Abstract
Background
Epstein-Barr virus (EBV) frequently causes temporary liver injury during initial infection, and in severe cases, fulminant hepatitis and liver failure can occur. This study aimed to examine the expression of key Absent in Melanoma 2 (AIM2)-pathway pyroptosis mediators (AIM2, Caspase-1, Gasdermin D[GSDMD], IL-1β, and IL-18) in the blood of children experiencing primary EBV infection and to assess their correlation with viral load and liver injury.
Methods
Sixty-five children hospitalized with primary EBV infection were enrolled and categorized based on liver function (Abnormal Liver Function, n = 35; Normal Liver Function, n = 30). Control groups included 30 healthy children with past EBV infection and 30 healthy seronegative children. Real-time reverse transcription polymerase chain reaction was used to detect the mRNA expression levels of AIM2, Caspase-1, and GSDMD. IL-1β and IL-18 serum concentrations were measured by enzyme-linked immunosorbent assay. The institutional clinical laboratory was responsible for routine biochemical indicators, including EBV-DNA load.
Results
The study indicated that children with primary EBV infection exhibited significantly elevated mRNA expression of AIM2, Caspase-1, and GSDMD, alongside increased serum IL-1β and IL-18 concentrations, compared to both control groups. Within the primary infection group, serum EBV-DNA load showed positive correlations with these pyroptosis markers. Furthermore, patients with primary EBV infection and abnormal liver function had significantly higher levels of these mediators than infected patients with normal liver function. AIM2 mRNA expression also positively correlated with Caspase-1 mRNA, GSDMD mRNA, IL-1β, and IL-18 levels.
Conclusions
AIM2-dependent pyroptosis is implicated in the systemic inflammatory response to EBV and may contribute to the immunopathogenesis of EBV-associated hepatitis.
Keywords: Epstein-Barr virus, Pyroptosis, AIM2 inflammasome, Liver injury
Background
Epstein-Barr virus (EBV), also known as Human herpesvirus 4, is a ubiquitous gammaherpesvirus that infects a vast majority of the global adult population, with seroprevalence rates typically exceeding 90–95% [1]. While primary EBV infection, particularly in early childhood, is often asymptomatic or results in mild, nonspecific symptoms, a delay in initial exposure until adolescence or young adulthood frequently leads to infectious mononucleosis (IM) [2]. This common clinical syndrome is characterized by fever, pharyngitis, lymphadenopathy, and malaise. A significant, yet often underappreciated, aspect of systemic EBV infection is hepatic involvement. Transient and asymptomatic elevations in liver transaminases are common, making hepatic dysfunction one of the most frequently observed clinical manifestations during primary infection [3]. This consistent liver involvement, even when subclinical, underscores the liver’s role as a crucial site for viral interaction with the host immune system, potentially involving viral replication, latency establishment, or susceptibility to immune-mediated damage. Although most EBV infections, including IM, are self-limiting in immunocompetent individuals, a minority of cases can lead to severe complications, including acute severe hepatitis and, rarely, fulminant liver failure, a life-threatening condition [4].
The pathogenesis of EBV-associated hepatic injury is primarily understood to be an indirect consequence of the host’s immune response rather than direct viral cytopathic effects on liver cells [3]. The clinical features of IM, for example, are largely attributed to a vigorous cytotoxic T lymphocyte response targeting EBV-infected B lymphocytes, alongside a surge in pro-inflammatory cytokines [5]. This highlights a central paradox in the host’s defense against EBV: while a robust immune response is vital for controlling viral spread, an excessive or dysregulated response can inadvertently cause significant collateral tissue damage, including hepatitis.
