The key to defeating parasitic worms may lie in educating our most ancient immune cells.
Imagine a pathogen that infects nearly 1.5 billion people worldwide—almost one-fifth of humanity. These are not viruses or bacteria, but sophisticated parasitic worms known as helminths. For decades, scientists have struggled to develop vaccines against these complex organisms, which have evolved exquisite strategies to hide from our immune systems. But what if, instead of training the specialized special forces of our adaptive immunity, we could train the frontline infantry of our innate immune system? This is the revolutionary promise of targeting myeloid cells in the fight against helminth infections.
The current strategy for control relies primarily on preventive chemotherapy—mass drug administration programs that temporarily reduce worm burdens but fail to prevent reinfection 1 . To make matters worse, emerging anthelmintic resistance threatens to reverse even these limited gains 4 .
Target populations often have pre-existing immune responses to helminth products, increasing the likelihood of allergy or anaphylaxis 1 .
Current approaches typically reduce pathology rather than worm burden, offering only partial protection 1 .
So where does the solution lie? The answer may be in reprogramming our most ancient immune defenders: myeloid cells.
Myeloid cells include monocytes, macrophages, dendritic cells, and granulocytes (including eosinophils, neutrophils, basophils, and mast cells). These cells form the first line of defense against pathogens and have recently been discovered to possess a form of "memory" previously attributed only to adaptive immunity 6 .
Trained immunity describes the epigenetic and metabolic reprogramming of innate immune cells and their bone marrow progenitors, leading to enhanced responsiveness to subsequent challenges 5 . Unlike adaptive immunity with its antigen-specific T and B cells, trained immunity provides broad-based protection against diverse threats.
The concept gained traction from observations that certain vaccines, particularly the Bacillus Calmette-Guérin (BCG) tuberculosis vaccine, provide protection far beyond their target disease. BCG vaccination has been shown to protect against secondary infections with Candida albicans, Schistosoma mansoni, and influenza in a T-cell-independent manner 5 .
Similarly, latent herpesvirus infection increases resistance to bacterial pathogens like Listeria monocytogenes and Yersinia pestis through enhanced IFNγ production and macrophage activation 5 .
Most notably for helminth research, infection with the rodent parasite Nippostrongylus brasiliensis induces a long-term macrophage phenotype that damages the parasite and provides protection from reinfection—independently of T and B lymphocytes 5 . This finding suggests that helminths themselves can train myeloid cells for protection, a capacity we might harness in vaccine design.
Groundbreaking research has illuminated precisely how helminth infection can reprogram myeloid cells. Chen and colleagues demonstrated that the source and tissue location of macrophages critically determine their anti-helminth capabilities 1 .
Researchers used sophisticated cell-tracking techniques in mouse models infected with Nippostrongylus brasiliensis, a rodent hookworm that migrates through the lungs before settling in the intestine. They compared:
Existing in the lungs before infection
Recruited to the lungs after infection
Using fluorescence-activated cell sorting and genetic labeling, scientists could distinguish these populations and assess their respective contributions to parasite clearance during primary and secondary infections.
The experiments revealed striking differences between macrophage populations:
| Macrophage Type | Origin | Polarization Efficiency | Anti-helminth Activity |
|---|---|---|---|
| Tissue-resident alveolar macrophages | Embryonic development | Poor, due to limited glucose availability in airways | Limited |
| Monocyte-derived alveolar macrophages | Recruited from blood after infection | High, efficiently become alternatively activated | Significant, crucial for parasite killing |
The monocyte-derived macrophages that infiltrated the lungs after infection proved particularly effective at controlling N. brasiliensis. These cells expanded dramatically and polarized more efficiently into alternatively activated macrophages (AAMs) capable of killing parasites 1 .
Further investigation revealed the metabolic constraints that limit tissue-resident macrophages: glucose availability in the airways is naturally limited, restricting the energy-intensive process of alternative activation 1 . Monocyte-derived macrophages arriving later apparently circumvent this limitation.
| Experimental Model | Immune Component | Protection Level | Key Mechanism |
|---|---|---|---|
| Nippostrongylus brasiliensis reinfection | Monocyte-derived alveolar macrophages | Significant reduction in worm burden | Alternative activation leading to direct parasite killing |
| Heligmosomoides polygyrus bakeri infection | Distally activated eosinophils | Heterologous protection against N. brasiliensis | IL-5 mediated activation, requires CD4+ T cells |
| Strongyloides venezuelensis infection | Distally activated eosinophils | Heterologous protection against N. brasiliensis | IL-5 mediated activation, requires ILC2s |
Helminths haven't survived for millennia without developing sophisticated countermeasures. These parasites actively sabotage myeloid cell function through various mechanisms:
Helminths release a complex mixture of proteins, peptides, lipids, and RNA-carrying extracellular vesicles that reprogram host immune cells 5 .
These membrane-bound nanoparticles deliver regulatory molecules directly to host cells, modulating their function 1 .
Some parasites alter local nutrient availability or immune cell metabolism to favor their survival.
This evolutionary arms race means that successful vaccines must either overcome this sabotage or harness the very mechanisms parasites use to modulate immunity.
| Evasion Mechanism | Components Involved | Effect on Myeloid Cells |
|---|---|---|
| Excretory/Secretory Products (ESPs) | Proteins, peptides, lipids | Reprogram macrophage polarization, suppress effector functions |
| Extracellular Vesicles (EVs) | RNA, proteins, signaling molecules | Deliver regulatory cargo to innate immune cells |
| Immunomodulatory Molecules | TGFβ mimics, protease inhibitors | Skew toward regulatory phenotypes, suppress inflammation |
Advancing myeloid cell-based vaccines requires specialized tools and techniques. Here are key resources enabling this cutting-edge research:
Specific helminth-rodent pairs including Nippostrongylus brasiliensis (acute infection) and Heligmosomoides polygyrus bakeri (chronic infection) that recapitulate different aspects of human disease 7 .
Fluorescence-activated cell sorting (FACS) and magnetic-activated cell sorting (MACS) to separate specific myeloid populations from complex tissues.
Assays to map DNA methylation, histone modifications, and chromatin accessibility that underlie trained immunity.
Technologies to measure metabolic flux and nutrient utilization in reprogrammed myeloid cells.
Multiplex assays to quantify the complex cytokine milieu that shapes myeloid cell function during helminth infection.
While the potential of myeloid cell-focused helminth vaccines is compelling, significant challenges remain:
The same type 2 immune responses that control helminths can cause allergy and anaphylaxis—successful vaccines must navigate this delicate balance 1 .
Determining the ideal "educators" (specific antigens, adjuvants, or entire parasite extracts) to train myeloid cells without causing harm.
Identifying the best routes (mucosal vs. systemic) and formats to induce protective trained immunity in the right tissues.
The future may see mucosal-trained immunity-based vaccines that prepare lung and gut myeloid cells for helminth invasion, or helminth-derived products that safely induce protective training without establishing chronic infection 1 .
As we learn to better educate our myeloid defenders, we move closer to a world where helminth infections no longer plague billions, joining smallpox and polio as defeated enemies of humanity.
The journey to train your myeloid cells represents not just a way forward for helminth vaccines, but a revolution in how we harness the full power of our immune system.