Japanese encephalitis (JE) is the most important virus encephalitis worldwide, with nearly 67,900 JE cases occurring in 24 JE-endemic Asian and Western Pacific countries each year, approximately half of which occur in China (excluding Taiwan), and approximately 75% occur in children (0–14 years old) (Zheng et al., 2012; Campbell et al., 2011). While the majority of JEV infections are asymptomatic, a small proportion progress to encephalitis, of which 20%–30% are fatal. The transmission cycle of JEV involves mosquitoes, vertebrate hosts and environmental factors (Chugh et al., 2025). Culex mosquitoes, primarily Culex tritaeniorhynchus, serve as vectors, transmitting the virus between birds-such as egrets and herons, which act as natural reservoirs-and pigs, which function as amplifying hosts (Mulvey et al., 2021). Humans and horses are considered dead-end hosts, as they do not develop sufficient viremia to sustain onward transmission (Chugh et al., 2025). Furthermore, climate change, intensified agricultural practices, and environmental modificationshave contributed to the continued geographical expansion of JEV (Chugh et al., 2025). For instance, in March 2022, an outbreak was reported in temperate southeastern Australia, whereas previously JEV had been documented only in localized outbreaks in the tropical northeastern part of the country (Reyes et al., 2025).

West Nile virus, a member of the Japanese encephalitis serocomplex (JES), which was first isolated from the blood of an African febrile woman in 1937, is currently among the most widespread vector-borne flaviviruses in the world (Smithburn et al., 1940; Petersen et al., 2013; Giesen et al., 2023). Approximately 80% of patients with WNV infection are asymptomatic, 20% develop West Nile fever (WNF), and less than 1% develop West Nile neuroinvasive disease (WNND), including syndromes of meningitis, encephalitis, and acute flaccid paralysis (AFP)/poliomyelitis (Davis et al., 2006). The WNV is maintained in nature through a transmission cycle involving avian hosts and ornithophilic mosquito vectors (Martín-Acebes and Saiz, 2012). Humans and horses are considered accidental, dead-end hosts, as they typically do not develop sufficient viremia to sustain viral transmission, and primary WNV vectors predominantly feed on birds (Saiz et al., 2021). Therefore, reducing mosquito density and preventing human exposure to mosquito bites remain crucial strategies for interrupting WNV transmission (Singh et al., 2025). Nevretheless, accumulating evidence indicates that rising temperatures have enhanced mosquito vector activity, thus expanding the transmission range of WNV (Singh et al., 2025).

DENVs include four serotypes, DENV-1, DENV-2, DENV-3 and DENV-4, all of which can induce dengue, which is highly prevalent in tropical and subtropical climates, with an estimated 100–400 million new infections annually (Kularatne and Dalugama, 2022). The clinical manifestations of dengue range widely from symptomless infection to dengue fever (DF), DHF and DSS, the latter two of which are more severe and potentially life-threatening (Murphy and Whitehead, 2011). Unlike JEV and WNV, DENV infection in humans produces high-level viremia that allows the virus to pass efficiently between mosquito vectors and people, forming a “human-mosquito-human” transmission loop that sustains its continuous prevalence (Whitehead et al., 2007). In this cycle, Aedes aegypti plays the main role, while Aedes albopictus serves as the auxiliary vector.

Moreover, numerous studies have indicated that a distinct seasonal pattern in DENV outbreaks. In Guangdong, China’s most dengue-affected province, outbreaks consistently peak between July and October each year (Cui et al., 2022). Similarly, in Bangladesh, transmission intensifies from June to August (Hasan et al., 2024). These seasonal surges are largely precipitation-driven, as heavy rainfall creates extensive mosquito breeding sites and accelerates DENV transmission.

The first recorded outbreak of DENV can be traced back to 1779, after which recurrent epidemics have occurred across the Americas, Africa, and Asia (Roy and Bhattacharjee, 2021). In 2024, DENV continued its global expansion, with over 14.6 million reported cases reported. Currently, it is further spreading to new regions such as European and Eastern Mediterranean.

Yellow fever caused by the yellow fever virus is endemic to tropical regions of Africa and Central and South America, with symptoms ranging from asymptomatic infection to mild illness, fever with jaundice or hemorrhage and death (Garske et al., 2014). There are three main transmission cycles. In the jungle (sylvatic) cycle, YFV is transmitted between non-human primates and mosquitoes. The former serve as the principal reservoirs and amplifying hosts, while the latter act as vectors (Garcia-Oliveira et al., 2023). Furthermore, humans are accidental hosts who can be infected upon entering the jungle. In the urban cycle, the transmission of YFV occurs between humans and mosquitoes. Additionally, in Africa, there exists an intermediate (savannah) cycle in which YFV is transmitted from monkeys to mosquitoes and then to people who live or work in forest-border areas.