Recent advances in immunology have shed light on the critical role of the innate immune system as the first line of defense. Pattern recognition receptors (PRRs) detect pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), triggering inflammatory responses. Among these, the Absent in melanoma 2 (AIM2) inflammasome has emerged as a key cytosolic sensor of double-stranded DNA (dsDNA) [6], a molecular signature highly relevant to dsDNA viruses like EBV. Upon binding cytosolic dsDNA, AIM2 recruits the adaptor protein ASC and pro-caspase-1, forming the AIM2 inflammasome complex. This assembly leads to the activation of caspase-1, which then processes pro-inflammatory cytokines IL-1β and IL-18 into their mature, active forms [7]. Furthermore, activated caspase-1 cleaves Gasdermin D (GSDMD), whose N-terminal fragment forms pores in the cell membrane, inducing a pro-inflammatory form of programmed cell death known as pyroptosis [8]. This cascade—dsDNA sensing, inflammasome activation, cytokine release, and pyroptosis—is a potent host defense mechanism. However, if uncontrolled, it can drive excessive inflammation and contribute to tissue pathology, as has been implicated in other liver diseases, including viral hepatitis and chronic inflammatory conditions leading to fibrosis [9].
Given the frequent hepatic involvement in primary EBV infection, the immune-mediated nature of this liver injury, and the established role of the AIM2 inflammasome-pyroptosis pathway in sensing dsDNA viruses and mediating inflammation and cell death, its contribution to EBV-associated hepatitis warrants thorough investigation. Understanding whether this pathway is a significant driver of liver damage in EBV infection could have profound implications. It may lead to the identification of novel biomarkers to predict or assess the severity of hepatic injury in patients with primary EBV. More significantly, it could unveil new therapeutic targets aimed at modulating this specific inflammatory cascade, potentially offering strategies to mitigate severe liver complications in susceptible individuals.
Materials and methods
Research subjects
All pediatric participants presented with serological evidence of primary EBV infection upon admission, confirmed by positive EBV viral capsid antigen immunoglobulin M (EB-VCA-IgM) and serum EBV DNA. The cohort was divided into a liver dysfunction group (n = 35) and a normal liver function group (n = 30). Liver dysfunction (hepatic injury) was clinically defined as serum Alanine Aminotransferase (ALT) levels exceeding the upper limit of normal (> 40 U/L).Exclusion criteria were: (i) co-infection with other pathogens (bacterial, viral, mycoplasmal, or chlamydial); (ii) pre-existing primary or secondary liver disorders unrelated to EBV; (iii) recent use of hepatotoxic drugs; (iv) malignant neoplasms, autoimmune diseases, hematological malignancies, or recent immunosuppressive therapy; and (v) severe dysfunction of cardiac, hepatic, renal, or other major organs.Additionally, a control group of 30 healthy children with serological evidence of past EBV infection (positive for EBV viral capsid antigen immunoglobulin G [EB-VCA-IgG] and EBV nuclear antigen immunoglobulin G [EB-NA-IgG]; negative for EB-VCA-IgM), identified during routine outpatient examinations, was recruited. A further healthy control group (n = 30), seronegative for both EBV-IgG and EBV-VCA-IgM, was also included.
Specimen collection
Venous blood samples were collected from pediatric patients with primary EBV infection upon hospital admission, before any antiviral treatment. Participants with prior EBV infection and control group individuals provided fasting venous blood samples during their scheduled physical examination.
Detection of AIM2,GSDMD and caspase-1
Peripheral blood samples were centrifuged in a low temperature high-speed centrifuge at 15,000 g for 5 min at 4 °C, 0.5 mL TRIzol was added to the bottom of the tube to extract total RNA, reverse transcribed to synthesize cDNA. Real-time PCR was used to determine the expression levels of AIM2, GSDMD and caspase-1. The sequence of primers is shown in Table 1. The expression difference of each gene was compared by the 2−ΔΔCt method.
Table 1.
Forward and reverse primers used for real-time polymerase chain reactions
| Gene | Forward | Reverse |
|---|---|---|
| AIM2 | 5’-TGCAGTGATGAAGACCATTCGTA-3’ | 5’-GGTGCAGCACGTTGCTTTG-3’ |
|
Caspase-1 GSDMD |
5’-AGTGCAGGACAACCCAGCTATG-3’ 5’-ATGAGGTGCCTCCACAACTTCC-3’ |
5’-CAAGACGTGTGCGGCTTGA-3’ 5’-CCAGTTCCTTGGAGATGGTCTC-3’ |
| GAPDH | 5’-CTTCTCTGATGAGGCCCAAG-3’ | 5’-GCAGCAAACTGGAAAGGAAG-3’ |
Detection of IL-1β and IL-18
IL-1β and IL-18 cytokines in serum were detected by enzyme linked immunosorbent assay kit (Yanyu Chemical Reagent Co.Ltd, Shanghai, China). All procedures were conducted according to the manufacturer’s instructions.
