to the virus, with their activation potentially contributing to the devastating "cytokine storm" and even long-term pulmonary fibrosis 1 3 4 . This article will unravel how these cellular actors play paradoxical roles—both protective and destructive—in our battle against COVID-19.
Basophils and mast cells, representing less than 1% of immune cells, play disproportionately large roles in COVID-19 pathogenesis and outcomes.
Basophils are the rarest of white blood cells, constituting less than 1% of our circulating immune cells. Despite their scarcity, they pack a powerful punch. These cells are characterized by cytoplasm rich in basophilic granules and the expression of the high-affinity IgE receptor (FcεRI) on their surface 1 .
Unlike their circulating cousins, mast cells are tissue-resident soldiers strategically stationed at barriers between our body and the outside world—especially abundant in nasal epithelium and lung tissue where pathogens like SARS-CoV-2 first gain entry 1 7 .
| Feature | Basophils | Mast Cells |
|---|---|---|
| Origin | Hematopoietic stem cells | Hematopoietic stem cells |
| Location | Circulating in blood | Tissues (lungs, skin, intestines) |
| Lifespan | Short-lived | Long-lived residents |
| Key Surface Marker | FcεRI, CD123, CRTH2 | FcεRI, KIT (CD117) |
| Major Mediators | IL-4, IL-13, histamine | Histamine, tryptase, chymase, TNF-α, IL-6 |
| Primary Functions | Antigen presentation, Th2 polarization | First-line defense, inflammation, vascular permeability |
One of the most intriguing COVID-19 mysteries has been the curious case of the vanishing basophils. Multiple clinical studies have consistently observed that basophil counts drop significantly during acute COVID-19 infection, with the degree of depletion correlating with disease severity 1 3 4 .
If basophils are the vanishing commanders, mast cells are the overzealous infantry that sometimes causes friendly fire. Situated in the prime locations for SARS-CoV-2 entry, mast cells are among the first immune cells to encounter the virus.
| Mediator | Biological Function | Role in COVID-19 |
|---|---|---|
| Histamine | Increases vascular permeability, broncho-constriction | Contributes to lung inflammation, edema |
| Tryptase | Protease that activates PAR-2 receptors | Promotes inflammation, tissue damage |
| Chymase | Converts angiotensin I to angiotensin II | May drive pulmonary hypertension, fibrosis |
| TNF-α | Pro-inflammatory cytokine | Amplifies cytokine storm, endothelial activation |
| IL-6 | Pro-inflammatory cytokine | Key driver of systemic inflammation |
To truly understand the role of mast cells in COVID-19 pathogenesis, let's examine a crucial study published in Respiratory Research in 2022 that provided direct evidence of mast cell involvement in fatal COVID-19 cases 5 .
Researchers conducted a detailed histological analysis of lung specimens from 30 patients who died from COVID-19, comparing them to 9 control patients who died from unrelated causes with healthy lungs.
Lung specimens were collected during autopsies and fixed in formalin before being embedded in paraffin blocks.
Tissue sections were stained with Giemsa dye to identify mast cells based on their metachromatic granules.
Researchers used immunohistochemical staining to detect mast cell proteases—tryptase and chymase—to determine activation states.
Using microscopy and digital image analysis, the team counted total mast cells and determined activation states.
Mast cell density, degranulation percentage, and protease expression were statistically compared.
COVID-19 Group: 30 patients who died from COVID-19
Control Group: 9 patients with healthy lungs
Methods: Histological analysis, Giemsa staining, immunohistochemistry
Analysis: Mast cell quantification, activation states, protease profiles
The findings revealed striking differences between COVID-19 lungs and healthy controls:
Significantly increased in COVID-19 patients with further augmentation during late stage damage 5 .
Markedly higher percentage during both early and late stages of lung damage compared to controls 5 .
Significant elevation in COVID-19 lungs, potentially contributing to pulmonary complications 5 .
| Patient Group | Mast Cell Density (cells/mm²) | Degranulated Mast Cells (%) | Chymase-Positive Mast Cells (%) |
|---|---|---|---|
| Control Lungs | Baseline level | Low baseline | Baseline level |
| COVID-19 Early Stage | Significantly increased | Significantly increased | Significantly elevated |
| COVID-19 Late Stage | Further augmented | Remained significantly increased | Remained significantly elevated |
This experiment provided crucial direct evidence from human tissues that mast cells are not just present but actively participating in the lung pathology of fatal COVID-19. The increased numbers and especially the heightened activation state suggest these cells are being recruited and stimulated by the viral infection or subsequent inflammatory environment.
Recognizing mast cells' role in COVID-19 pathology has opened promising therapeutic avenues:
Drugs like sodium cromoglicate prevent degranulation, potentially reducing mediator release in early infection 7 .
Famotidine (a histamine H2 receptor antagonist) shows promise in some clinical studies for relieving COVID-19 symptoms 8 .
Quercetin supplements may modulate the inflammatory system and potentially reduce the risk of developing severe COVID-19 7 .
Perhaps the most compelling therapeutic implications involve Long COVID. Researchers have noticed striking similarities between Long COVID symptoms and Mast Cell Activation Syndrome (MCAS) 2 .
This overlap isn't coincidental. The persistent inflammatory state in Long COVID appears to activate specific mast cell genes that cause abnormal mast cell activation control 2 . This has led clinicians to trial MCAS treatments—including H1 and H2 antihistamines and mast cell stabilizers—for Long COVID patients with promising early results 2 .
While mast cells represent therapeutic targets, basophils offer diagnostic and prognostic value. The consistent observation that low basophil counts predict worse outcomes suggests that simply tracking these cells in standard blood tests could help identify patients at risk of severe disease 1 3 4 . One retrospective study of 548 COVID-19 patients found that a difference between admission and end-hospitalization levels of basophils greater than 0.02 × 10⁹/L represented a risk factor for fatal outcome 3 .
Basophils and mast cells, once overlooked in viral immunity, have emerged as crucial orchestrators of COVID-19 pathogenesis. These cells embody the delicate balance our immune system must strike—enough response to control the virus, but not so much that it damages our own tissues. Basophils, though depleted in circulation, appear essential for coordinating effective antibody responses, while mast cells' frontline defense sometimes turns destructive, contributing to both acute crisis and long-term complications.
The COVID-19 pandemic has highlighted the complexity of our immune system and the importance of understanding even its rarest components. As research continues, targeting mast cells and monitoring basophils may yield better treatments not just for COVID-19, but for other viral diseases and post-infection syndromes. These microscopic warriors remind us that in immunology, as in life, the smallest players often have the most significant impact.
"The authors declare no conflict of interest." 4