Open Veterinary Journal, (2026), Vol. 16(4): 2028-2033

Research Article

10.5455/OVJ.2026.v16.i4.7

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Augmentation of IL-21 and soluble CD14 in systemic aspergillosis through combined immunostimulation with beta-glucan and diphtheria toxoid

Mustafa Abdul Kareem Hameed^1,2*, Huda Sadoon Jassim Al Biaty¹ and Sabah Zyara Kadhim³

¹College of Veterinary Medicine, University of Baghdad, Baghdad, Iraq

²College of Veterinary Medicine, University of Karbala, Karbala, Iraq

³Shiland Animal Hospital and Urgent Care, Rock Hill, SC

*Corresponding Author: Mustafa Abdul Kareem Hameed. College of Veterinary Medicine, University of Baghdad, Baghdad, Iraq. Email: Mustafa.abdul [at] uokerbala.edu.iq

Submitted: 07/12/2025 Revised: 28/02/2026 Accepted: 11/03/2026 Published: 30/04/2026

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ABSTRACT

Background: Aspergillus fumigatus leads to serious systemic infections in immunocompromised patients, thereby emphasizing the need for novel immunomodulatory therapies acting on both innate (sCD14) and adaptive (IL-21) immune systems. Beta-glucans are established fungal immunomodulators, and diphtheria toxoid (DT) has non-specific stimulatory activity.

Aim: This experiment determined the effects of beta-glucan, biphasic beta-glucan, and DT on the systemic immune response to A. fumigatus beta-glucan, DT, and a combination of both.

Methods: It was done on 50 male albino rats, and they were then subjected to a systemic injection of A. fumigatus challenge. Serum IL-21 and soluble CD14 (sCD14) levels were measured on day 21 using the enzyme-linked immunosorbent assay kits.

Results: The results revealed a significant increase in IL-21 and sCD14 levels in the beta-glucan group compared with those in the control group. Nevertheless, the beta-glucan + DT group had the most potent effect, with an increase in both markers.

Conclusion: The combination of beta-glucan and diphtheria toxoid provides a potent immunomodulatory regimen that boosts innate (sCD14) and adaptive (IL-21) immune pathways and enhances host defense against systemic fungal infection.

Keywords: Beta glucan, Fungal infection, IL21, sCD14, Toxoid.

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Introduction

Aspergillus fumigatus is one of the most widespread airborne fungi. Aspergillus fumigatus is more frequently the cause of systemic aspergillosis, chronic pulmonary aspergillosis, and allergic bronchopulmonary aspergillosis (Latgé and Chamilos, 2019; Ibrahim et al., 2024).

In A. fumigatus, β-glucans are major structural components of the cell wall, contributing to cellular rigidity, morphogenesis, immunostimulatory action, and environmental protection. Immunostimulatory use of β-glucans against fungal infections, especially those caused by the opportunistic fungal pathogen A. fumigatus, which has opportunistic invasiveness, has recently attracted considerable scientific and clinical interest. Thus, β-glucans are efficient modulators of the immune system that enhance host resistance without cytotoxicity and therefore represent ideal candidates for adjunctive immunotherapy in immunocompromised patients (Amirinia et al., 2025).

The mechanism by which the immunostimulatory effect of β-glucan occurs through the process of induction of immunity, where the monocytes and macrophages are epigenetically repolarized to respond to the fungal pathogen in a more enhanced manner, even in the absence of T-cells, is a clear advantage in T-cell dysfunctional patients (Acevedo et al., 2021).

Interleukin-21 (IL-21) belongs to the common gamma-chain (γc) family of cytokines and is mainly produced by CD4+ T helper cells, particularly T follicular helper (Tfh) and Th17 cells. Bcl-6 and c-Maf are transcription factors that strictly control the IL-21 expression. The effects of IL-21 on cells are mediated by the IL-21 receptor (IL-21R) and the standard gamma chain, which is shared with other cytokines such as IL-2, IL-4, IL-7, and IL-15. The JAK-STAT signaling pathway (primarily STAT1 and STAT3) activates the transcription of genes controlling cell growth, differentiation, and apoptosis when bound. (Spolski and Leonard, 2014).

The pleiotropic effects of IL-21 on innate and adaptive immune cells are well documented enter. IL-21 is a potent stimulator of B-cell proliferation, isotype class-switching, and plasma cell differentiation; hence, it is a master regulator of the germinal center response. Moreover, IL-21 stimulates Th17cell differentiation, growth, and functional preservation in an autocrine loop. It also affects the activation of CD8+ T cells and NK cells, increasing their cytotoxic capacity. Such a wide range of activities makes IL-21 a key cytokine target for developing an effective humoral and cellular immune response (Bellemare-Pelletier and Haddad, 2021).

