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Frontiers in Virology ·

Volume 6 - 2026 | https://doi.org/10.3389/fviro.2026.1791383

Immune evasion of human metapneumovirus during respiratory tract infections: systematic review

  • Yuling Han1,2,3
  • Lishu Zheng4,5
  • Chao Wang4,5
  • Fang Huang1,2,3
  • Cheng Gong1,2
  • Xuejiao Guan1,2,3*corresponding author
  1. 1School of Public Health, Capital Medical University, Beijing, China
  2. 2Beijing Key Laboratory of Surveillance, Early Warning and Pathogen Research on Emerging Infectious Diseases, Beijing Center for Disease Prevention and Control, Beijing, China
  3. 3Beijing Research Center for Respiratory Infectious Diseases, Beijing, China
  4. 4National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Viral Disease Control and Prevention, China CDC, Beijing, China
  5. 5NHC Key Laboratory of Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, China CDC, Beijing, China
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Abstract

Human metapneumovirus (hMPV) is a major cause of acute respiratory infections across all age groups, having developed a range of strategies to evade host immune responses. Currently, there is an absence of a comprehensive systematic review addressing these immune evasion mechanisms. We conducted a systematic search of PubMed, Scopus, and Web of Science for articles published on hMPV immune evasion mechanisms up to March 1, 2025, including all English-language citations. The quality of the included articles was evaluated using the RTI Item Bank, CAMARADES, ARRIVE 2.0 guidelines, and a self-developed structured scale. We specifically analyzed the immune evasion mechanisms of hMPV during respiratory tract infections (RTIs). A total of 1322 articles were retrieved, of which 61 met the inclusion criteria. The findings reveal that hMPV has evolved a sophisticated, multilayered, and synergistic network for immune evasion. During the innate immune response, viral proteins (G, M2-2, SH, and P) suppress interferon (IFN) production by targeting pattern recognition receptors (e.g., RIG-I, TLR4) and their downstream adaptor molecules (e.g., MAVS, MyD88). Concurrently, the SH and G proteins disrupt the JAK-STAT signaling pathway, thereby impairing cellular responsiveness to IFN. During the adaptive immune phase, hMPV promotes T cell exhaustion through the activation of the PD-1/PD-L1 pathway and may evade antibody-mediated neutralization via structural extensions in the G protein, such as 180- and 111-nucleotide duplication. Furthermore, hMPV modulates host non-coding RNAs and epigenetic modifications, thereby orchestrating a comprehensive and multi-tiered disruption of immune defenses. The immune evasion network of hMPV operates through coordinated actions of multiple viral proteins across innate and adaptive immunity. Key features include targeted blockade of IFN production and signaling, T-cell exhaustion, and emerging mechanisms involving RNA methylation and non-coding RNA regulation. These findings establish a conceptual framework for understanding hMPV persistence and provide potential targets for antiviral intervention. Understanding this network provides a theoretical foundation for developing targeted antiviral therapies and vaccines. https://www.crd.york.ac.uk/prospero/, identifier CRD420251018019.

Keywords

1 Introduction

Human metapneumovirus (hMPV), a member of the Pneumoviridae family and Metapneumovirus genus, is an enveloped, single-stranded, negative-sense RNA virus (1). hMPV was first identified in 2001 (1). The genome is approximately 13.3 kb in length and contains 8 coding genes, encoding nine proteins. From the 3’ end to the 5’ end, they are N-P-M-F-M2-SH-G-L (2). Based on the genetic variability of two genes (F and G genes), hMPV is classified into two main genetic lineages (A and B), which can be further subdivided into six sub-lineages: A1, A2.1, A2.2.1, A2.2.2, B1, and B2 (3). hMPV is a globally distributed respiratory pathogen, with its prevalence and seasonality exhibiting distinct geographic patterns (4). During the COVID-19 pandemic, nonpharmaceutical intervention measures reduced the prevalence of various respiratory pathogens (5). Notably, multiple countries reported off-season outbreaks of hMPV in the COVID-19 post-pandemic phase (6, 7). Existing studies have shown that hMPV infection has caused significant disease and hospitalization burdens for both children and the elderly (8, 9).

Infants are highly vulnerable to hMPV-related ARTI (7, 8), which also causes substantial morbidity and hospitalization rates in the elderly, individuals with underlying comorbidities, and those who are immunocompromised (10, 11). Although hMPV affects all age groups, it fails to induce long-term immunity, resulting in frequent reinfections (12). Despite its clinical significance, hMPV remains less studied than respiratory syncytial virus (RSV) or influenza, particularly in molecular pathogenesis and vaccine development (13, 14). Currently, no specific antiviral therapy is approved for hMPV, and treatment remains supportive; however, investigational agents such as ribavirin, fusion inhibitors, and monoclonal antibodies targeting the F protein have shown promise in preclinical studies (15). A major challenge in combating hMPV is elucidating its immune evasion mechanisms to identify therapeutic targets.