Routine biochemical indicator
Biochemical markers (Alanine Aminotransferase [ALT], Aspartate Aminotransferase [AST], Lactate Dehydrogenase [LDH]) were measured by the institutional clinical laboratory using an ADVIA 2400 Clinical Chemistry System (Siemens Healthineers, Erlangen, Germany) with its reagents. Peripheral blood EBV DNA load was quantified by real-time PCR with commercial kits (Da’an Gene Co., Ltd. of Sun Yat-sen University, Guangzhou, China) on an ABI 7500 Real-Time PCR System (Applied Biosystems, Foster City, CA, USA). The Real-Time PCR assay’s lower limit of detection was 5.0 × 102 copies/mL. Peripheral blood lymphocyte subsets were immunophenotyped by flow cytometry using a FACS Canto II instrument (BD Biosciences, San Jose, CA, USA) with validated monoclonal antibodies and reagents. FACS DIVA™ software (BD Biosciences) was used for data acquisition and to determine the relative proportions of each lymphocyte subset.
Statistical analysis
Statistical analyses were performed using SPSS 24.0 software (IBM-SPSS, Chicago, IL, USA). Count data were analyzed by χ2 test. Quantitative data are presented as mean ± SD. Student’s t-test compared means between two groups, and one-way ANOVA for multiple groups. Non-normally distributed data are reported as median (IQR; 25th-75th percentiles); these were compared using the Kruskal-Wallis H test, with Nemenyi’s test for pairwise post-hoc comparisons. Pearson’s correlation coefficient (r) evaluated linear associations between continuous variables. P < 0.05 was considered as statistically significant.
Results
Clinical data
No statistically significant differences were observed in gender distribution or age among the three study cohorts (P > 0.05).Patients with primary EBV infection exhibited statistically significant alterations in LDH levels and the relative proportions of distinct peripheral blood lymphocyte subpopulations when contrasted with the other two study groups (P < 0.05), as detailed in Table 2.
Table 2.
Comparison of clinical data among three groups of subjects
| Characteristic | primary infection group | previous infection group | healthy control group |
|---|---|---|---|
| Age(years) | 5.0(4.5-7.0) | 4.6(4.0–7.0) | 4.4(4.0-6.3) |
| Female/male | 34/31 | 13/17 | 16/14 |
| LDH(U/L) | 526.0(457.5–651.0)a, b | 171(144.5–227.0) | 168(137.5-187.2) |
| CD3+ T cells (%) | 87.3(83.9–89.6)a, b | 62.6(59.3–65.0) | 60.4(59.0-62.9) |
| CD3+ CD4+ T cells (%) | 16.9(11.7–20.3)a, b | 30.8(26.8–34.4) | 32.3(28.1–38.0) |
| CD3+ CD8+T cells (%) | 68.1(62.9–73.2)a, b | 31.9(28.4–34.8) | 28.4(24.2–32.2) |
| CD4+/CD8+ | 0.25(0.16–0.33)a, b | 0.95(0.8–1.1) | 1.20(0.9–1.5) |
| NK cells (%) | 6.1(5.0-7.8)a, b | 20.4(17.9–25.2) | 22.9(17.1–25.8) |
| CD19+B cells (%) | 4.6(3.3–6.6)a, b | 14.8(12.5–16.6) | 15.7(13.5–19.4) |
a, Compared with the healthy control group, P < 0.05; b, Compared with the previous infection group, P < 0.05
Within the primary EBV infection cohort, subgroup analysis revealed that individuals experiencing hepatic dysfunction, relative to those with normal liver function, demonstrated a significant elevation in the percentage of total peripheral blood lymphocytes and, more specifically, CD3+CD8+ T cells (both P < 0.05). Conversely, the proportions of CD3+CD4+ T cells and CD19+ B cells were diminished in patients with hepatic impairment (both P < 0.05). This immunological shift was further characterized by a significantly reduced CD4+/CD8+ T cell ratio (P < 0.05) in the liver dysfunction subgroup. Concomitantly, LDH concentrations were also significantly increased in these patients (P < 0.05). These comparative findings are summarized in Table 3.