The Th17 response and antibody production are crucial for mounting an immune response against A. fumigatus in fungal infections, with IL-21 as a key factor. Recruitment and activation of neutrophils increase the clearance of A. fumigatus conidia and hyphae, and the IL-17 and IL-21 axis facilitates this process. In addition, IL-21 promotes the production of high-affinity, opsonizing antibodies against fungal antigens by acting on Tfh and B cells in germinal centers (Gresnigt et al., 2014; De Jesus and Ng, 2022).

The fungal cell wall contains different pathogen-associated molecular patterns (PAMPs), such as 2-glucans, which are detected by a set of host pattern recognition receptors. Although the primary receptor for β-glucan is dectin-1, CD14 is involved in this recognition mechanism. It has been proposed that CD14 can recognize certain fungal substances and present them to TLR2, triggering intracellular signaling cascades that ultimately result in cytokines and chemokines required for neutrophil recruitment and macrophage activation. Such collaborative understanding emphasizes that the complex nature of innate immune response to fungi underscores the importance of CD14 as an accessory molecule in detecting fungal infections (Bellemare-Pelletier and Haddad, 2021; Drummond et al., 2019; Nasre et al., 2019; Underhill, 2022).

In addition to its classical role in innate sensing, the role of CD14 in connecting to the adaptive immune system is increasingly recognized. Effective antigen presentation and subsequent T-cell polarization are prerequisites for the initiation of a strong innate response via CD14-TLR signal. The activated cytokine milieu, through CD14-mediated activation of antigen-presenting cells, such as dendritic cells, directly influences whether a Th1, Th2, or Th17 adaptive response occurs before the onset of the disease. A balance between Th1 and Th17 responses is commonly associated with protection in aspergillosis, whereas a Th2 shift is a potential cause of allergic pathology. Thus, the scale and setting of CD14 activation can be of significant consequence for the subsequent adaptive immune response, making it a key control node at the interface of innate and adaptive immune responses and a potential target for immunomodulatory therapy (Zanoni and Granucci, 2021; Mohammed, and Ahmed 2025). Because of the lack of effective immunotherapeutic strategies to augment the host's defective immune response during invasive systemic aspergillosis, this study aimed to fully investigate the immunomodulatory capacity of β-glucans, diphtheria toxoid (DT), and their combination in thereof in a rat model infected systemically with A, fumigatus by quantifying and comparing interleukin-21 (IL-21) and soluble CD14 (sCD14) in the sCD14-positive rat model serum.

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Materials and Methods

Preparation of the solutions

The diphtheria toxoid was prepared according to the manufacturer’s instructions (Native Antigen Company). Each vial was reconstituted to 0.5 ml with sterile distilled water, containing 1 mg of diphtheria toxoid in 0.01 M Tris (pH 7.5) and 0.001 M Na2EDTA.

The beta-glucan stock solution was prepared by weighing 10 mg of the from extracted beta glucan from A. Fumigates using the alkaline extraction method (Pengkumsri et al., 2017), then 10ml of sterile distilled water was added and heated to 70°C with continuous stirring for 20 minutes (Rahar et al., 2011).

Design of the experiment and schedule of Immunization

A total of 50 male albino rats (Rattus Rattus), with an average weight between (200 ± 20 g) and the ages of animals were ranged (from 8 to 10) weeks, were housed for 2 weeks for adaptation before the experiment. These rats were randomly selected to be assigned to five experimental groups. The infection group (10 rats) was inoculated intraperitoneally with a single dose (300 µl) of A. fumigatus cultured on Czapek-Dox Agar at 37°C for 7 days (2.5 × 10⁷ CFU), as described by Lilly et al., (2012). The second group (10 rats) received an IPP injection of 200 µl (1 mg/kg) beta-glucan daily for 2 weeks (Vetvicka and Vetvickova, 2010). The third group (10 rats) received a combination of (200 µl) glucan and diphtheria toxoid intraperitoneally every day. The fourth group (10 rats) received 200 µl (2 mg/kg) of diphtheria toxoid alone (Blander, 2018). The fifth group (10rats) was administered 200 µl of phosphate-buffered saline only.

Two weeks after the described protocol above. The second, third, and fourth groups of the experiment were challenged by intraperitoneal injection of a virulent A. fumigatus strain (300 µl) that was previously detected by using virulence genes such as aspartic proteases and alkaline protease genes. A conventional method for assessing the induction of vaccine-mediated protection and immunological memory before exposure to the pathogen is a pre-challenge immunization period (Pulendran et al., 2021). Moreover, the intraperitoneal route of immunization followed by an attempt to induce infection is an established systemic immune response model to evaluate the protective efficacy and immunity against fungal pathogens (Caffrey-Carr et al., 2017).