Theoretically, primary viral infection can trigger host immune responses to control the infection (16). Early in vitro studies confirmed that hMPV exhibits partial resistance to type I interferon (IFN) in Hep−2 cells, suggesting that it has evolved mechanisms to evade the host’s core antiviral defenses (17). During the early stage of infection, hMPV employs escape strategies mediated by its encoded proteins: glycoprotein (G), matrix protein (M), small hydrophobic protein (SH), and phosphoprotein (P) (18). These viral proteins interfere with pattern recognition receptor (PRR) signaling, including retinoic-acid-inducible gene-I (RIG-I)-like receptors, Toll-like receptors (TLRs), NOD-like receptors (NLRs), cyclic GMP-AMP synthase (cGAS), and interferon-stimulating factor (STING) (18–22). Additionally, SH and G proteins suppress innate immune responses by disrupting Janus kinase (JAK)-transcription activator (STAT) and NF-kappa B (NF-κB) signaling, thereby blocking the IFN pathway (23–26). During the intermediate/last stage of infection, hMPV impedes the initiation of adaptive immune responses primarily by activating the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) signaling pathway, leading to dysfunction of CD8+ T cells (27). Nouën et al. (28) reported that G and SH proteins interfere with viral endocytosis into dendritic cells (DCs), reducing the capacity to activate Th1−polarized CD4+ T cells, thereby inducing T−cell exhaustion and functional inhibition. Furthermore, hMPV immune evasion also involves the pathogen−sensing phase of humoral immunity. Pinana et al. (29) described a novel hMPV mutant carrying 180−nt and 111−nt duplications in the G gene, which can mask fusion protein (F) epitopes and likely facilitates humoral immune evasion. Beyond classical innate and adaptive evasion mechanisms, hMPV has developed novel strategies, including host epigenetic regulation and viral RNA m6A methylation (30). Despite this growing body of evidence, these findings remain fragmented across individual studies, and a systematic synthesis of how hMPV integrates these diverse strategies into a coordinated immune evasion network is still lacking. Therefore, this review aims to comprehensively summarize the immune evasion mechanisms of hMPV during acute respiratory tract infections over the past two decades. Elucidating these mechanisms may reveal new antiviral targets and guide vaccine development, laying a theoretical foundation for therapeutic and preventive strategies while advancing research into hMPV molecular pathogenesis.

2 Methods

2.1 Search strategy

This systematic review searched the PubMed, Scopus, and Web of Science databases to identify eligible studies published up to March 1, 2025 (Table 1). The search algorithm in the PubMed database was (“human metapneumovirus”[Title/Abstract] OR “hMPV”[Title/Abstract] OR “hMPV-A”[Title/Abstract] OR “hMPV-B”[Title/Abstract]) AND (“immune response”[Title/Abstract] OR “immunity”[Title/Abstract] OR “immune evasion”[Title/Abstract] OR “immune cells”[Title/Abstract]) AND (Respiratory infection OR acute respiratory tract infection OR ARTI) (Supplementary Table 2). A similar search strategy was applied to Scopus and Web of Science. Meanwhile, eligible studies were also included through manual tracing of reference articles. This review adhered to PRISMA guidelines (51) and was registered in PROSPERO (CRD420251018019). Articles not meeting inclusion criteria after full-text screening were excluded, with reasons provided in Supplementary Table 4.

Table 1. The immune evasion mechanisms associated with hMPV-encoded proteins during the innate immune response.