Table 3.
Comparison of clinical data between abnormal liver function group and normal liver function group in the primary EBV infection
| Characteristic | abnormal liver function group | normal liver function group | P |
|---|---|---|---|
| ALT (U/L) | 108.0(87.0-164.0) | 29.0(26.0–33.0) | < 0.001 |
| AST (U/L) | 51.0(41.0–66.0) | 25.5(22.0–30.0) | < 0.001 |
| LDH(U/L) | 620(515.0-720.0) | 477.5(401.0-537.5) | < 0.001 |
| EBV-DNA (log10 copies/mL) | 4.1(3.5–4.5) | 3.4(2.8–3.5) | < 0.05 |
| CD3+ T cells (%) | 88.7(87.0-91.1) | 84.5(82.2–87.3) | 0.003 |
| CD3+ CD4+ T cells (%) | 12.5(10.3–17.2) | 18.8(16.7–23.3) | < 0.001 |
| CD3+ CD8+T cells (%) | 72.4(67.6–75.9) | 63.4(60.3–67.1) | < 0.001 |
| CD4+/CD8+ | 0.18(0.13–0.26) | 0.31(0.25–0.38) | < 0.001 |
| NK cells (%) | 6.0(5.3–7.8) | 6.3(4.9–7.8) | 0.336 |
| CD19+B cells (%) | 3.7(2.7–5.1) | 5.6(4.4–7.8) | < 0.001 |
Comparison of AIM2, caspase-1 and GSDMD mRNA expression and IL-1β and IL-18 levels
Peripheral blood mRNA levels of AIM2, caspase-1, and GSDMD, and serum IL-1β and IL-18 concentrations, were significantly higher in pediatric patients with primary EBV infection compared to those with previous EBV infection and healthy controls (P < 0.05). However, these parameters did not significantly differ between the previous EBV infection and healthy control groups (P > 0.05) (Fig. 1).
Fig. 1.
Comparison of AIM2, caspase-1 and GSDMD mRNA expression and IL-1β and IL-18 levels in three groups of subjects. Note: a, compared with the healthy control group, P<0.05; b, compared with the previous infection group, P<0.05
Within the primary EBV infection group, AIM2, caspase-1, and GSDMD mRNA levels, and IL-1β and IL-18 concentrations, were significantly elevated in patients with either normal or abnormal liver function compared to healthy controls (P < 0.05). Furthermore, in patients with primary EBV infection, these mRNA and cytokine levels were significantly higher in those with abnormal liver function compared to those with normal liver function (P < 0.05) (Fig. 2).
Fig. 2.
Comparison of AIM2, caspase-1 and GSDMD mRNA expression and IL-1β and IL-18 levels between abnormal liver function group and normal liver function group in the primary EBV infection. Note: a, Compared with the healthy control group, P<0.05; b, Compared with the previous infection group, P<0.05; c, Compared with the normal liver function group, P<0.05
Correlation of AIM2 with caspase-1, GSDMD, IL-1β and IL-18 in the primary EBV infection group
Pearson correlation analysis revealed that AIM2 mRNA expression in children with primary EBV infection exhibited a significant positive correlation with the mRNA expression of caspase-1 and GSDMD, as well as with the serum concentrations of IL-1β and IL-18 (r = 0.429, 0.502, 0.684, and 0.413, respectively; P < 0.05 for all) (Fig. 3).
Fig. 3.
Correlation of AIM2 with caspase-1, GSDMD, IL-1β and IL-18 in the primary EBV infection group
Correlation of EBV-DNA load with AIM2, caspase-1, GSDMD, IL-1β and IL-18 in the primary EBV infection group
EBV-DNA load in the primary EBV infection cohort demonstrated a significant positive correlation with AIM2, caspase-1, and GSDMD mRNA expression levels, and with IL-1β and IL-18 serum concentrations (r = 0.344, 0.345, 0.522, 0.263, and 0.300, respectively; P < 0.05 for all) (Fig. 4).