Historically, YFV has been responsible for multiple large-scale epidemics over the past few centuries. In 1793, a major yellow fever outbreak in Philadelphia resulted in approximately 4,000 deaths within 3 months, representing nearly 10% of the city’s population at the time (estimated at 55,000) (Rodhain, 2022). Another severe epidemic in the United States in 1878 caused more than 74,000 cases and 16,000 deaths (Rodhain, 2022).

ZIKV was first isolated from a rhesus monkey with fever in 1947 in Uganda (Dick et al., 1952). Before 2007, only sporadic human cases had been reported in countries across Africa and Asia (Hennessey et al., 2016). In 2007, the Zika spread to Yap Island in the Federated States of Micronesia, causing the first documented outbreak; approximately three-quarters of the population was infected, with most cases presenting only mild symptoms, and no reported fatalities (Duffy et al., 2009). Between 2013 and 2014, an outbreak occurred in French Polynesia, a where a subsequent case-control study provided the first evidence linking ZIKV infection to Guillain-Barré syndrome (Cao-Lormeau et al., 2016). In 2015, Brazil reported its first cases of autochthonous Zika transmission, after which the virus spread extensively throughout the Americas (Zanluca et al., 2015; Relich and Loeffelholz, 2017). That same year, in November, the Brazilian Ministry of Health noted an increase in microcephaly among newborns, a rise that coincided geographically and temporally with the ZIKV outbreak (Marrs et al., 2016). Subsequently, accumulating evidence has demonstrated the association between microcephaly and ZIKV infection. From September 2015 to April 2017, Colombia recorded 19,935 suspected ZIKV infections in pregnant women, of whom 157 were associated with neonatal microcephaly (Mattar et al., 2017). In one reported case, a 34-year-old woman exhibited ZIKV symptoms at 19 weeks of gestation; fetal ultrasound revealed multiple abnormalities, including ventriculomegaly and reduced cerebellar volume, and postnatal head CT confirmed microcephaly with intracranial calcifications. In Brazil, the prevalence of microcephaly has been largly attributed to congenital ZIKV infection (De Araújo et al., 2016). Among 87 infants diagnosed with congenital Zika syndrome (CZS) based on abnormal neuroimaging and positive ZIKV-specific IgM in cerebrospinal fluid, 66 of their mothers reported symptoms of ZIKV infection during pregnancy (Meneses et al., 2017). In the United States, 11% of fetuses or infants born to women infected with ZIKV during early pregnancy developed ZIKV-associated birth defects, such as microcephaly accompanied by intracranial calcifications (Honein et al., 2017).

Kyasanur Forest disease virus (KFDV) was first discovered in 1957 in the Kyasanur Forest of Shimoga District, Karnataka State, India, following an outbreak that cause significant mortality in two local monkey species (Mehla et al., 2009). The primary vector of KFDV is the hard tick Haemaphysalis spinagera (N et al., 2024). Small mammals such as rodents act as amplifying hosts, while larger mammals serve as maintenance hosts. Human infections occur predominantly through tick bites in forested areas with high tick density (N et al., 2024).

The clinical manifestations of Kyasanur Forest disease are typically biphasic. The initial phase is characterized by sudden onset of high fever with chills, accompanied by symptoms such as myalgia, headache, gastrointestinal disturbances, conjunctival congestion, lymphadenopathy, and hepatosplenomegaly (Gupta et al., 2022). Approximately 82%–88% of recovre after this phase, the remaining 12%–18% progress to a second phase characterized by recurrent fever and neurological manifestations (Gupta et al., 2022).

Major human outbreaks were recorded in 1957–1958 (681 cases), 1983–1984 (2,589 cases), 2002–2003 (1,562 cases), and 2016–2017 (809 cases) (Chakraborty et al., 2019). Until 2011, KFDV was restricted to southern India. However, surveillance in 2016 confirmed its geographic expansion into new areas along the Western Ghats, including parts of Karnataka, Tamil Nadu, Kerala, Goa, and Maharashtra.

Tick-borne encephalitis virus (TBEV) is endemic across parts of Europe and Asia. Human infection occur through the bite of infected ticks, mainly Ixodes ricinus and Ixodes persulcatu, leading to tick-borne encephalitis (TBE).