hMPV proteinsPhases of the host immune responseKey targetsSpecific mechanismReference
G proteinThe initial phaseRIG-I/MDA5-MAVS pathway1. G protein can form a complex with RIG-I to avoid viral sensing;2. G protein can inhibit the transcription of RIG-I;3. G protein can interfere with the assembly of mitochondrial signalosomes, inhibit the signal transduction regulated by MAVS;4. G protein inhibits the binding of RIG-I to MAVS through the CARD domain of RIG-I;5. G protein can inhibit the signal transduction of MDA5.(18, 31–37)
TLR-MyD88 pathwayG protein regulates the phosphorylation and nuclear translocation of IRF3 and IRF7, and inhibits TLR4-dependent signaling, thereby suppressing the IFN response.(33, 36, 38–40)
cGAS-STING pathwayG protein can block the interaction between mitochondria and STING.(32)
DCsG protein interferes with the endocytosis process of the virus into DCs.(28)
The intermediate and late phasesIFN pathway (JAK-STAT pathway)G protein blocks the phosphorylation and nuclear translocation of STAT1/STAT2, thereby reducing the transcription of ISGs.(26, 33, 27, 31, 38, 39)
NK-activating receptor (NKG2D)G protein either independently mediates the downregulation of ULBP2 on the cell surface or collaborates with other proteins to upregulate ULBP3, thereby avoiding NK cell killing.(41)
M2–1 proteinThe initial phaseUnknownM2–1 and M2–2 proteins during transcription prevent hypermutation of the genome, and possibly the accumulation of defective interfering particles (DIs), thereby preventing the activation of IFN response(42)
M2–2 proteinThe initial phaseRIG-I-MAVS pathway1. M2–2 can weak MAVS to inhibit the RIG-I-MAVS pathway;2. M2–2 protein prevent TRIM25-mediated RIG-I ubiquitination;3. M2–2 blocks MAVS through its PDZ motifs (29-DEMI-32 and 39-KEALSDGI-46), inhibiting NF-κB signaling transduction and/or the production of IRF-3;4. M2–2 is capable of forming a complex with MAVS.(33–36, 39, 43–46)
M2–2 proteinTLR-MyD88 pathway1. M2–2 inhibits the production of IFN-α induced by TLR7/9 through suppressing MyD88/TRAF6/IKKα-mediated IRF7 homodimerization;2. M2–2 protein can regulate transcription to prevent the activation of the type I interferon pathway;4. M2–2 protein can form a complex with MyD88 to weak TLR7/MyD88 pathway.(18, 33, 34, 39, 42, 43, 47)
M2–2 proteinThe intermediate and late phasesNK-activating receptorM2–2 protein either independently mediates the downregulation of MICA and MICB on the cell surface or collaborates with other proteins to upregulate ULBP2/3, thereby avoiding NK cell killing.(41)
SH proteinThe initial phaseTLR-MyD88 pathway1. SH can obstruct TLR7/MyD88/TRAF6/IKKα signaling.2. SH can prevent the phosphorylation and nuclear translocation of IRF3 and IRF7.(18, 33, 34, 38, 48, 49)
DCsSH protein interferes with the endocytosis process of the virus into DCs.(28)
The intermediate and late phasesIFN pathway1. SH protein suppress the phosphorylation of STAT1, reducing the transcription levels of ISGs;2. SH protein promotes the proteasomal degradation of JAK1;3. SH protein can inhibit the phosphorylation and acetylation of NF-κB, thereby suppressing NF-κB-dependent gene transcription.(18, 23, 24, 36, 38, 48)
NLRP3 inflammasomeSH protein can activate the NLRP3 inflammasome, promoting the release of IL-1β and thereby intensifying the inflammatory response.(21)
P proteinThe intermediate and late phasesRIG-I-MAVS pathwayP protein restricts the ability of RIG-I to recognize 50-triphosphate viral RNA, reducing the expression of IFN-I and ISGs.(18, 35, 36, 50)

This table systematically summarizes the molecular mechanisms involved in the evasion of the innate immune response and clearance of the hMPV-encoded proteins that were included in this study. DCs, dendritic cells; CARD, caspase activation and recruitment domain; Tyk2, Tyrosine Kinase 2; IL-1β, Interleukin-1β.

2.2 Inclusion and exclusion criteria

All retrieved studies were imported into EndNote for duplicate removal. This review included original English-language studies published before March 1, 2025, that reported at least one defined immune evasion mechanism of hMPV (whether clinical isolates or laboratory strains) during RTIs. Excluded were studies investigating non-respiratory infection sites, non-English publications, studies lacking accessible full texts, those not centered on specific hMPV immune evasion mechanisms (e.g., limited to epidemiological trends or clinical symptomatology), and research involving animal-origin metapneumovirus. No restrictions were imposed on country, race, or gender (Supplementary Table 3).

2.3 Data extraction and quality assessment

We compiled the characteristics and primary findings of included studies (Supplementary Table 5). Two independent reviewers assessed study quality using design-specific tools: observational studies with the RTI Item Bank (7 items); in vivo studies with a modified CAMARADES checklist (9 items); in vitro studies with a scale based on CAMARADES and ARRIVE 2.0 (9 items); review articles (n=10) with a self-developed structured scale (4 items); and the in silico study with a FAIR principle-based scale. Items were scored as “yes” (1 point) or “no”/”unclear” (0 points); conflict of interest statements were recorded for transparency but not scored. Studies were categorized as high, moderate, or low quality based on predefined score ranges. Detailed scoring criteria and results are provided in Supplementary Table 6.

2.4 Statistical analysis

We used EndNote X9 to import and manage retrieved records. Create the world map utilizing the maps package of RStudio 4.4.2. Sanky diagram and Mechanism diagram were generated using BioRender, Adobe Illustrator, and the ChiPlot.

3 Results

3.1 Search results and quality assessment

The flowchart of study selection is shown in Figure 1. We identified 1322 articles, of which 61 met the inclusion criteria. Supplementary Table 5 presents the abstracts of these included studies, while Supplementary Table 6 provides a systematic quality assessment. Of the 61 studies, 3 observational studies (scores >3) and 17 in vivo studies (scores 3–5) were rated “moderate quality”. Among 30 in vitro studies, 20 scored 5–6 (“high quality”), and 10 scored 4–5 (“moderate quality”). Of 10 reviews, 6 met all evaluation items (“high quality”), and 4 met more than half (“moderate quality”). The one in silico study was rated “moderate quality” (Supplementary Table 6).

