Controlled cell death during human respiratory syncytial virus infection

The discovery of apoptosis was a fundamental hallmark in the study of cell death and expanded our understanding of various types of cell death (Park et al., 2023). In 1972, John F. Kerr, Andrew H. Wyllie and A. R. Currie coined the term “apoptosis” to differentiate naturally occurring developmental cell death from the necrosis that results from acute tissue injury (Kerr et al., 1972). Caspase family proteases have long been regarded as the “executioners” of cell death, initiating an irreversible apoptotic cascade upon activation, akin to a domino effect (Li et al., 2025). Apoptosis is carried out by intracellular caspase-3 and caspase-7, which cleave diverse intracellular substrates, leading to cell shrinkage, chromatin fragmentation, membrane blebbing, and breakdown into membrane-wrapped vesicles called apoptotic bodies, which is also a morphological characteristic of apoptotic cells (Ai et al., 2024). Apoptosis is a complex interplay of two main signaling pathways: the intrinsic (mitochondrial) and the extrinsic (death receptor). The extrinsic signaling through death receptors that leads to the formation of the death-inducing signaling complex (DISC), and intrinsic signaling mainly through mitochondria leads to the formation of the apoptosome. Formation of the DISC or apoptosome, respectively, activates initiator and common effector caspases that execute the apoptosis process. The key genes and pathways involved in apoptosis have been increasingly clarified after more than 50 years. The value of apoptosis in explaining the pathological mechanisms of various diseases has been further explored, supporting the development of new therapeutic strategies. Indeed, apoptosis has revolutionized our understanding of cell death and its importance in various physiological and pathological conditions (Capela E Silva and Rodrigues, 2023).

Anoikis was coined by Frisch and Francis in 1994 (Frisch and Francis, 1994). The term was borrowed from the Greek words meaning “the state of being without a home”. Anoikis, also known as matrix detachment-induced apoptosis or detachment-induced cell death, is directly induced by a disruption in cell-cell attachments or cell-extracellular matrix (ECM) attachments (Wang et al., 2024). The disruption of cytosolic connectors leads to intracellular cytoskeletal and signaling pathway alterations, ultimately activating caspases and initiating PCD, which is an outside-in process that mediated by a caspase cascade reaction (Dai et al., 2023). Anoikis is a distinct form of apoptosis that cannot be simply categorized as traditional apoptosis due to its unique initiation process (Mei et al., 2024). Anoikis maintains tissue homeostasis by eliminating cells that are detached or misplaced due to physiological or pathological conditions.

Paraptosis is a distinct form of PCD characterized by massive cytoplasmic vacuolation involving the dilation of endoplasmic reticulum (ER) and/or mitochondria. Paraptosis is caspase-independent and lacks the typical morphological changes of apoptosis (Li et al., 2022). Membrane blebbing, chromatin condensation, and nuclear fragmentation—characteristic morphological hallmarks of apoptosis—are absent in the process of paraptosis. It is regulated by several signaling pathways, for instance, those associated with ER stress, calcium overload, oxidative stress, and specific cascades. Paraptosis is a distinct form of non-apoptotic cell death gaining attention for its potential role in cancer therapy and resistance (Kunst et al., 2024). As a novel type of PCD, paraptosis was first identified by Sperandio in 2000 (Sperandio et al., 2000). Despite its extensive and long research history in pathophysiology, the incidence of Paraptosis is likely underestimated due to insufficient understanding of its biochemical mechanisms and a lack of specific biomarkers.