Fig. 4.
Correlation of EBV-DNA load with AIM2, caspase-1, GSDMD, IL-1β and IL-18 in the primary EBV infection group
Discussion
EBV infection is a systemic pathogen capable of affecting multiple organ systems, with the liver frequently identified as a primary target. Epidemiological data indicate that approximately 40% to 80% of pediatric patients experiencing primary EBV infection exhibit hepatic dysfunction, typically manifesting as mild to moderate elevations in serum transaminase levels.In severe instances, this can escalate to cholestasis or fulminant liver failure [10, 11].The precise molecular mechanisms underpinning EBV-mediated liver injury remain incompletely elucidated; however, a consensus implicates immune-mediated pathology as a principal contributor. Following the infection of B lymphocytes, EBV is understood to trigger the proliferation and hepatic infiltration of CD8+ cytotoxic T lymphocytes. These activated T cells subsequently release pro-inflammatory cytokines, including interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α), thereby instigating immunopathological damage to hepatocytes [12]. Furthermore, activated T cells can potentiate liver injury via the Fas/Fas ligand pathway and the release of cytotoxic granules, such as perforin [13].
Pyroptosis, a recently characterized form of programmed lytic cell death mediated by inflammasomes, occupies a distinct mechanistic space between apoptosis and necrosis. Its morphological hallmarks include cellular swelling, membrane rupture, and the substantial release of pro-inflammatory mediators, leading to its alternative designation as inflammatory necrosis [8, 14]. As a highly conserved component of the innate immune system, pyroptosis is increasingly recognized for its pivotal role in the pathogenesis of numerous infectious diseases. Indeed, viral pathogens including Adenovirus (AdV), Coxsackievirus, Enterovirus 71 (EV-71), Rhinovirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), and Human Immunodeficiency Virus (HIV) have been demonstrated to induce pyroptosis to varying extents [15–17]. Cytoplasmic dsDNA recognition by the AIM2 inflammasome initiates its oligomerization and recruitment of ASC, leading to Caspase-1 activation. Activated Caspase-1 cleaves GSDMD, producing the N-terminal domain containing GSDMD fragment (GSDMD-N). GSDMD-N then oligomerizes, forming plasma membrane pores, ultimately causing cell lysis and the secretion of mature IL-1β and IL-18 [18].
Consistent with a role for this pathway in EBV pathogenesis, the current study found that children with primary EBV infection exhibited significantly elevated mRNA expression levels of AIM2, Caspase-1, and GSDMD in PBMCs, alongside increased serum concentrations of IL-1β and IL-18, compared to previously infected individuals and healthy controls. These findings are supported by research showing EBV can activate the AIM2 inflammasome [19]. Notably, these molecular signatures of pyroptosis demonstrated a positive correlation with EBV DNA viral load. Furthermore, serum LDH levels, an indicator of cell membrane damage and lysis, were significantly elevated in the primary EBV infection cohort. Collectively, these findings suggest the involvement of pyroptosis in the pathological sequelae of primary EBV infection.
Pyroptosis, while a crucial host defense mechanism, can also contribute to pathology if dysregulated. Excessive pyroptotic activity can lead to an overproduction of inflammatory cytokines, exacerbating inflammatory responses and contributing to the development of conditions such as asthma, Kawasaki disease, and disseminated intravascular coagulation [20]. Emerging research highlights a significant association between pyroptosis and the progression of various liver diseases. For instance, studies by Zhao et al. have reported that pyroptosis is a predominant form of hepatocyte death in patients with acute liver failure secondary to Hepatitis B Virus (HBV) infection, where in vitro investigations indicated that HBV-infected hepatocytes, characterized by downregulated Major Histocompatibility Complex class I (MHC-I) molecule expression, trigger NK cell-mediated cytotoxicity, culminating in GSDMD/Caspase-8-dependent pyroptosis [21]. Similarly, clinical investigations involving patients with non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) have demonstrated elevated hepatic tissue levels of GSDMD and its pyroptosis-inducing GSDMD-N. These levels correlated positively with NAFLD activity scores and fibrosis stage, underscoring the relevance of pyroptosis in chronic liver pathologies [22, 23].