PRISMA flowchart of the study selection.
Figure 1. PRISMA flowchart of the study selection.

3.2 Description of included studies

Supplementary Table 5 summarizes key information from the included studies, such as reporting countries, publication years, critical determinants, and molecular mechanisms of hMPV immune evasion.

hMPV employs viral proteins, primarily G, M2, SH, and P proteins, to evade innate immunity by blocking host PRRs and inhibiting IFN production. Once innate defenses are bypassed, the virus further subverts adaptive immunity; the G and SH proteins play key roles in suppressing T-cell responses and JAK-STAT signaling. Additionally, the PD-1/PD-L1 pathway is also critical in driving T-cell exhaustion during infection. This comprehensive immunosuppression not only facilitates viral replication but may also exacerbate immunopathology. Furthermore, the M2 protein contributes to persistence by modulating viral genome replication in synergy with these immune evasion mechanisms.

3.3 Innate immune evasion mechanism

The IFN response, an important part of innate immunity, is divided into type I and type III IFN, both of which play a key role in antiviral defense (52, 53). hMPV proteins can evade the innate immune response by suppressing the activation and function of the host type I or III IFN response via distinct mechanisms (18). Figure 2 demonstrates the multiple strategies employed by hMPV to hinder the host’s innate immune response.

The innate immune evasion mechanism of hMPV. This cell model diagram integrates the key insights from 31 published articles. Far Left: RIG-I/MDA5-MAVS pathway. Center Left: TLR/MyD88 pathway. G and SH proteins regulate the TLR4-MyD88 signaling pathway and TLR7/9-MyD88 pathway respectively, and inhibit the production of IFN and pro-inflammatory cytokines by interfering with downstream NF-κB signaling transduction. SH protein inhibits the phosphorylation and acetylation of NF-κB, as well as the phosphorylation and homodimerization of interferon regulatory factors IRF3/7. G protein inhibits the phosphorylation and homodimerization of IRF3/7. M2–2 protein is also capable of inhibiting IRF7 homodimerization. Center right: cGAS-STING pathway. G protein can block the interaction between mitochondria and STING. IL-1β can activate mtDNA and promote the cGAS-STING response. Far right: IFN pathway. By activating the JAK-STAT pathway via autocrine or paracrine signaling mechanisms, it induces the expression of ISGs. SH proteins inhibit the conduction of the JAK-STAT pathway. The differently colored sections serve to highlight the action processes of distinct pathways. Red short dashes (“-”) indicate inhibitory effects; the red arrow (“→”) indicates a promoting effect. The question mark (“?”) highlights that the exact mechanism by which hMPV exerts its inhibitory effects in this context remains to be elucidated through further research.
Figure 2. The innate immune evasion mechanism of hMPV. This cell model diagram integrates the key insights from 31 published articles. Far Left: RIG-I/MDA5-MAVS pathway. Center Left: TLR/MyD88 pathway. G and SH proteins regulate the TLR4-MyD88 signaling pathway and TLR7/9-MyD88 pathway respectively, and inhibit the production of IFN and pro-inflammatory cytokines by interfering with downstream NF-κB signaling transduction. SH protein inhibits the phosphorylation and acetylation of NF-κB, as well as the phosphorylation and homodimerization of interferon regulatory factors IRF3/7. G protein inhibits the phosphorylation and homodimerization of IRF3/7. M2–2 protein is also capable of inhibiting IRF7 homodimerization. Center right: cGAS-STING pathway. G protein can block the interaction between mitochondria and STING. IL-1β can activate mtDNA and promote the cGAS-STING response. Far right: IFN pathway. By activating the JAK-STAT pathway via autocrine or paracrine signaling mechanisms, it induces the expression of ISGs. SH proteins inhibit the conduction of the JAK-STAT pathway. The differently colored sections serve to highlight the action processes of distinct pathways. Red short dashes (“-”) indicate inhibitory effects; the red arrow (“→”) indicates a promoting effect. The question mark (“?”) highlights that the exact mechanism by which hMPV exerts its inhibitory effects in this context remains to be elucidated through further research.

3.3.1 Inhibition of pattern recognition receptor signaling

During early infection, hMPV rapidly expresses viral proteins (G, M2−2, SH, and P) to suppress PRR signaling, thereby blunting innate immunity and promoting viral replication (18) (Table 1). These hMPV-encoded proteins target RIG−I−like receptors, TLRs, and the adaptor MyD88.

