When the body encounters an infection, it can respond in two ways: by eliminating the pathogen—known as resistance—or by minimizing damage caused by the pathogen and the immune response itself—a strategy referred to as tolerance.
Tolerance is significant in respiratory infections such as influenza, where lung tissue damage often leads to death. Tolerance promotes tissue repair and maintains lung integrity and function, potentially without affecting viral replication.
Innate immune cells, the body’s first line of defense, can remember prior infections—a phenomenon known as trained immunity. It enhances resistance, making the host more resilient to future infections. However, can trained immunity also enhance disease tolerance?
Researchers at McGill University’s Department of Microbiology and Immunology (Montreal, Canada) demonstrated that β-glucan promotes tolerance to influenza via regulatory neutrophils.
β-glucan is a component of fungal cell walls. It can reprogram hematopoietic stem cells in the bone marrow, which give rise to all innate immune cells. Previously, β-glucan was shown to help defend against bacterial, fungal, and even cancerous diseases. However, its effects on respiratory viral infections remained unclear.
The researchers focused on neutrophils—the most abundant white blood cells- the first to arrive at infection sites. Typically, neutrophils destroy pathogens but can cause tissue damage by triggering inflammation. However, neutrophils generated in response to β-glucan behave differently.
Upon β-glucan stimulation, a subset of regulatory neutrophils is formed. These cells are less mature and have altered metabolic programming. Unlike mature neutrophils, which rely primarily on glycolysis for energy, regulatory neutrophils use mitochondrial respiration. They also produce IL-10, an anti-inflammatory cytokine, enabling them to limit lung inflammation during influenza infection and promote tissue recovery—without affecting viral replication.
Thus, β-glucan reprograms bone marrow stem cells to generate a unique neutrophil population that does not directly attack the virus but protects the lung tissue from damage, reducing the severity of flu infection.
In a mouse model, β-glucan improved survival during influenza by reprogramming hematopoietic stem cells to produce regulatory neutrophils. These cells were essential for enhancing tolerance to infection. Mice given β-glucan a week before influenza exposure had milder disease and higher survival rates.
Notably, viral loads in the lungs were unchanged compared to control mice, suggesting that β-glucan did not intensify antiviral immunity. Instead, it reduced inflammation and tissue damage—edema was lower, vascular permeability decreased, and lung lavage contained less protein and red blood cells.
Regulatory neutrophils explicitly mediated the survival benefit. When these cells were depleted in β-glucan-treated mice, the protective effect disappeared. Moreover, transferring regulatory neutrophils from treated mice to untreated controls improved survival in the recipients.
The protective effects of β-glucan depend on specific molecular pathways, including the Dectin-1 receptor, which recognizes β-glucan, and the type I interferon signaling pathway. In the absence of these signals, bone marrow reprogramming does not occur.
Interestingly, β-glucan relies on different pathways in other infections—such as IL-1 signaling during tuberculosis, suggesting that the signals needed for stem cell reprogramming depend on the pathogen and inflammatory context.
While regulatory neutrophils are generated independently of adaptive immunity, their recruitment to the lungs requires T cells. Although the cytokines involved in neutrophil recruitment were not identified in this study, the authors hypothesized that IL-17 may be involved, underscoring the need for coordinated action between innate and adaptive immunity to protect against lung infections.
The protective effects of β-glucan persisted for up to 30 days post-injection. Other studies have shown that the BCG vaccine reprograms hematopoietic stem cells, with protection lasting at least a year and cross-protection against influenza lasting 6 months.
Like BCG, β-glucan may induce long-term stem cell reprogramming—but this requires further investigation.
Until now, most research on innate immune memory has focused on enhancing inflammation to eliminate pathogens. Far less is known about its ability to regulate inflammation and promote disease tolerance.
Given the limited treatment options for severe viral lung infections, enhancing innate immune memory to promote disease tolerance could be a promising therapeutic strategy.
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Reference
β-Glucan reprograms neutrophils to promote disease tolerance against influenza A virus