Mostly TBEV infection are asymptomatic. Symptomatic cases may follow either a monophasic or a biphasic clinical course (Kwasnik et al., 2023). He initial phase typically presents with non-specific influenza-like symptoms such as fever, headache, and myalgia. In biphasic cases, a second phase may follow, characterized by neurological signs of encephalitis (Kwasnik et al., 2023). TBEV is classified into three subtypes: European, Siberian, and Far-Eastern. The Far-Eastern subtype generally causes a severe monophasic illness, whereas the European subtype typically exhibits a biphasic progression (Mansfield et al., 2009).

Omsk Hemorrhagic Fever (OHF) is endemic in certain areas of Siberia. The principal vectors of Omsk Hemorrhagic Fever Virus (OHFV) are ticks–Dermacentor reticulatus, Dermacentor marginatus and Ixodes persulcatus–with muskrats and local voles serving as reservoir hosts (Diani et al., 2025). Human infection occurs mainly via the bite of an infected tick. Incidence peaks between May and June, correlating with the seasonal activity of Dermacentor reticulatus (Diani et al., 2025). Clinical manifestations can include fever, headache, myalgia, and cough, and may progress to hemorrhagic symptoms or meningitis (Diani et al., 2025).

Human cases of Saint Louis encephalitis virus (SLEV) infection are reported almost exclusively in the United States. SLEV is maintained in an enzootic mosquito-bird transmission cycle, and humans are incidental hosts infected through mosquito bites. The peak transmission period occurs from late summer to early autumn (Ardakani et al., 2024). While most infections are asymptomatic, some individuals develop influenza-like illness; a small proportion progress to neuroinvasive disease, presenting as encephalitis or meningitis (Ardakani et al., 2024).

Interferons (IFNs), first discovered in 1957, are a group of cytokines that are responsible for antiviral, antitumor and immune regulation (Isaacs and Lindenmann, 1957; Borden et al., 2007). On the basis of their structural features, receptor usage and biological activities, IFNs are grouped into three types: I, II and III (Donnelly and Kotenko, 2010). In humans and mice, type I IFNs include IFN-α, β, ε, κ, ω (humans) and ζ (mice), which bind to and signal through IFNAR, a ubiquitously expressed heterodimeric transmembrane receptor consisting of the IFNAR1 and IFNAR2 subunits (Lazear et al., 2019). In addition, IFN-β can signal through IFNAR1 alone and regulate unique gene expression via non-JAK-STAT-mediated pathway(s) (De Weerd et al., 2013). In contrast, type II IFNs include only IFN-γ, which binds to and signals through the IFNGR complex composed of IFNGR1 and IFNGR2 (Chow and Gale, 2015). In humans, type III IFNs include IFN-λ1 (IL-29), IFN-λ2 (IL-28A), IFN-λ3 (IL-28B) and IFN-λ4, whereas in mice, type III IFNs include only IFN-λ2 and IFN-λ3. All type III IFNs signal through a common heterodimeric receptor known as IFNLR, which consists of IFNLR1 (IL-28Rα) and IL-10R2 (IL-10Rβ) (Lazear et al., 2019). In contrast to ubiquitously expressed IFNAR, IFNLR is expressed preferentially on epithelial cells and neutrophils (Lazear et al., 2019). Specifically, the expression of IL-10R2 is widespread, whereas the expression of IFNLR1, which is associated with the response to IFN III, is confined to epithelial cells, subsets of myeloid cells, and certain neuronal cells (Chow and Gale, 2015; Sommereyns et al., 2008). This expression pattern results in nearly all cells responding to type I IFNs, whereas only a limited subset of cells responds to type III IFNs (Odendall and Kagan, 2015). Consequently, type I IFNs are responsible for establishing a systemic antiviral state, whereas type III IFNs control infection mainly at barriers, including the respiratory and gastrointestinal tracts, the blood-brain barrier (BBB) and placental trophoblasts (Wells and Coyne, 2018). In this review, we concentrate on the antiviral functions of type I and III IFNs at the BBB and placental barrier.

Pattern recognition receptors (PRRs), which recognize pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), along with their associated signalling pathways, constitute a large part of the innate immune system (Carty et al., 2021; Wicherska-Pawłowska et al., 2021). PRRs include Toll-like receptors (TLRs), retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), NOD-like receptors (NLRs) and cytosolic DNA sensors such as cyclic GMP-AMP synthase (cGAS) (Cao, 2016) (Figure 2). TLRs recognize double-stranded RNA (dsRNA), single-stranded RNA (ssRNA) or unmethylated CpG DNA (Onomoto et al., 2021). While RLRs sense viral RNA in the cytoplasm, cGAS is a DNA sensor (Kim and Song, 2022; Sun et al., 2013). Generally, RNA viruses are detected in the endosomal compartment by TLRs or in the cytoplasm by RLRs (Park and Iwasaki, 2020). Once PAMPs are sensed, PRRs trigger a signalling cascade that results in the production of IFNs, inflammatory cytokines and chemokines to establish an immune response (Gürtler and Bowie, 2013).