Sample collection and analysis

All animals were sampled on day 21 after cardiac punting treatment. The serum was stored at −80°C before analysis. CD14 and IL21 are soluble immune markers that were determined in serum with the commercially available sandwich enzyme-linked immunosorbent assay (ELISA) kits based on the recommendations of the manufacturers (Sun Long Biotech, China, the Catalogue Number of CD14 kit is SL0629Ra and detection range is 0.3 ng/ml−20 ng/ml; the Catalogue Number of IL21 kit is Catalogue Number:SL0404Ra and detection range is 0.3 ng/ml−20 ng/ml). The temporal series of blood samples is a methodological approach essential for sampling the dynamic aspects of the immune response, which change in response to early signals of innate immunity and subsequently with adaptive immunity (Devarajan and Chen, 2020).

ELISA-based measurements of systemic levels of cytokines and soluble receptors are also a gold-standard, high-throughput technique for measuring humoral immune biomarkers in experimental immunology and yield strong, reproducible data (Slota et al., 2011).

Statistical analysis

Data were analyzed using the statistical program SPSS (2023), and the differences among groups were determined by one way a nova, post hoc assay, depending on letters, p > 0.05 represented a significant difference. Statistical Analysis System. (2018).

Ethical approval

Ethical permission to conduct the research was obtained from the local animal care and use committee at the College of Veterinary Medicine, University of Baghdad, according to the number and date (P-G/346: 11/2/2026).

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Results

The data in Table 1 reveal a clear and statistically significant (p < 0.05) upward trend in both IL-21 and sCD14 levels when transitioning from single-treatment groups to the combination therapy.

Table 1. Summary of IL-21 and sCD14 concentrations across experimental groups.

Blood IL-21 levels in experimental animals

IL-21 production was evident across the treatment groups—the infected-only group having the lowest IL-21 value. A significant increase in IL-21 levels (Fig. 1) was observed in the beta-glucan-alone group, and a mild increase was seen in the diphtheria toxoid-alone group. Finally, the most drastic increase was observed in the beta-glucan/diphtheria toxoid group, which showed a significantly higher level of IL-21 than all the other groups.

Fig. 1. IL-21 levels in each group: 32.78 ± 2.39 pg/ml, 62.90 ± 12.28 pg/ml, 101.94 ± 6.94 pg/ml, 44.81 ± 3.27 pg/ml and 35.55 ± 3.09 pg/ml for the infected, beta-glucan alone, beta-glucan + diphtheria toxoid, diphtheria toxoid-alone, and control groups, respectively with significant difference (p < 0.05); (A–C) Same letters represent no significant differences; different letters represent asignificant difference.

The high expression of IL-21 in the treatment with beta-glucan may be directly explained by its ability to act as a strong PAMP and a well-defined ligand of the pattern recognition receptor dectin-1. Dectin-1 recognizes the beta-glucan on antigen-presenting cells such as Macrophages and dendritic cells. The resultant ligation initiates a signal cascade that positively regulates the secretion of essential polarizing cytokines, such as interleukins (IL6, IL-23, IL-1, and so on). The given cytokine environment is essential to stimulate the differentiation and proliferation of CD4+ T helper cells, especially Th17 and Tfh cells. As Th17 and Tfh cells are both known to be initial producers of IL-21, their activation and growth during the inflammatory response to the beta-glucan condition provides a direct mechanistic basis for of the significantly elevated levels of this cytokine, in circulation. In this way, IL-21 upregulation by beta-glucan demonstrates its ability to stimulate an adaptive immune response biased to Th17 and Tfh development, which is critical in the regulation of fungal challenges. (Leibundgut-Landmann et al., 2008; Huda and Mohammed, 2021).

Leibundgut-Landmann et al. (2007) showed that apoptotic T-cells, when responding to fungal β-glucans, directly differentiate into Th17 and Tfh cells that are can produce good amounts of IL-21. Ueno et al. (2015) have emphasized the effects of IL-21 on B-lymphocytes proliferation, class-switch recombination, and plasma cell proliferation in the germinal center.

Diphtheria toxoid contains certain T cell epitopes that lead to T cell clonal expansion and T cell functional maturation. When antigen-presenting cells are stimulated through the dectin-1 pathway process and present toxoid-derived peptides, they induce T-cell receptors, providing a strong, antigen-specific signal to interact with the cytokine environment promoted by the beta-glucan. The DT antigen is useful in directing the innate, adjuvant capability of beta-glucan into a highly selective and broad population of IL-21-producing T cells, a mechanistic principle of the effective vaccine adjuvant activity (Coffman et al., 2010; Reed et al., 2013).

