Open access peer-reviewed chapter
Abstract
The pandemic era has underscored an urgent demand for more human-relevant and ethical models in viral research. Animal models have been the primary method for studying viral infection dynamics, immune responses, and potential treatments for decades. However, their limitations in accurately simulating human-specific responses raise critical questions about the effectiveness of these models in predicting human disease outcomes. Organoids—three-dimensional, stem cell-derived structures replicating human tissues’ architecture and functionality—present a groundbreaking alternative. This review examines the transformative potential of organoids to replace animal models in virology, particularly under pandemic conditions that require rapid, precise, and ethically sound approaches. With their ability to closely mimic human tissue environments, organoids enable more accurate analysis of virus-host interactions and more predictive drug screening. Beyond advancing scientific precision, organoids significantly reduce the ethical concerns and logistical challenges associated with animal testing. As the virology field pivots toward these innovative, human-centered models, organoids stand to redefine research approaches, promising a new era in viral research that can accelerate the development of effective treatments and preventive strategies in the face of future pandemics.
Keywords
- viral pathogenesis
- infectious diseases
- organoids
- human disease models
- 3D cell culture
1. Introduction
Viruses are obligate intracellular pathogens that rely on infecting host cells for their replication. Viral infections can manifest as asymptomatic courses or lead to clinical presentations ranging from mild to severe morbidity and mortality. Zoonotic viruses, in particular, possess the potential to cross-species barriers and cause epidemics and pandemics in human populations. The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has underscored the substantial impact of zoonotic viruses on global health.
SARS-CoV-2 primarily transmits
Figure 1.
Potentially affected organs by SARS-CoV-2 infection and their complications.
Understanding human diseases and developing effective treatments remain critical challenges in biomedical research. While animal models have long served as essential tools for elucidating disease mechanisms and evaluating potential therapeutic interventions, they often fail to accurately recapitulate human-specific immune responses, viral-host interactions, and the complex pathophysiology of viral diseases. The COVID-19 pandemic starkly highlighted these limitations. Despite their contributions to our understanding of viral pathogenesis, the development of vaccines, and antiviral therapies, animal models demonstrated significant translational gaps when predicting human responses.
In the pandemic period, widespread lockdowns, and travel restrictions led to significant disruptions in laboratory operations, resulting in reduced access to animal facilities and delays in ongoing studies. These disruptions were compounded by supply chain issues, including shortages of essential reagents and personal protective equipment, further impeding research progress. Moreover, the urgent need to rapidly develop effective treatments and vaccines highlighted the translational shortcomings of animal models, as their predictive validity for human responses was called into question [5, 6]. Another problem encountered during the pandemic is that vaccines and therapies developed for earlier strains often lost efficacy when faced with new variants characterized by altered spike proteins and additional mutations. As a result, the animal models created for these initial strains were unsuitable for accurately representing the virus’s changing pathogenesis. This limitation highlighted the need to quickly develop new animal models to capture the updated viral characteristics, further delaying the timely assessment and implementation of effective countermeasures [7, 8]. In viral disease research, working with animal models poses direct risks to laboratory personnel. Handling infected animals increases the potential for zoonotic transmission, as researchers may inadvertently contact infectious agents through bites, scratches, or exposure to contaminated fluids. Moreover, some animals’ unpredictable behavior—including aggression or attempts to escape from controlled environments—further elevates the risk of accidental exposure. In addition to scientific and logistical challenges, ethical concerns and the increasingly strict enforcement of regulations pose significant obstacles to the use of animal models.
Given the logistical, scientific, ethical, and safety concerns surrounding traditional animal models, particularly during a global health crisis, there is an increasing impetus to explore alternative approaches that provide faster, more reliable insights into human physiology and disease mechanisms while ensuring enhanced biosafety. Therefore, there is a growing belief that human-based
In this chapter, the application of organoids in viral research will be evaluated in detail, considering how these three-dimensional structures can overcome the limitations of traditional animal models and whether they provide a more reliable platform for studying viral pathogenesis and evaluating therapeutic interventions.