All IFNs signal through the JAK/STAT pathway (Chow and Gale, 2015) (Figure 2). Typically, the binding of type I and III IFNs to their respective receptors activates JAK1 and TYK2, resulting in STAT1-2 heterodimerization and interferon-stimulated gene factor 3 (ISGF3) formation (Chow and Gale, 2015). Activated ISGF3 translocates to the nucleus and binds to IFN-stimulated response elements (ISREs) to induce the transcription of ISGs (Schoggins, 2019). ISG effectors target different steps in the viral replication cycle, including viral entry, viral genome nuclear import, viral gene or protein synthesis, viral genome replication, and virion assembly/egression, to perform antiviral functions (Schoggins, 2019).

The placental barrier is a specialized biological interface separating maternal and fetal circulations. It is consists of a multilayered membrane structure comprising diverse cellular components derived from both maternal and fetal tissues (Arumugasaamy et al., 2020; Levkovitz et al., 2013). Maternal contributions include decidual stromal cells, whereas fetal-derived populations include trophoblast lineages (villous cytotrophoblasts [VCTs], syncytiotrophoblasts [STBs], extravillous trophoblasts [EVTs], and trophoblast giant cells [TGCs]) alongside nontrophoblastic cells such as Hofbauer macrophages and fetal endothelial cells (Arumugasaamy et al., 2020). This dynamic interface acts as a bidirectional regulatory system, coordinating nutrient transport, hormone synthesis, and growth factor secretion essential for fetal development, while also facilitating waste elimination and limiting fetal exposure to xenobiotics (Arumugasaamy et al., 2020). Beyond its metabolic and protective functions, the placenta serves as a critical immunological sentinel, deploying multiple defence mechanisms against microbial invasion. However, certain pathogens, collectively referred to as TORCH agents (including Toxoplasma gondii, rubella virus, cytomegalovirus, herpes simplex virus, syphilis, Zika virus, Plasmodium spp., and HIV), have evolved strategies to bypass these defences, often resulting in severe congenital infections that can lead to fetal demise or lifelong morbidity (Lynn et al., 2023). The mechanisms by which flaviviruses traverse the placental barrier have been extensively studied (Figure 5).

The BBB is a physical barrier in the CNS that separates the CNS parenchyma from the peripheral blood, thereby maintaining the normal physiology of the brain. However, the BBB is not a single physical structure but rather represents the comprehensive effect of various physiological characteristics possessed by endothelial cells (ECs), which collectively restrict vascular permeability (Profaci et al., 2020). Specifically, the restricted paracellular permeability of the capillary EC layer is achieved through adherens junctions (AJs) and tight junctions (TJs) (Erdő et al., 2017). AJs maintain adhesion between ECs and are composed of two transmembrane components: cadherins and nectins (Campbell et al., 2017). In adjacent cells, cadherins bind to each other, and the cytoplasmic tail of cadherin recruits β-catenin, which binds to α-catenin (Campbell et al., 2017). Similarly, the cytoplasmic tail of nectin recruits afadin, while the extracellular regions dimerize with those on neighboring cells (Campbell et al., 2017). In ECs, the most apical intercellular junctions are the TJs (Erdő et al., 2017). TJs have two functions, which are supposed to be mutually exclusive (Hartsock and Nelson, 2008). One is the barrier or gate function, which controls the paracellular passage of ions, water and macromolecules (Campbell et al., 2017; Hartsock and Nelson, 2008). Another is the fence function, which restricts lipid distribution within the membrane to establish and maintain cell polarity (Campbell et al., 2017). TJs are composed of claudins, occludin, ZO proteins and junctional adhesion molecules (JAMs) (Campbell et al., 2017). In addition to ECs, the cellular components of the BBB include pericytes, astrocytes, microglia, and neurons. The interaction between ECs and these cells is typically known as the neurovascular unit (NVU) (Profaci et al., 2020). In addition to its cellular components, the BBB consists of the extracellular matrix and basal lamina, which serve as part of the protective system (Erdő et al., 2017). Despite the protective role of the intact BBB in safeguarding the CNS against viral infections, certain ortho-flaviviruses can traverse the BBB via diverse mechanisms, thereby infecting neurons and inducing a spectrum of manifestations (Figure 6).