Pyroptosis is a lytic and inflammatory type of PCD that is triggered by inflammasomes and executed by gasdermin proteins. Pyroptosis is characterized by the activation of inflammatory caspases (mainly caspase-1, 4, 5, 11) and cleavage of various members of the Gasdermin family to form membrane perforation components (Wei et al., 2022). Cell swelling, membrane perforation, and release of cellular contents are its major cell morphological changes. In fact, pyroptosis in infected macrophages was discovered in early 1992 but mistakenly classified as apoptosis (Liu et al., 2024). However, the term “pyroptosis” was first proposed by Cookson and Brennan in 2001 to describe this PCD type. Pyroptosis from the Greek roots pyro, relating to fire or fever, and ptosis (to-sis) to denote a falling, to describe pro-inflammatory programmed cell death (Cookson and Brennan, 2001). In terms of physiology, pyroptosis plays a critical role in host defense against pathogen infection (Rao et al., 2022). As the sole form of PCD that intimately couples cell death with an intense inflammatory response, pyroptosis possesses unique value.

Lysosomal cell death (LCD) is a form of PCD triggered by increased lysosomal membrane permeabilization (LMP), leading to the cytoplasmic release of lysosomal enzymes and subsequent execution of the cell death cascade. In 1955, Christian de Duve discovered lysosomes—a breakthrough that inaugurated a new era in cellular physiology and pathophysiology. He was awarded the Nobel Prize in Physiology or Medicine in 1974 for his discovery and characterization of lysosomes as cellular ‘recycling bins’. The concept of LCD was first proposed by Christian de Duve (Aits and Jäättelä, 2013). There is much controversy exist when the term “lysosomal cell death” was first proposed. However, it was actually first proposed in 2005, by Kroemer et al., who discussed it as an independent form of PCD (Kroemer and Jäättelä, 2005).

Necroptosis, as an independent term, was first proposed by Degterev et al. in 2005 (Degterev et al., 2005). Necroptosis is a form of programmed inflammatory cell death, characterized by distinct morphological and biochemical hallmarks, including cell membrane rupture, organelle swelling, cytoplasmic and nuclear disintegration, cellular contents leakage, and release of damage-associated molecular patterns (DAMPs), accompanied by the inflammatory responses (Zhu and Wu, 2024). Necroptosis differs from apoptosis and other forms of PCD because it does not rely on caspase activity. Necroptosis is mediated by the necrosome, which consists of mixed lineage kinase domain-like protein (MLKL), receptor-interacting protein kinase 1 (RIPK1), and RIPK3 (Ye et al., 2023).

Entosis is one of the known types of vacuole-dependent, non-apoptotic PCD (Gaptulbarova et al., 2024). In 2007, entosis was proposed by Overholtzer M (Overholtzer et al., 2007), which was derived from the Greek word that means “inside” or “within”. Entosis is a form of PCD in which one cell inserts itself into a neighboring cell, leading to the eventual death of the invading cell. This creates a characteristic cell-in-cell (CIC) pattern, a phenomenon observed as early as 1891 by Steinhaus in tumor samples (Kianfar et al., 2022). During entosis, the inner cell actively invades the host cell, a process driven by the activation of Rho proteins, the formation of adhesion bonds, and actomyosin filaments. Once the phenomenon happened, the inner cell is enclosed within a double-membraned entotic vacuole, featuring a large space between the membranes (Mlynarczuk-Bialy et al., 2020). The four possible fates in entosis are: death of the inner cell, death of the outer cell, death of both cells, or survival of both cells.

“NETosis” is a term first introduced by Steinberg and Grinstein in 2007 to describe the process of programmed neutrophil death associated with the formation of neutrophil extracellular traps (NETs) (Steinberg and Grinstein, 2007). NETosis is characterized by neutrophil cell death accompanied by the release of NETs, auto-inflammatory factors, and antigens. NETs are extracellular web-like structures composed of decondensed DNA decorated with cytosolic and granule proteins. Since it was initially shown that NET formation is accompanied by cell death, this process was termed NETosis (Vorobjeva and Chernyak, 2020). As the most typical and predominant form of cell death in neutrophils, NETosis is the only type of PCD that fights pathogens by releasing NETs.