The RIG−I−MAVS axis is a major target. Multiple lines of evidence show that hMPV disrupts this pathway at several levels. The G protein inhibits RIG-I activation by forming a complex with RIG-I or repressing its transcription, and further blocks RIG-I-MAVS interaction via the RIG-I CARD domain (31, 32). The M2−2 protein impairs RIG−I ubiquitination by interfering with TRIM25 (46) and directly binds to MAVS, forming a stable complex that disrupts MAVS function (43). The P protein restricts RIG−I recognition of viral RNA (50). Consequently, downstream NF−κB activation is markedly attenuated. Consistent with this, M2−2 also blocks NF−κB signaling via its PDZ domain (44).

hMPV also targets TLR signaling. The G protein suppresses TLR4−dependent activation in monocyte−derived dendritic cells (40). M2−2 and SH interact with TLR7/9 in plasmacytoid dendritic cells (pDCs)—M2−2 with TLR7/9, SH selectively with TLR7—collectively impairing pathogen signal recognition (49, 54). Moreover, M2−2 forms a stable complex with MyD88, attenuating downstream signaling (43).

hMPV engages the NLRP3 inflammasome. The SH protein activates NLRP3 in mice, promoting IL−1β release, which on one hand exacerbates pathology and on the other activates the cGAS−STING pathway, paradoxically aiding immune evasion (21, 22).

Importantly, seemingly contradictory findings reveal the multi−layered nature of hMPV immune evasion. At the molecular level, viral RNA m6A methylation specifically suppresses RIG−I (not MDA5) recognition, blunting type I IFN responses early in infection (30). At the cellular level, however, host cells (e.g., DCs) can still sense the virus via alternative pathways, including RIG−I and MDA5 (30). This dynamic interplay between active suppression of a primary pathway and engagement of alternative pathways underscores the complexity of the hMPV immune regulatory network.

3.3.2 Interference with the interferon signaling pathway

Following hMPV invasion, IFN pathway activation is mediated by PRR signaling; IFN signal transduction is primarily governed by the JAK-STAT pathway, and IFN transcription is regulated by NF-κB (Figure 2; Table 1).

During the intermediate and late phases of innate immunity, hMPV targets both NF-κB and JAK-STAT signaling. The SH protein directly inhibits NF-κB phosphorylation and acetylation, thereby suppressing NF-κB-dependent gene transcription (48). In contrast, the G protein indirectly affects the NF-κB by inhibiting the upstream RIG-I signaling pathway (31). Regarding JAK-STAT, the SH protein promotes JAK1 degradation and inhibits STAT1 phosphorylation, suppressing the IFN signaling pathway (23–25). However, one study has reported that hMPV also interferes with JAK1 and Tyk2 degradation, though the precise mechanism remains unclear (26). Notably, while an early study found SH protein dispensable for viral replication in vitro (55), recent evidence confirms its key role in immune regulation in vitro and in vivo, with discrepancies likely attributable to differences in experimental models.

For the M2–2 protein, complementary perspectives exist. Early studies showed that the M2–2 protein directly binds and inhibits MAVS, actively blocking the IFN signaling (43). Recent genetic evidence indicates that M2-2’s core function is to synergize with M2–1 to maintain viral replication fidelity; the IFN response observed upon M2–2 deletion is largely an indirect consequence of accumulated RNA replication errors (42). Thus, M2–2 protein may employ two concurrent strategies: a fundamental mechanism that prevents immune recognition by ensuring replication quality, and an active mechanism that directly interferes with signal transduction.

Beyond viral-encoded proteins, hMPV modulates host non-coding RNAs to disrupt immune responses. For instance, it upregulates miR-146a to suppress NF-κB/IFN signaling or induces hsa-miR-4634 to inhibit the type I IFN responses and ISG expression (56, 57). Additionally, a novel IFN−independent evasion mechanism has been identified: hMPV infection suppresses the transcription factor C/EBPα in human macrophages, reducing expression of the antiviral cathelicidin peptide and thereby weakening innate immunity. These findings reveal potential therapeutic targets.

3.4 Adaptive immune evasion mechanism

hMPV impairs adaptive immunity through three interconnected pathways: PD−1/PD−L1−mediated T−cell exhaustion, Th2/Th17−biased cytokine networks, and G protein structural variation−mediated humoral immune evasion. Together, these mechanisms establish a vicious cycle of immunosuppression, inflammatory imbalance, and antibody escape, promoting viral persistence and reinfection.

PD−1/PD−L1 pathway. hMPV upregulates PD−L1 expression on infected cells and antigen−presenting cells, engaging PD−1 on virus−specific CD8+ T cells and inducing functional exhaustion (58, 59). PD-1/PD-L1 signaling also promotes viral reinfection and limits the protective efficacy of hMPV-specific epitope vaccines (60). Collectively, these findings identify the PD−1/PD−L1 axis as a potential therapeutic target for hMPV infection.