2. Organoids: A new paradigm in viral research
Three-dimensional cultures, starting with forming simple structures such as spheroids, have been developed using different approaches to generate various human-specific tissues. At the current stage, the integration of complex organoid models, which enable interactions between different cell types with microfluidic systems, has led to the development of organ-on-a-chip platforms, providing results that more closely resemble the clinical condition (Figure 2) [9, 10, 11]. Among these approaches, organoids have garnered significant attention and are increasingly preferred due to their ability to integrate different cell types into complex structures and be organized according to specific research needs. Organoids are commonly defined as complex, multicellular, three-dimensional (3D)
Figure 2.
Different methods used to model human biology.
2.1 Organoid models used in viral research
Organoid models enable researchers to investigate epidemic, pandemic, and non-epidemic viruses in a physiologically relevant context. Understanding the distinctions between these classifications is crucial for comprehending the scope and impact of viral diseases. An epidemic refers to the incidence of an infectious disease surpassing the expected baseline within a community. If this epidemic spreads across international borders, impacting a substantial portion of the global population, it is designated a pandemic, and the virus is called a pandemic virus. Conversely, non-epidemic viruses circulate within populations without causing widespread outbreaks [14].
2.1.1 Non-epidemic viruses and organoids
In non-epidemic viruses, recent studies utilizing human intestinal enteroids have demonstrated distinct infection patterns and immune activation mechanisms for enteroviruses, adenoviruses, and astroviruses. Enteroviruses were shown to infect specific intestinal cell lineages, triggering antiviral signaling in a cell type-dependent manner, thereby revealing the complexity of host immune responses. Adenoviruses exhibited a preferential tropism for goblet cells, highlighting the role of mucus-producing intestinal cells in viral pathogenesis, while interferon signaling was identified as a key factor in restricting viral replication. Similarly, astroviruses displayed multicellular tropism, infecting multiple intestinal cell types and eliciting a diverse innate immune response. These findings underscore the significance of enteroid-based models in virology research, providing an advanced
2.1.1.1 Liver organoids
Liver organoids derived from human induced pluripotent stem cells (hiPSCs) have been successfully employed to investigate hepatitis B virus (HBV)–host interactions, supporting viral infection and replication while closely mimicking liver tissue architecture and function. These models provide critical insights into HBV pathogenesis, highlighting viral entry mechanisms, intracellular immune responses, and interferon-stimulated gene activation [18]. Additionally, intrahepatic organoids (ICOs) have been utilized to examine HBV tropism beyond hepatocytes, revealing cholangiocytes as secondary targets and demonstrating inter-host variations in infection susceptibility and immune responses [19]. Beyond HBV research, multicellular liver organoids incorporating hepatocytes, hepatic stellate cells, and Kupffer-like macrophages have been developed to study hepatitis C virus (HCV) infection and its impact on nonalcoholic fatty liver disease (NAFLD) progression. These models effectively replicate key NAFLD features, including lipid accumulation, inflammation, and fibrosis, while also demonstrating that HCV infection exacerbates NAFLD-related pathology, emphasizing the intricate interplay between viral hepatitis and metabolic liver diseases [20]. Collectively, these studies underscore the value of organoid-based platforms in recapitulating human disease pathology, enabling patient-specific investigations, and facilitating drug screening in a scalable and translationally relevant manner. The shared ability of these models to mimic complex tissue-specific interactions and host responses highlights their potential as indispensable tools for advancing virology, toxicology, and regenerative medicine research.