Methuosis is one of the most recent additions to the list of nonapoptotic cell death phenotypes. The most prominent attribute in cells undergoing this form of death is the accumulation of large fluid-filled cytoplasmic vacuoles that originate from macropinosomes (Maltese and Overmeyer, 2014). Methuosis is a process that lacks the classic morphological features of apoptosis. In 2008, Overmeyer et al. discovered that treatment of human glioblastoma cells with a small molecule called MIPP ([3-(2-methyl-1H-indol-3-yl)-1H-pyrrolo[3,2-b]pyridine]) induced a unique type of cell death, coined the term “methuosis” (from the Greek word methuo, which means to drink to intoxication) (Overmeyer et al., 2008). Methuosis, as a novel, protease-independent form of cell death that expands the known diversity of cell death networks.

Parthanatos, also known as PARP-1 dependent cell death, named in 2009 by Ted Dawson and Valina Dawson, who defined the term “Parthanatos” after Thanatos, the personification of death in Greek mythology (David, 2009). Its core mechanism involves hyperactivation of poly (ADP-ribose) polymerase-1 (PARP1). The excessive consumption of NAD+ and ATP subsequently leads to cellular energy crisis. Concurrently, the accumulation of poly (ADP-ribose) (PAR) polymers facilitates the nuclear translocation of apoptosis-inducing factor (AIF), culminating in massive DNA fragmentation and cell demise (Fang et al., 2025). Therefore, the main characteristics of Parthanatos are considered to be PARP1 hyperactivation, PAR polymer accumulation, mitochondrial depolarization, and AIF nuclear translocation, distinct from other cell death pathways, Parthanatos is caspase-independent and does not require Bax or apoptotic activating factor-1 (Apaf-1) (Yang et al., 2024).

Ferroptosis is caused by the accumulation of iron and lipid peroxidation, it was first observed in cells treated with erastin, a small-molecule inducer discovered by Dolma et al. in 2003 (Dolma et al., 2003). Ferroptotic cells lack of classic apoptosis features like chromatin condensation, apoptotic bodies, autophagosome formation, or nuclear structural changes. However, mitochondria exhibit unique characteristics, including reduced volume, loss of structural integrity, increased membrane density, outer membrane rupture, and decreased or absent cristae (Shen et al., 2025). The concept of this distinct form of regulated, iron-dependent cell death driven by lipid peroxidation, along with the term “Ferroptosis” was later introduced by Dixon et al. in 2012 (Dixon et al., 2012).

In 2013, Liu and Levine identified a novel form of autophagy-induced cell death, termed “autosis”. They found that the selective overactivation of autophagy results in cell death with unique morphological features distinct from those of apoptosis or necrosis (Liu et al., 2013). Before this concept was proposed, the relationship between autophagy and PCD was often considered to be contradictory. Autotic cells are characterized by a dramatic initial increase in cytoplasmic autophagic and empty vesicles, followed by later-stage changes including electron-dense mitochondria, ballooning of the perinuclear space due to the separation of nuclear membranes, and concavity of the nucleus (Schwartz, 2021). Autosis is uniquely characterized by its direct dependence on the overactivation and execution of the autophagic process.

Acid-base homeostasis is essential for normal physiology, cellular metabolism, and function. Alkaliptosis is defined by the lethal rise in intracellular pH, regulated by the interplay of ion channels and transporters in intracellular and extracellular pathways. Compared to other forms of RCD, the induction of alkaliptosis does not involve the commonly recognized cell death effectors, such as caspases and MLKL (Chen et al., 2023). As a type of pH-dependent non-apoptotic PCD, alkaliptosis was first identified by Tang et al. in 2018 in pancreatic ductal adenocarcinoma (PDAC) cells (Song et al., 2018).