In the context of the study focusing on primary EBV infection in children, individuals presenting with hepatic dysfunction exhibited significant alterations in lymphocyte subpopulations compared to those with normal liver function. Specifically, T lymphocyte and CD3+CD8+ T cells were elevated, whereas CD19+ B cells, CD3+CD4+ T cells, and the CD4+/CD8+ T cell ratio were significantly diminished. These observations indicate a more pronounced immune dysregulation in children with EBV-associated liver injury, corroborating previous research findings [24] Critically, the cohort with hepatic dysfunction displayed significantly higher mRNA expression of AIM2, Caspase-1, and GSDMD, and augmented serum levels of IL-1β and IL-18, relative to the group with normal liver function. Moreover, AIM2 mRNA expression exhibited a strong positive correlation with the mRNA levels of Caspase-1 and GSDMD, as well as with the serum concentrations of IL-1β and IL-18. These data support a model wherein EBV-derived dsDNA is sensed by the AIM2 inflammasome, leading to Caspase-1 activation. Activated Caspase-1 subsequently processes pro-IL-1β and pro-IL-18 into their mature, secreted forms and cleaves GSDMD. The resultant GSDMD-N fragment then translocates to the plasma membrane, forming pores that facilitate cytokine release and ultimately induce pyroptotic cell death.
Conclusions
This investigation demonstrates that primary EBV infection in children is associated with alterations in the expression of key pyroptosis-related mediators, particularly in individuals who develop EBV-associated hepatitis. These findings implicate pyroptosis as a pathophysiological mechanism in EBV-induced liver injury and suggest that targeting pyroptotic pathways may offer novel therapeutic avenues for mitigating hepatic damage in this patient population.
Acknowledgements
We sincerely thank all individuals who participated in this study.
Abbreviations
- EBV
Epstein-Barr virus
- IM
Infectious Mononucleosis
- PRRs
Pattern Recognition Receptors
- PAMPs
Pathogen-associated Molecular Patterns
- DAMPs
Danger-associated Molecular Patterns
- AIM2
Absent in Melanoma 2
- dsDNA
double-stranded DNA
- GSDMD
Gasdermin D
- GSDMD-N
N-terminal Domain containing GSDMD fragment
- EB-VCA-IgM
EBV Viral Capsid Antigen Immunoglobulin M
- EB-VCA-IgG
EBV Viral Capsid Antigen Immunoglobulin G
- EB-NA-IgG
EBV Nuclear Antigen Immunoglobulin G
- ALT
Alanine Aminotransferase
- AST
Aspartate Aminotransferase
- LDH
Lactate Dehydrogenase
- MHC-I
Major Histocompatibility Complex class I
- NAFLD
Non-alcoholic Fatty Liver Disease
- NASH
Non-alcoholic Steatohepatitis
Authors’ contributions
Yuelei Wu: conceptualization, methodology, writing–review & editing. Jihong Huang: formal analysis, methodology, writing – original draft, writing–review & editing. Weikun Zheng and Haifan Shi : investigation, data collection & curation, writing – original draft. Zhengwang Wen: data collection, formal analysis. Longteng Jin: supervision, conceptualization. Yan Sun: supervision, project administration. Yuelei Wu and Jihong Huang contributed equally to this paper.
Funding
This work was financially supported by the Science and Technology Project Foundation of the Wenzhou Science and Technology Bureau (Y20240145, Y20240148).
Data availability
The datasets generated and/or analyzed during the current study are not publicly available due to privacy or ethical restrictions. Still, they are available from the corresponding author on reasonable request.
Declarations
Ethics approval and consent to participate
Study approval was granted by the Ethics Committee of The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University (Ethics Approval No: 2021-K-125-01) and adhered to the Declaration of Helsinki. Informed consent to participation has been obtained from their parents.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Yuelei Wu and Jihong Huang contributed equally to this work.
Contributor Information
Longteng Jin, Email: jlt786@wmu.edu.cn.
Yan Sun, Email: maggies@wmu.edu.cn.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets generated and/or analyzed during the current study are not publicly available due to privacy or ethical restrictions. Still, they are available from the corresponding author on reasonable request.