2.1.1.2 Neural organoids
Neural organoids, including cerebral organoids and neurospheroids, have been extensively utilized to investigate neurotropic viruses such as human cytomegalovirus (HCMV), herpes simplex virus 1 (HSV-1), and varicella-zoster virus (VZV). Studies on HCMV infection in brain organoids have revealed its strong tropism for neural progenitor cells, leading to impaired neurogenesis, increased apoptosis, and disrupted cortical layer formation, mimicking congenital microcephaly. Similarly, HSV-1 infection in cerebral organoids demonstrated widespread neuronal cell death, structural disorganization, and a robust neuroinflammatory response, closely resembling viral encephalitis [21, 22, 23]. In parallel, VZV-infected neurospheroids exhibited neural tropism and immune evasion, allowing the virus to persist in a latent state, highlighting viral reactivation and neuroimmune modulation mechanisms. These findings underscore the potential of neural organoid models for investigating viral neuropathogenesis, latency, and antiviral therapeutic strategies. Beyond the central nervous system, maternal-fetal interface organoids, including trophoblast and decidua organoids, have been developed to study pregnancy-related viral infections. These models revealed that trophoblast organoids exhibit stronger innate immune activation and resistance to viral infections, while decidua organoids display greater susceptibility, characterized by heightened inflammatory signaling. This differential immune response highlights the complexity of antiviral defenses at the maternal-fetal interface, providing a valuable system for studying virus-induced pregnancy complications [24]. Similarly, ocular organoids, such as conjunctiva organoids, have been employed to model ocular surface homeostasis and disease. These organoids successfully replicate key epithelial features, including goblet cell differentiation and mucin secretion, making them a useful platform for studying inflammatory ocular conditions such as dry eye disease and conjunctivitis [25]. Together, these studies demonstrate the versatility of organoid models in virology and immunology, providing physiologically relevant systems to explore virus-host interactions, immune modulation, and disease progression across multiple tissue types. Importantly, the shared ability of organoid-based models to recapitulate key structural and functional features of their respective tissues highlights their translational value in therapeutic development, antiviral drug screening, and regenerative medicine.
2.1.2 Pandemic viruses and organoids
Early applications of organoid models in viral research that cause outbreaks focused primarily on studying gastrointestinal and respiratory viruses. Human intestinal organoids, for example, were used to model rotavirus infection, especially for patient-derived rotavirus strains, providing insights into viral replication, antiviral response, and host-pathogen interactions [26]. Similarly, lung organoids have been employed to study influenza virus infection (avian H1N1, H5N6, and H7N9) and respiratory syncytial virus (RSV), enabling researchers to investigate and evaluate cellular tropism, viral pathogenesis, and potential antiviral therapies [26, 27]. These early applications of organoid technology have played a crucial role in studying viruses that cause outbreaks, particularly gastrointestinal and respiratory viruses. However, over time, organoid research has expanded to model different organ systems and become a valuable tool for understanding diseases and developing treatments.
2.1.2.1 Brain organoids
Brain organoids have been widely utilized to study Zika virus (ZIKV) neuropathogenesis, demonstrating that ZIKV exhibits a strong tropism for neural progenitor cells, leading to reduced proliferation, increased apoptosis, and impaired neuronal differentiation. These effects result in smaller, structurally disorganized brain organoids, effectively modeling ZIKV-induced microcephaly. Additionally, infected organoids exhibit upregulated inflammatory responses and dysregulated neurodevelopmental pathways, closely mirroring the neurodevelopmental defects observed in congenital ZIKV infections. These findings highlight the critical role of brain organoids in elucidating ZIKV-induced neural damage, providing a valuable platform for studying viral neuropathogenesis and developing potential therapeutic interventions [28, 29]. To further refine disease modeling, brain-region-specific organoids generated using mini-bioreactors have enabled the study of region-specific vulnerabilities to ZIKV infection. Findings indicate that cortical organoids show the highest levels of viral replication, neuroinflammation, and cellular apoptosis, closely mimicking the cortical thinning observed in microcephaly. In contrast, other brain regions exhibit varying degrees of viral susceptibility and inflammatory responses, emphasizing the region-dependent effects of ZIKV infection on brain development [30]. Beyond disease modeling, brain organoids have been employed for therapeutic screening. Studies using human brain organoids have demonstrated that broad-spectrum antiviral compounds effectively inhibit ZIKV replication, block viral progeny release, and reduce virus-induced neurotoxicity. These treatments have also been shown to preserve neural progenitor function and restore normal neurodevelopmental processes, highlighting their potential for preventing congenital ZIKV-associated brain damage [31]. Developing self-organized cerebral organoids with human-specific features has further advanced high-throughput antiviral drug screening. Several studies have successfully identified compounds that reduce viral replication, protect neural progenitor cells, and restore neurodevelopmental pathways. Additionally, these models have provided new insights into human-specific cellular responses to ZIKV infection, addressing species-specific differences in viral susceptibility and brain development [32]. These studies highlight the value of brain organoids in modeling congenital viral infections, providing mechanistic insights, supporting comparative viral research, and creating a translational platform for antiviral drug discovery. The capacity of organoid models to replicate species-specific neural responses, evaluate brain-region-specific vulnerabilities, and enable high-throughput drug testing makes them essential tools for understanding viral neuropathogenesis and developing neuroprotective therapies.