Oxeiptosis is a novel caspase-independent PCD pathway with apoptotic-like features, first proposed as an academic concept by Holze et al. in 2018 (Holze et al., 2018). Reactive oxygen species (ROS) play essential roles in all forms of cell death. ROS-induced cell death includes apoptosis, necroptosis, ferroptosis and autosis (Villalpando-Rodriguez and Gibson, 2021). However, Oxeiptosis operates in a non- inflammatorily, independently of caspases, and is induced by ROS or ROS-generating. Distinguished from other cell death pathways, oxeiptosis shown a unique damage-causing factors pivotal genes, and Kelch-like ECH-associated protein-1 (KEAP1)/Phosphoglycerate mutase family member 5 (PGAM5)/apoptosis-inducing factor mitochondrial associated 1(AIFM1) signaling pathways (Chen et al., 2024). Pathologically high ROS cause oxidative stress, which damages macromolecules (proteins, lipids, DNA) and cellular organelles. This ultimately compromises cellular integrity and leads to apoptosis-like cell death.

PANoptosis is a unique inflammatory cell death, representing the convergence of apoptosis, pyroptosis, and necroptosis, and plays a crucial role in regulating cell death and immune responses (Gao et al., 2024). Pyroptosis, apoptosis, and necroptosis, three previously considered separate and independent PCD pathways, actually exhibit mechanistic overlap and extensive, multifaceted crosstalk. Crosstalk among pyroptosis, apoptosis, and necroptosis was systematically reported as early as 2016 (Kuriakose et al., 2016). However, the concept of “PANoptosis” was not proposed until 2019 by R K Subbarao Malireddi et al (Malireddi et al., 2019). The emergence of the concept of PANoptosis has provided a novel perspective for cell death research, drawing increasing attention to the crosstalk mechanisms underlying PCD.

Disordered cytosolic calcium [Ca²⁺]_(c) signaling plays a critical role in cell death (Bhosale et al., 2015). The concept of calcicoptosis as a new type of cell death was recently proposed by Zhang et al. in 2019 (Zhang et al., 2019). The calcicoptosis is a novel form of cell death characterized by calcium-induced damage and oxidative stress, triggered by Ca²⁺ over-loading that leads to mitochondrial dysfunction with excess ROS generation. Under oxidative stress, abnormal function of cellular calcium channels impairs Ca²⁺ concentration modulation, which subsequently causes cell membrane mineralization by Ca₃(PO₄)₂ precipitation (Guo et al., 2022). Calcicoptosis is proposed as a distinct form of PCD, different from other cell types, suggesting cell death induced by calcium.

Cuproptosis is a recently discovered form of mitochondria-related cell death triggered by excess Cu²⁺. In 2022, Tsvetkov et al. published a landmark study in Science, systematically unraveling and naming its molecular mechanism (Tsvetkov et al., 2022). Cuproptosis, a metal-dependent pathway of cell death, is triggered by excessive copper exposure and subsequent proteotoxic stress. The mechanism involves intracellular copper targeting and binding to lipoylated components in the tricarboxylic acid (TCA) cycle. Aggregation of these copper-bound lipoylated mitochondrial proteins, along with the subsequent reduction in Fe–S (iron–sulfur) clusters, ultimately induces proteotoxic stress and cuproptosis (Chen et al., 2022).

Disulfidptosis, as a new form of PCD triggered by disulfide stress, is characterized by the collapse of cytoskeleton proteins and F-actin due to the intracellular accumulation of disulfides (Zheng et al., 2023). J Chen and B Gan found that the aberrant accumulation of intracellular disulfides in Solute carrier family 7 member 11 (SLC7A11) - cells under high glucose starvation induces a previously uncharacterized type of cell death, which they term “Disulfidptosis” in 2023 (Liu et al., 2023).

For example, “zinc-induced cell death” currently lacks a formally designated independent cell death mode or academic term within the mainstream classification system (Vitale et al., 2023; Galluzzi et al., 2018) published by the Nomenclature Committee on Cell Death (NCCD). As for now, the term “zinc death” has not been formally proposed in a single paper. Rather, it is a literal translation or simplified expression used by researchers to describe “zinc-induced cell death.” It has not yet been formally recognized as a distinct cell death mode, unlike ferroptosis, necroptosis, and cuproptosis. The expanding landscape of PCD, with its diverse molecular mechanisms and profound implications for disease outcomes, offers a critical theoretical and research framework for understanding how viral infections precisely orchestrate cell death pathways to control viral replication and associated tissue damage.