Blood levels of sCD14 in experimental animal

The low average of sCD14 in the infected-alone group, as shown in Figure 2, is associated with low systemic innate immune. On the contrary, beta-glucan injection had a marked effect on sCD14. This is explainable due to the role that beta-glucan plays as an excellent ligand to activate macrophages and monocytes through dectin-1 and other receptors. It has been established that this activation increases the shedding of the CD14 receptor on the cell surface into the blood as soluble CD14. This enhances the innate immune response because sCD14 can be used as a soluble pattern recognition molecule, that opsonizes microorganisms and expands the surveillance ability of the immune systems.

Fig. 2. CD14 levels in each group: 0.63 ± 0.51 pg/ml, 6.14 ± 1.34 pg/ml, 11.30 ± 1.11 pg/ml and 2.51 ± 0.76 pg/ml and 1.324 ± 0.66 pg/ml for the infected, beta-glucan alone, beta-glucan + diphtheria toxoid, and diphtheria toxoid-alone and control groups, respectively with significant difference (p < 0.05). (A–D) Same letters represent no significant differences; different letters represent a significant difference.

The greatest increase in sCD14 occurred in the group that received beta-glucan and diphtheria toxoid. This effect shows that the innate immune system was more preconditioned with combined stimulation. This adaptive immune system induced by the protein antigen diphtheria toxoid is speculated to induce a feedback mechanism that further induces the innate immune cells. The increased sCD14 concentrations in this group indicate a heightened innate immune condition of readiness, which can describe an augmented pathogen clearance.

The sCD14 was highest in the beta-glucan and diphtheria toxoid groups. This means that the adaptive immunological problem (diphtheria toxoid) acts as a secondary stimulus that enhances the response, whereas the beta-glucan primes or trains the innate immune system. Netea et al. (2016) identified this phenomenon as one of the distinguishing features of trained immunity. One of the manifestations of this elevated level of innate preparedness is the much greater sCD14 in our combination compared with that in our study group.

It is widely established that sCD14 is an opsonic and pro-inflammatory mediator molecule. March et al. (2020) revealed that sCD14 boosted the ability of the macrophages (tumor necrosis factor-alpha-α, IL-6) to respond to A. fumigatus conidia. The protection in this experiment was likely enhanced by the induced beta-glucan-bound sCD14, which opsonized the A. fumigatus challenge and enhanced its recognition and clearance by a wider array of immune cells.

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Conclusion

Overall, prior exposure to beta-glucan and diphtheria toxoid triggers an enhanced immunomodulatory action, which prepares the host to mount a more effective response to a second A. fumigatus challenge. It is important to note that the strong increase in IL-21 in the combination group reflects intensive adaptive immune push, in which the respective T-cell antigens of the toxoid successfully direct the innate adjuvant message of beta-glucan (through dectin-1) to increase the number of IL-21-producing Th17 and Tfh cells.

At the same time, the dramatic rise in systemic sCD14 is an indication of an enhanced condition of innate immune vigilance, while β-glucan is known to induce trained immunity under specific experimental conditions. The present study does not evaluate epigenetic reprogramming, metabolic changes, or recall responses that would be required to confirm this phenotype. Therefore, the potential role of trained immunity in mediating these effects remains speculative and warrants further investigation. This two-fold amplification of the humoral/cellular bridge (IL-21) and innate surveillance (sCD14) propose a possible mechanism underlying the observed improved protective immunity. Consequently, exploiting these interactions between the innate immune primers and certain antigens represents a promising avenue for developing new immunotherapeutic or vaccines with adjuvants against invasive fungal infections.

Limitation of study

The cost associated with reagents, animals, and specialized kits for ELISA may limit its scalability and immediate use in resource-limited environments.

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Acknowledgments

The authors would like to express their special thanks to the Dean of the College of Veterinary Medicine, University of Baghdad, Prof. Dr. Hameed Ali kadhim. Thanks to Huda Sadoon Jassin Al-Biaty and Sabah Zyara kadhim for the supervision, and special thanks to all staff members of Microbiology Department, College of Veterinary Medicine, University of Baghdad.

Conflict of interest

The authors declare that there is no conflict of interest.

Funding

This research received no specific grant.

Authors' contributions

All authors participated in data analysis, manuscript drafting, and revisions. Consent to assume responsibility for all aspects of this study.

Data availability

All data were provided in the manuscript.

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