Brain organoid-based studies have provided crucial insights into the neurotropism, replication dynamics, and pathogenic effects of SARS-CoV-2, highlighting its potential impact on the central nervous system (CNS). Several investigations utilizing human neural progenitor cells (NPCs) and pluripotent stem cell (hPSC)-derived brain organoids have shown that SARS-CoV-2 efficiently infects neural cells, particularly the choroid plexus epithelium, rather than cortical neurons, resulting in compromised blood-cerebrospinal fluid (CSF) barrier integrity, increased apoptosis, and heightened inflammatory responses [33]. These findings suggest that the choroid plexus may act as a critical entry point for SARS-CoV-2 into the CNS, potentially contributing to the neurological complications observed in COVID-19 patients. Infected brain organoids demonstrated upregulated inflammatory gene expression, structural disorganization, and disrupted neural differentiation, indicating potential neurodevelopmental and neurodegenerative consequences of viral infection [34]. Furthermore, metabolic dysregulation and increased cell death within glioma organoids imply that SARS-CoV-2 may exacerbate glioma progression or alter tumor microenvironments, raising concerns about its impact on neuro-oncology [35]. Therapeutic investigations using sofosbuvir in brain organoids revealed its potential as a neuroprotective antiviral agent, significantly reducing viral replication, preserving neuronal integrity, and mitigating virus-induced inflammation [36]. Collectively, these findings highlight the capability of brain organoid models to replicate key aspects of SARS-CoV-2 neuropathogenesis, providing a physiologically relevant platform for studying CNS infections, evaluating neuroprotective interventions, and understanding virus-induced neuroinflammation and blood-brain barrier disruption.
2.1.2.2 Respiratory organoids
Respiratory organoid-based models, including airway, alveolar, bronchial, and nasal mucosa organoids, have provided crucial insights into viral tropism, replication efficiency, and immune activation, offering physiologically relevant platforms for modeling respiratory viral infections. SARS-CoV-2 has been shown to efficiently infect and replicate within these organoids, leading to epithelial damage, ciliary dysfunction, and dysregulated inflammatory responses, closely resembling
2.1.2.3 Intestinal and kidney organoids
Intestinal and kidney organoids have been instrumental in investigating SARS-CoV-2 enteric and renal infections, particularly in the context of host metabolism, ACE2 expression regulation, and disease severity in high-risk populations. Studies have demonstrated that SARS-CoV-2 efficiently infects intestinal epithelial cells, leading to disrupted barrier integrity, altered immune responses, and metabolic reprogramming, which contribute to the gastrointestinal manifestations observed in COVID-19 patients. Additionally, strain-specific differences have been identified in influenza A (H5N6/H5N8) viruses, demonstrating efficient replication in human intestinal organoids, suggesting a high potential for cross-species transmission and human infection [40, 42]. Comparative analyses have further revealed that different strains of SARS-CoV-2 exhibit variations in replication efficiency and cytopathic effects within the intestinal epithelium, underscoring the need for strain-specific therapeutic approaches. In kidney organoids, SARS-CoV-2 infection has been associated with epithelial damage, oxidative stress, and impaired renal function, effects that are exacerbated under diabetic conditions [43]. Notably, hyperglycemic environments have been shown to upregulate ACE2 expression, facilitating enhanced viral entry and replication, which may explain the increased susceptibility of diabetic patients to severe renal complications. Additionally, the redundancy in viral entry mechanisms within kidney organoids suggests that SARS-CoV-2 can utilize multiple pathways to infect renal cells, indicating that ACE2 inhibition alone may not be sufficient to block infection [44]. These organoid-based models have also been applied to therapeutic screening, identifying potential antiviral compounds that effectively inhibit SARS-CoV-2 replication in intestinal and renal tissues. Moreover, studies have highlighted the role of host metabolic pathways in modulating viral susceptibility, demonstrating that targeting metabolic reprogramming could serve as a viable strategy to mitigate SARS-CoV-2-induced tissue damage [42, 45]. These findings emphasize the critical role of gastrointestinal and renal organoids in studying COVID-19 complications, identifying patient-specific vulnerabilities, and evaluating potential therapeutic strategies for high-risk populations. The ability of these models to recapitulate disease pathology, assess metabolic influences on viral infection, and serve as platforms for targeted drug discovery highlights their importance in advancing our understanding of SARS-CoV-2 pathogenesis and treatment strategies.