Apoptosis is the most prevalent form of cell death in RSV infection. It was also the first type of PCD to be documented, both in general and specifically within the context of RSV research. Apoptosis is the key mechanism in RSV pathogenesis with its ability to subvert the apoptotic pathway in host cells. RSV infects and alters the apoptotic fate of a wide range of cells, from structural epithelial cells to defensive immune cells like macrophages and T-cells. This targeted manipulation of cell death is a cornerstone of RSV infection and propagation.

Necroptosis has been implicated as a critical cell death pathway in virus-infected cells (Cotsmire et al., 2021). RSV has been shown to trigger necroptosis in an infected lungs. Necroptosis blockade may represent a therapeutic strategy for a range of lung pathologies with viral etiologies (Gautam et al., 2024).

RSV infection is a complicated process, several cell types are implicated in the disease progression. As the primary barrier against respiratory pathogens, the airway epithelium can be bypassed by viruses via various means, with their most straightforward approach being the direct infection of epithelial cells. RSV infection readily induces necroptosis in RSV-infected airway epithelial cells. This is detrimental to viral clearance and accentuates immunopathology and the ensuing propensity to develop asthma (Harker and Snelgrove, 2020). RSV infection of airway epithelial cells induces phosphorylation of necroptosis proteins prior to the induction of cell death. RSV infection induced an “early” (6 hpi) and “late” (24 hpi) phosphorylation of receptor-interacting protein kinase 3 (RIPK1)/receptor-interacting protein kinase 3 (RIPK3)/mixed-lineage kinase domain-like (MLKL). However, necroptotic cell death was restricted to the late phase (Simpson et al., 2022). Inhibition of necroptosis may be a viable strategy to limit the severity of viral bronchiolitis and break its nexus with asthma (Simpson et al., 2020).

Macrophages may exacerbate the severity of RSV-induced disease, and necroptosis is closely associated with this process. One of the key factors driving exaggerated lung inflammation during RSV infection is the necroptosis of RSV-infected immune cells, particularly macrophages. The RIPK1-dependent necrotic cell death was termed “Necroptosis”. Despite morphological similarities, it is distinct from necrosis, which is an accidental cell death caused by irreversible cellular injury. RIPK3 and MLKL are the key downstream molecules of RIPK1, with MLKL serving as the ultimate executor of necroptosis (Makuch et al., 2024). During RSV infection of macrophages, viral replication promotes tumor necrosis factor (TNF) production and secretion; TNF then binds to TNF receptor 1 (TNFR1), triggering RIPK1/RIPK3 phosphorylation, subsequent MLKL activation, and ultimately leading to macrophage necroptosis (Santos et al., 2021). Previous studies have confirmed that macrophages undergo necroptosis during RSV infection, a process that depends on RIPK3 and MLKL (Da Silva, 2018; Bedient et al., 2020). RIPK3 forms a complex called the necrosome, which then recruits and phosphorylates MLKL. This triggers MLKL oligomerization, enabling the formation of pore-like structures in the plasma membrane that execute necroptosis (Shi et al., 2023). Persistent or aberrant ER stress induces cell injury (e.g., apoptosis, necroptosis), whereas activating transcription factor 6 (ATF6)—acting as a transcription factor—induces ER chaperone proteins (Li et al., 2023). Notably, the ATF6-dependent ER stress pathway plays a positive role in RSV-mediated necroptosis of macrophages, and this effect is exerted via the induction and activation of ATF6 protein in RSV-infected macrophages (Kothwela, 2022).