The IL-4 and IL-6 signaling. hMPV skews the adaptive immune response toward a Th2−biased or Th17−biased phenotype. IL−4 activates STAT6, promoting Th2 polarization while suppressing protective Th1 and cytotoxic T lymphocytes (CTL) responses, CTL−mediated antiviral immunity, and memory CD8+ T cell expansion (33, 61). Meanwhile, IL-6 drives STAT3 activation, enhancing Th17-mediated inflammation and inhibiting regulatory T cells, thereby creating an immune microenvironment conducive to pathogen persistence (62) (Figure 3). Importantly, both cytokines impair type I IFN effector function through JAK-STAT signaling, further impeding viral clearance. Collectively, these mechanisms weaken antiviral defense and exacerbate immunopathology.

The IL-4 and IL-6 signaling pathways in the adaptive immune evasion mechanism of hMPV. IL-4/6, produced via innate immune responses, autocrine, or Th2 cells, further activates the JAK-STAT pathway, leading to the production of IL-4/6. This process exerts a significant negative influence on the host’s immune defense mechanisms. IL-4 can activate the IL-4 pathway and promote the replication of viruses. SH protein suppresses IL-6 signaling by promoting the proteasomal degradation of JAK1. Red short dashes (“-”) indicate inhibitory effects. The question mark (“?”) highlights that the exact mechanism by which hMPV exerts its inhibitory effects in this context remains to be elucidated through further research.
Figure 3. The IL-4 and IL-6 signaling pathways in the adaptive immune evasion mechanism of hMPV. IL-4/6, produced via innate immune responses, autocrine, or Th2 cells, further activates the JAK-STAT pathway, leading to the production of IL-4/6. This process exerts a significant negative influence on the host’s immune defense mechanisms. IL-4 can activate the IL-4 pathway and promote the replication of viruses. SH protein suppresses IL-6 signaling by promoting the proteasomal degradation of JAK1. Red short dashes (“-”) indicate inhibitory effects. The question mark (“?”) highlights that the exact mechanism by which hMPV exerts its inhibitory effects in this context remains to be elucidated through further research.

G protein structural variation. Emerging evidence indicates that hMPV escapes humoral immunity through nucleotide duplications in the G gene. Piñana et al. reported that A2c lineage hMPV strains carrying 111−nt or 180−nt duplications in the G gene increased in prevalence during the 2014–2017 seasons in Barcelona (29, 63). Computational modeling predicted that these duplications extend the G protein further from the viral surface, improving steric shielding of the F protein—from 23% (wild−type) to 39% (111−nt) and 46% (180−nt)—thereby facilitating immune evasion (29). A similar mechanism has been described for RSV, where the G protein C−terminal extension contributes to enhanced virulence (64). However, these findings are based on bioinformatic and correlational analyses and lack direct biological validation. Future studies using reverse genetics, neutralizing antibody assays, and animal models are needed to establish a direct causal link between G protein elongation and increased viral pathogenesis.

Integrating the three pathways, we propose a working model of hMPV adaptive immune evasion. First, the PD−1/PD−L1 pathway directly suppresses CD8+ T cell function. Second, cytokine networks (IL−4 and IL−6) shift adaptive immunity toward Th2/Th17 phenotypes and impair type I IFN responses. These two mechanisms operate synergistically, while G protein duplications enable the virus to evade pre−existing neutralizing antibodies. This model may explain the high frequency of hMPV reinfections and suggests that combination strategies targeting both T cell exhaustion and cytokine imbalance could be more effective than single−agent approaches. Future studies should validate this model and investigate potential genotype−specific differences in adaptive immune evasion.

3.5 Host’s stress responses and viral replication support hMPV immune evasion

Beyond direct immune suppression, hMPV indirectly supports immune evasion by enhancing viral replication, modulating host cytokines, and inducing stress responses (Supplementary Table 4). These mechanisms collectively establish a “high replication–low clearance” microenvironment that favors viral persistence.

Viral proteins promote replication. The M2 protein enhances viral genome replication through transcriptional regulation (42, 65). The P protein facilitates inclusion body formation and promotes N−mediated assembly of inclusion bodies, thereby increasing viral RNA replication (66). These pro−replication mechanisms prolong viral exposure within the host, creating a wider window for immune evasion.

Host cytokines exert dual roles. Host−derived cytokines and chemokines, including IFN−γ, IL−1β, IL−4, and TSLP, critically modulate hMPV replication (22, 61, 67, 68). However, these mediators play dual roles in immune evasion. On one hand, they may suppress or dysregulate Th1/Th2 responses, impairing adaptive immunity. On the other hand, excessive pro−inflammatory factors can cause immunopathological damage and disrupt respiratory barrier integrity. Clinical evidence indicates that hMPV infection is associated with a nasal Th2 bias (69). Given that hMPV−encoded proteins inhibit type I IFN—a key driver of Th1 immunity—we hypothesize that virus−mediated suppression of the IFN pathway during innate immunity may skew adaptive immunity toward a Th2 bias, thereby impeding viral clearance and exacerbating disease. This hypothesis requires direct validation through in vivo intervention studies. Dysregulation of adaptive immunity ultimately fosters a “high inflammation–low clearance” microenvironment that facilitates viral immune evasion.