The cardiovascular impacts of SARS-CoV-2 have been studied using human cardiac organoids, providing physiologically relevant models for understanding virus-induced pathology and potential therapeutic strategies. iPSC-derived cardiac organoids have provided key insights into virus-induced myocarditis, cytokine storm-mediated cardiac injury, and contractile dysfunction, revealing that SARS-CoV-2 directly infects cardiomyocytes, leading to metabolic dysregulation, oxidative stress, and inflammatory responses [46]. Infection has been shown to disrupt sarcomere organization, impair mitochondrial function, and activate pro-inflammatory cytokine signaling, contributing to contractile dysfunction and cardiac cell apoptosis [47]. Moreover, cytokine storm conditions, characterized by elevated IL-6 and TNF-α, further exacerbate SARS-CoV-2-induced cardiomyopathy, demonstrating the compounding effects of systemic inflammation on cardiac tissue damage. Importantly, BET inhibitors and other anti-inflammatory compounds have shown potential in mitigating virus-induced cardiac damage, highlighting their therapeutic relevance for COVID-19-associated cardiovascular complications [48]. These studies show that the utility of cardiac organoids in modeling SARS-CoV-2-induced cardiovascular dysfunction, providing critical platforms for understanding disease mechanisms, identifying therapeutic targets, and evaluating potential drug interventions.
2.1.2.4 Vascular immune organoids
Vascularized macrophage-islet organoids and vascular immune organoids have provided critical insights into virus-induced β-cell destruction, immune-driven vascular dysfunction, and inflammatory signaling in SARS-CoV-2 infections, serving as valuable models for studying COVID-19-related metabolic and vascular complications. Investigations have revealed that SARS-CoV-2 infection induces pro-inflammatory macrophage activation, endothelial damage, and disruption of vascular integrity, closely mimicking COVID-19-associated systemic inflammation, coagulopathy, and multi-organ complications [49]. These models have demonstrated that infected macrophage-containing islet organoids secrete high levels of pro-inflammatory cytokines, leading to β-cell pyroptosis, insulin secretion defects, and fibrosis-like structural changes commonly observed in diabetic COVID-19 patients [50]. Furthermore, islet organoid studies have highlighted the role of fibroblast growth factor 7 (FGF7) in upregulating ACE2 expression, increasing β-cell susceptibility to SARS-CoV-2 infection, and exacerbating pancreatic dysfunction in diabetic patients [51]. Notably, hyperglycemic conditions have been shown further to enhance ACE2 expression in kidney and pancreatic organoids, contributing to higher viral loads and increased metabolic dysregulation, emphasizing the heightened risk of severe disease in diabetic individuals [44]. These findings collectively underscore the importance of vascularized and immune-integrated organoid models in studying SARS-CoV-2-mediated metabolic and vascular pathologies. They provide a translational platform for investigating immune-targeted therapies, metabolic interventions, and potential protective strategies against COVID-19-induced pancreatic and vascular dysfunction.