Pyroptosis plays a pivotal role in eradicating intracellular pathogen replication niches and modulating the immune system via the release of danger signals. Pyroptosis is an important innate immune response that is critical in fighting infections (Wei et al., 2022). Viruses precisely activate or inhibit host pyroptotic pathways, thereby evading immune surveillance, promoting dissemination, and establishing persistent infections (Zhang et al., 2025). Previous studies confirm that RSV infection induces severe inflammation and lung tissue damage via pyroptosis. The Nod-like receptor protein containing pyrin 3(NLRP3) inflammasome-induced pyroptosis pathway contributes to enhanced lung immunopathology during RSV infection and promotes the development of RSV-associated asthma (Lin and Porto, 2025). The NLRP3 inflammasome leads to caspase-1 activation and the cleavage of different cellular proteins, including pro-interleukin (IL)-1β and pro-IL-18, as well as gasdermin D (GSDMD). The resulting GSDMD N-terminal fragment oligomerizes in the plasma membrane, forming GSDMD pores, inducing large ruptures in the membrane, thereby leading to pyroptosis (Schachter et al., 2025).

Epithelial cells are structural cells that maintain the stability of lung function and serve as an important battlefield for RSV infection. The human bronchial epithelial cell line, 16HBE14o- (16HBE), is widely used as a model for respiratory epithelial diseases and barrier function (Callaghan et al., 2020). RSV can induce 16HBE cell pyroptosis, thereby promoting viral replication and spread (Chen et al., 2022). BEAS-2B cells are immortalized cells derived from normal human bronchial epithelial cell. Electron microscopy was used to assess morphology changes associated with RSV-induced pyroptosis in BEAS-2B cells, including mitochondrial swelling and nuclear disruption. RSV infection elevates the expression of pyroptosis markers, such as NLRP3, apoptosis-associated speck-like protein(ASC), and cleaved caspase-1 (Jiao and Yang, 2025). Macrophage pyroptosis plays a critical role in virus infected pathophysiology. The caspase-1 dependent pyroptosis pathway, specifically the ASC/NLRP3/caspase-1 axis, serves as a key mechanism promoting lytic cell death in RSV-infected macrophages, while infection-generated ROS positively regulate this lytic cell death (Bedient et al., 2020).

NETosis is a special form of PCD with remarkable specificity. Neutrophils are one of the host’s first defensive measures against viral infection. Neutrophils employ three major defensive mechanisms, including phagocytosis, degranulation and NETosis (Sebina and Phipps, 2020). NETs can capture and kill RSV, contributing to host defense. Extensive neutrophil accumulation in the lungs is a distinct feature of severe RSV-LRTD, and these activated neutrophils release NETs (Cortjens et al., 2016). Neutrophils recognize the fusion protein of RSV via TLR4, subsequently releasing NETs (Hong et al., 2022). ROS are essential for NET formation or NETosis, excess ROS produced during neutrophil activation induces NETosis by inducing extensive DNA damage, and the subsequent DNA repair pathway, leading to chromatin decondensation. RSV can induce classic ROS-dependent NETosis in neutrophils (Muraro et al., 2018).

Numerous studies have demonstrated that ferroptosis plays a significant regulatory role in various respiratory infectious diseases (Hong et al., 2025). RSV-infected mice exhibit increased secretion of the pro-inflammatory chemokines CCL5 and CCL3, elevated mitochondrial iron content, and upregulated expression of 12/15-lipoxygenase (12/15-LOX, which catalyzes the deoxygenation of polyunsaturated fatty acids [PUFAs]). All these changes correlate with increased activation of the 12/15-LOX signaling pathway (Salimi et al., 2017). The cellular damage observed following RSV infection is mediated by the activation of ferroptosis, and these findings indicate that RSV acts as a trigger for ferroptosis (Kombe Kombe et al., 2024).