Host stress responses aid viral evasion. hMPV infection induces TSLP production, which exacerbates pulmonary pathology (68). Moreover, heat shock protein 70 (HSP70) is upregulated upon hMPV infection and suppresses caspase activation, thereby blocking apoptosis and delaying viral clearance. This may worsen respiratory infections in patients with underlying conditions such as asthma (70). By inhibiting host cell apoptosis, hMPV prolongs infected cell survival, further enhancing viral replication and persistence. In summary, hMPV employs a multi−pronged strategy—enhancing its own replication, hijacking the host cytokine network, and blocking apoptosis—to convert host stress responses into allies for immune evasion, thereby establishing a self−reinforcing cycle of viral persistence.

4 Discussion

This systematic review synthesizes two decades of research on hMPV immune evasion, revealing a complex network of virus–host interactions involving viral nucleic acids, structural and nonstructural proteins, and multiple immune signaling pathways. The sophisticated evasion mechanisms identified here have important implications for understanding viral evolution and developing effective prevention and treatment strategies.

hMPV has evolved a multi-protein, multi-pathway evasion strategy. Accumulating evidence suggests three complementary explanations. First, functional redundancy enhances the robustness of immune evasion. When one viral protein is compromised by host immune pressure or genetic drift, other proteins can maintain suppression of the same pathway. Both the G and M2–2 proteins inhibit the RIG-I-MAVS signaling axis, providing a backup mechanism (43). Second, viral proteins exert spatiotemporally specific roles at different infection stages or in different cell types. This fine-tuned regulation allows the virus to adapt to microenvironmental changes. For instance, the G and SH proteins interfere with dendritic cell endocytosis during early infection (28), whereas the M2–2 protein maintains replication fidelity at later stages (42). Third, synergistic amplification enhances immunosuppression. Simultaneous targeting of multiple signaling nodes (e.g., RIG-I, TLR, JAK-STAT) produces stronger overall suppression than targeting any single node, thereby lowering the threshold for successful evasion. As an example, the SH protein inhibits both NF-κB and JAK-STAT pathways (48), while the G protein inhibits RIG-I and TLR4 (31). hMPV is not the only respiratory virus employing a multi-target strategy. Syndrome coronavirus (SARS-CoV)-encoded proteins contribute to innate immune evasion by reducing IFN-alpha receptor subunit 1 (IFNAR1) levels, inhibiting STAT1 phosphorylation, and blocking IRF nuclear translocation (71). The NS1 proteins of RSV and influenza A virus inhibit RIG-I ubiquitination via TRIM25 (72, 73). hMPV shares some of these targets but also exhibits unique features, such as the dual function of its M2–2 protein in maintaining replication fidelity while directly inhibiting MAVS (42, 43). These comparisons suggest that a multi-protein, multi-pathway evasion strategy is a common evolutionary adaptation among respiratory viruses, although the specific mechanisms vary.

Like other respiratory pathogens, hMPV exhibits substantial genetic variability and encompasses multiple genotypes (74). Cross−protection between hMPV genotypes A and B is limited, with notable inter−genotype differences. Ferret infection experiments have demonstrated that homologous neutralization titers are 16− to 128−fold higher than heterologous titers, indicating that the immune response is less efficient at neutralizing viruses of the other genotype (75, 76). This limited cross-protection stems primarily from antigenic differences in surface proteins: the relatively conserved F protein mediates baseline neutralization, while the highly variable G protein is a major driver of immune evasion between lineages (77). In the A2c lineage, 111−nt and 180−nt duplications in the G protein increase steric shielding of F protein epitopes from 23% (wild−type) to 39% and 46%, respectively, thereby enhancing humoral immune evasion (29). Epidemiological surveillance has shown that A2c variants carrying these duplications have become the predominant sub−lineage in Beijing (56.9%), with high positivity rates in children aged 0–4 years (3.4%) and the elderly ≥60 years (1.2%) (7). Given the high prevalence of such variants in susceptible populations, their immune evasion features may have important implications for vaccine development. Although most current vaccine strategies target the highly conserved F protein, immunization with post−fusion F protein from genotype B2 has been shown to elicit cross−neutralizing antibodies against both A2 and B2 strains in mice (78). However, as a potential immune evasion mechanism, G protein duplications may compromise the protective efficacy of F protein−based vaccines against emerging variants by increasing steric shielding of F protein epitopes. This observation suggests that immune evasion features may influence vaccine effectiveness. Therefore, future vaccine development and evaluation should monitor circulating strains for immune evasion characteristics (e.g., G protein structural variations) and systematically assess their impact on F protein epitope accessibility.