2.1.2.5 Microphysiological systems
Microphysiological Systems (MPS) integrated with multi-organ organoid models have revolutionized virological research, allowing for dynamic interactions between different tissue compartments and creating a more physiologically relevant environment to study systemic viral effects beyond static organoid cultures. Lung-brain MPS models have provided compelling evidence that systemic inflammatory signaling triggered by SARS-CoV-2 leads to blood-brain barrier (BBB) damage, increased neuroinflammation, and endothelial dysfunction, closely mimicking the neurological complications observed in severe COVID-19 cases [52]. These findings suggest that inflammatory cytokines released from infected lung tissue may contribute to secondary neurological damage, highlighting critical pathways for therapeutic intervention. Similarly, bronchial-vascular MPS systems have demonstrated that SARS-CoV-2-induced type-I interferon responses contribute to endothelial injury, increased vascular permeability, and systemic inflammatory damage, resembling COVID-19-associated coagulopathy and vascular dysfunction [53]. These models have been instrumental in identifying molecular pathways involved in virus-induced multi-organ dysfunction, revealing key inflammatory mediators responsible for endothelial damage and immune dysregulation. Additionally, lung-on-a-chip systems combined with airway and alveolar organoids have facilitated high-throughput antiviral drug screening, allowing for real-time monitoring of viral infection dynamics, drug efficacy testing, and precision medicine approaches [54]. These advanced models have been particularly useful for evaluating antiviral therapies targeting SARS-CoV-2 entry mechanisms, immune-modulating treatments, and strategies to prevent lung injury. Collectively, these findings highlight the transformative role of MPS-integrated organoid models in virology research, providing a dynamic and translationally relevant approach to studying multi-organ dysfunction in viral infections. The ability of these systems to recapitulate inter-organ signaling, inflammatory crosstalk, and systemic viral pathogenesis makes them indispensable tools for identifying therapeutic targets and optimizing antiviral strategies in precision medicine.
3. Conclusion
The ongoing advancements in virology research necessitate the development of human-relevant models that accurately mimic viral pathogenesis, immune responses, and therapeutic efficacy. While animal models have historically played a pivotal role in understanding viral infections, their limitations—including species-specific differences, ethical concerns, and translational gaps—highlight the need for alternative systems [5, 6]. Organoids, as three-dimensional, stem cell-derived structures that replicate human tissue functionality, have emerged as transformative tools in virology. These models provide a physiologically relevant microenvironment to study virus-host interactions, overcoming the challenges associated with traditional
The ability of organoids to closely resemble
Beyond serving as disease models, organoids have proven essential for drug discovery and high-throughput antiviral screening. These platforms have allowed researchers to rapidly assess the efficacy of antiviral compounds, immunomodulatory therapies, and host-directed interventions in physiologically relevant systems [9, 10, 13]. The ability to culture patient-derived organoids has further enhanced personalized medicine approaches, enabling the identification of patient-specific drug responses and the development of precision therapies [13, 42]. Moreover, the integration of microphysiological systems (MPS) with organoids has addressed the challenge of studying multi-organ interactions in viral infections, particularly in the context of systemic inflammation, blood-brain barrier disruption, and cardiovascular complications [52, 53].
Despite these advancements, several challenges remain in the widespread adoption of organoid-based models in virology research. The lack of mature immune components, which limits the ability to fully recapitulate adaptive immune responses, remains a key hurdle [5, 9]. Additionally, standardization of culture conditions, reproducibility across laboratories, and scalability for high-throughput studies are essential areas for improvement. Furthermore, the regulatory acceptance of organoid-based models in clinical and translational research requires further validation to ensure consistency and alignment with existing preclinical models [10, 12, 40].
Nevertheless, as emerging viral threats continue to pose global health challenges, organoid-based models are expected to play an increasingly critical role in pandemic preparedness, precision medicine, and vaccine development [42]. Their ability to bridge the gap between traditional
In summary, organoid-based models are not just an incremental advancement; they signify a transformative approach in virology research. As we navigate the complexities of viral infections and therapeutic development, these models offer unprecedented opportunities for innovation. With ongoing advancements in organoid engineering and a commitment to overcoming existing challenges, the future of infectious disease modeling and therapeutic strategies appears promising. The potential to revolutionize our understanding of viral pathogenesis and enhance pandemic preparedness cannot be overstated, making organoids a cornerstone of modern virology research.
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