PCD is considered a key player in a variety of cellular processes that help to regulate tissue growth, embryogenesis, cell turnover, immune response, and other biological processes (Kari et al., 2022). Although the forms of cell death are becoming increasingly diverse and studied, existing evidence suggests that RSV-induced PCD consists of only 5 forms: apoptosis, necroptosis, pyroptosis, NETosis, and ferroptosis. Given the diversity of cell death forms, it is reasonable to assume that many viral strategies to promote/inhibit cell death remain unexplored. Compared with the related research on other viral infections and PCD, there are still many gaps in the research on RSV and PCD. For example, like RSV, Severe Acute Respiratory Syndrome Coronavirus 2(SARS-CoV-2) coronavirus infection also modulates multiple PCDs, such as necroptosis, apoptosis, pyroptosis (Liang et al., 2024), NETosis (Zhu et al., 2022), ferroptosis (Wang et al., 2022). However, it can also regulate lysosomal cell death (Sun et al., 2022), PANoptosis (Yang et al., 2025) and cuproptosis (Wang et al., 2024). These PCD forms have not been reported in RSV studies. Related research on other viruses regulating host cell death can also provide new research ideas and references for RSV intervention in cell death. As a virus with a long history, the complex relationship between RSV and cell death can also provide reference for emerging viruses.

Induction or inhibition are two distinct relationships between RSV and PCD, their dynamics remain a unresolved question. Different PCD forms, cell types, and stages of infection will lead to different RSV induction/inhibition interventions. However, the relatively stable structure of RSV seems to provide some theoretical basis for this issue. For example, the inhibition/induction of apoptotic mechanism of RSV seems to be related to viral proteins. The RSV genome encodes 11 viral proteins, including viral membrane glycoproteins (G), fusion proteins (F), and small hydrophobic proteins (SH). The crucial function of the SH protein is the inhibition of apoptosis through the suppression of TNF-alpha signaling, leading to the attenuation of caspase-8 activity (Okura et al., 2024). Furthermore, the RSV P-protein impairs the extrinsic apoptosis pathway in a macrophage-like cell line persistently infected with RSV (Nakamura-Lopez et al., 2015). The nonstructural NS proteins of RSV suppress premature apoptosis of the infected cell by a mechanism that is independent of suppression of interferon pathway by these proteins (Bitko et al., 2007). F protein expression can induce caspase-dependent cell death, suggesting its role as a potent inducer of apoptosis in RSV-infected cells (Faghirabadi et al., 2024). However, the binding forms and dominance of these proteins across different PCDs and different cells types remain largely unknown.

Studies over the years have revealed the distinctive molecular mechanisms and functional consequences of several key cell death pathways in RSV infection. Whether for host cells or viruses, PCD is a double-edged sword, playing the roles of both “protector” and “executioner”. Crosstalk is an unavoidable phenomenon in cell death research. Multiple cell death pathways, including apoptosis, necroptosis, pyroptosis, ferroptosis, and autosis, does not function in isolation but rather form a highly interconnected regulatory network. They frequently share the same signaling molecules, upstream triggers, and downstream effectors. RSV infection is a clear example; for example, RSV can induce the classical ROS-dependent NETosis through necroptosis pathways activation (Muraro et al., 2018). The crosstalk mechanisms between different forms of cell death, such as apoptosis and necroptosis (Rojas-Rivera et al., 2024), necroptosis and pyroptosis (Frank and Vince, 2019), and apoptosis and ferroptosis (Sun et al., 2021), have been reported. However, similar studies are rarely reported in RSV infection. The specific molecular interactions and crosstalk relationships among these PCDs in RSV infection are still relatively limited, and a systematic understanding has not yet been formed.

RSV induces distinct PCD patterns across various cell types, reflecting cell-specific functions in host defense and viral pathogenesis. Epithelial cells, the primary targets of RSV, exhibit stage-dependent apoptosis: early infection inhibits apoptosis to support viral replication, whereas late infection promotes apoptosis for viral spread. Macrophages show dual apoptotic regulation during the RSV infected process. NETosis is a program for formation of NETs, and both NETosis and apoptosis can occur in RSV-infected neutrophils. These differences arise from cell-specific functions and RSV’s tailored manipulation of PCD pathways. RSV primarily infects the respiratory epithelium links to neurologic sequelae with proof of previous studies (Pollard et al., 2024). PCD of neuronal cells confirms the mechanism of RSV nerve damage and provides a reference for Virus Infections in the nervous system, but the number of related studies is still insufficient.