Direct comparisons of immune evasion networks between hMPV genotypes A and B are scarce. A2c lineage-specific G protein duplications (111−nt and 180−nt) are predominantly reported in genotype A (29), suggesting that genotype A may have evolved enhanced humoral immune evasion via G protein structural variation. Moreover, the M2–2 protein, which suppresses innate immunity by targeting MAVS (43), is 90% conserved between the two genotypes (79); whether this slight divergence translates into functional differences in MAVS binding remains unknown. Future reverse genetics studies swapping G or M2–2 between genotypes are needed to directly compare their immune evasion capacities.

The present systematic review has some limitations. In our study, 90.1% (55/61) of the studies originated from the Americas and Europe. This bias may be attributed to multiple factors. Our restriction to English−language publications may have excluded high−quality studies from countries such as China, Japan, South Korea, and Brazil, many of which were published in non−English journals or focused on epidemiology rather than immune evasion mechanisms. Additionally, hMPV has historically been considered a low−incidence pathogen (pooled prevalence of approximately 5.3% in patients with acute respiratory tract infections) and has long received less research attention and funding compared to COVID−19 and influenza (80). However, the resurgence of hMPV in many Northern Hemisphere countries from late 2024 to early 2025 underscores the urgent need for more research (81). Third, vaccine development for respiratory viruses has historically been dominated by Europe and North America. Research institutions and pharmaceutical companies in these regions, leveraging advanced technology platforms (e.g., mRNA) and substantial funding, have taken a leading position in the development of hMPV vaccines, resulting in a large body of related research (11, 81). Consequently, current research on the immune evasion mechanisms of hMPV is largely concentrated within a limited number of institutions and developed regions. Expanding the geographical and viral strain diversity of future studies is essential to elucidate the virus’s region−specific adaptive evolution and to support the development of broad−spectrum therapeutic and preventive strategies.

This systematic review elucidates that hMPV employs a multilayered and multi-protein coordinated immune evasion network to counteract host defenses. Core mechanisms involve viral proteins (G, M2-2, SH, P) inhibiting interferon production and signaling pathways, alongside strategies like antigenic variation (e.g., G protein mutant) and host non-coding RNA regulation. These mechanisms exhibit cell-type and context dependency. Current research is limited by geographical and strain diversity. Future studies should utilize clinical isolates and in vivo models to validate causal relationships of key mechanisms and explore their regulatory networks, thereby laying the groundwork for developing broad-spectrum therapeutic strategies.

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Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fviro.2026.1791383/full#supplementary-material

The distribution of 61 included articles on the immune evasion mechanism of hMPV during respiratory tract infections. Supplementary material at the source

The immune evasion-related targets of hMPV in the (A) initiation stage, (B) signal transduction stage, and (C) effector stage of the host’s innate immune response. To the left of the lines are sources, pointing to different targets to the right. The color of the lines is determined by sources. The diagram is drawn by the online tool Chiplot. Supplementary material at the source

The immune evasion-related targets of hMPV in the (A) initiation stage and (B) effector stage of the host’s adaptive immune response. To the left of the lines are sources, pointing to different targets to the right. The color of the lines is determined by sources. The diagram is drawn by the online tool Chiplot. Supplementary material at the source

The immune evasion-related targets of hMPV in the (A) host’s stress response, and (B) viral replication and re-infection of the adaptive immune response. To the left of the lines are sources, pointing to different targets to the right. The color of the lines is determined by sources. The diagram is drawn by the online tool Chiplot. Supplementary material at the source

Supplementary material Supplementary material at the source

Footnotes

Edited by: Juan C. Hernandez, Cooperative University of Colombia, Colombia

Reviewed by: Abayeneh Girma, Mekdela Amba University, Ethiopia

Yaser Arafath, Pondicherry University, India

Statements

Conflict of interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Funding

The author(s) declared that financial support was received for this work and/or its publication. The study was supported by the Capital’s Funds for Health Improvement and Research (2024-1G-3015) and the Beijing Research Center for Respiratory Infectious Diseases Project (BJRID2026-008).

Data availability

The datasets presented in this study can be found in online repositories. The retrieved information/statistical literature can all be found in the article/Supplementary Material.

Author contributions

YH: Writing – original draft, Visualization, Formal analysis. LZ: Conceptualization, Writing – review & editing. CW: Investigation, Formal analysis, Writing – review & editing. FH: Supervision, Writing – review & editing, Funding acquisition, Validation. CG: Writing – review & editing, Validation, Supervision. XG: Conceptualization, Writing – review & editing.

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Citation

Han, Y., et al. (2026). Immune evasion of human metapneumovirus during respiratory tract infections: systematic review. Frontiers in Virology, Volume 6. https://doi.org/
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6 - 2026

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Copyright © 2026 Han, Zheng, Wang, Huang, Gong and Guan.

License: https://creativecommons.org/licenses/by/4.0/

*Correspondence: Xuejiao Guan

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