La Crosse Virus: A Comprehensive Review of Its Emerging Public Health Importance

Introduction

The Bunyavirales order represents one of the largest groups of arboviruses, encompassing over 300 known viruses, many of which are pathogenic to humans. In recent years, this order has seen an increasing number of important emerging and reemerging viruses (Boshra, 2022). Within this order, the family Peribunyaviridae is classified into seven genera: Orthobunyavirus, Herbevirus, Pacuvirus, Shangavirus, Khurdivirus, Lakivirus, and Lambavirus (Hughes et al., 2020). These genera are further divided into various serogroups, with LACV belonging to the California serogroup (CSG) within the genus Orthobunyavirus (Beaty and Calisher, 1991). The CSG viruses are phylogenetically categorized into three distinct groups: the California encephalitis virus (CEV) group, the Melao virus (MELV) group, and the Trivittatus virus (TVTV) group, with LACV being part of the CEV group. Phylogenetic studies have shown that LACV is most closely related to Snowshoe hare virus (SSHV) and Chatanga virus (CHATV) (Hughes et al., 2017; Rogers et al., 2017). Like all bunyaviruses, LACV has a single-stranded, negative-sense RNA genome divided into three segments that encode proteins crucial for viral replication and pathogenesis (Elliott, 1990).

Currently, 18 CSG members are recognized based on serological and genetic evidence, eight of which have been linked to human disease. Of these seven viruses, including LACV, are known to cause neuroinvasive diseases. The remaining virus, Keystone virus (KEYV), does not affect the central nervous system and has been associated with a single case of febrile illness and diffuse rash (Lednicky et al., 2019; Putkuri et al., 2016; Thompson et al., 1965). In the United States, LACV is the leading cause of neuroinvasive disease among CSG viruses, with an estimated 30 to 90 cases of LACV neuroinvasive disease reported annually (Prevention CfDCa, 2024). The vast majority of these cases occur in children (Davis et al., 2024; Day et al., 2024). LACV’s transmission cycle mirrors that of other mosquito-borne viruses, involving mosquitoes as vectors and vertebrate hosts as reservoirs. Mosquitoes acquire the virus from infected animals and subsequently transmit it to humans through their bites (Borucki et al., 2002). Global climate change and land use modifications are expanding the ranges of mosquito vectors, leading to the emergence of new vectors and overlapping geographic ranges of viruses (Goldman and Hamer, 2024). This increases the potential for genome reordering and viral cross-infection (Bara and Muturi, 2014; Leisnham and Juliano, 2012). In addition, asymptomatic or mildly symptomatic cases often go unnoticed and unreported, and deficiencies in diagnostic tests complicate the determination of LACV prevalence and incidence (Boutzoukas et al., 2023).

This review aims to provide a comprehensive overview of current knowledge on LACV, including its molecular structure, transmission and geographic distribution, clinical manifestations, and neuropathology, as well as diagnosis, treatment, and prevention strategies. Understanding these aspects is crucial for better prevention and control of LACV to mitigate its impact on public health.

Gene Structure and Replication

LACV features a tri-segmented RNA genome encapsidated by the nucleocapsid (N) protein to form ribonucleoprotein (RNP) complexes, which include the large (L), medium (M), and small (S) segments. The L segment encodes the RNA-dependent RNA polymerase, responsible for both replication and transcription of the viral genome. The M segment encodes a polyprotein that is posttranslationally processed into the nonstructural protein NSm and the glycoproteins Gc and Gn. The N-terminus of the NSm protein is essential for virus assembly, though its further functions remain unclear. The glycoproteins Gc and Gn facilitate virus entry into host cells. The extracellular domain of the Gc glycoprotein can form oligomers and undergo pH-dependent conformational changes, which are critical for virus-host interactions and membrane fusion (Pekosz and González-Scarano, 1996). The S segment encodes the nucleocapsid protein (N) and a nonstructural protein (NSs). The N protein forms the viral capsid and protects the RNA genome. Advances in reverse genetic systems have deepened our understanding of LACV molecular biology, particularly the role of nonstructural proteins (Blakqori and Weber, 2005). The NSs protein, while not essential for viral replication, contributes to virus-host interactions and pathogenicity (Bridgen et al., 2001; Hart et al., 2009). LACV lacking NSs exhibits reduced growth rates and diminished capacity to inhibit protein synthesis in mammalian cells compared to wild-type LACV (Bridgen et al., 2001). Moreover, the NSs protein counteracts short interfering RNA, a key component of the host antiviral defense. Overexpression of LACV NSs in 293T cells has been shown to inhibit RNA interference (RNAi) (Blakqori and Weber, 2005). In addition, LACV NSs proteins play a critical role in evading host immune responses by inhibiting interferon production (Blakqori et al., 2007). Recent studies have revealed that NSs trigger interferon induction via the retinoic acid-inducible gene-I (RIG-I) pathway and activate interferon regulatory factor 3 (IRF-3), which uses the DNA damage response pathway to degrade RNA polymerase II and inhibit interferon transcription (Verbruggen et al., 2011). Furthermore, NSs proteins interact with the apoptosis-regulating protein Scythe, promoting apoptosis in infected cells (Colón-Ramos et al., 2003).

LACV replication follows typical Bunyavirus patterns. Upon host cell attachment, LACV enters via reticulin-mediated endocytosis (Hollidge et al., 2012). Virus replication begins when LACV reaches the cytoplasm. In early endosomes, pH changes induce conformational shifts in envelope proteins mediated by Gc fusion peptides, facilitating the release of RNPs into the cytoplasm (Plassmeyer et al., 2005). The RNA-dependent RNA polymerase (RdRp) exhibits primer-stimulated RNA polymerase activity for viral mRNA synthesis and cap-dependent endonuclease activity, cleaving host-capped primers from host mRNA to initiate transcription (Arragain et al., 2020). LACV transcription must be synchronized with host translation to prevent premature termination by RdRp, which can lead to mRNAs lacking poly(A) tails (Barr, 2007). Newly synthesized viral genomes and proteins are assembled in the cytoplasm into new viral particles, which bud from the infected cell and spread to other cells. Glycoproteins Gc and Gn are synthesized in the endoplasmic reticulum, processed and modified in the Golgi apparatus, and then inserted into the host cell membrane. They eventually bud with the encapsidated genome to form new virions (Salanueva et al., 2003; Shi et al., 2007). In summary, LACV replication involves a complex series of processes, underscoring the importance of understanding the structure and function of its various proteins for future research.

Transmission Mode and Factors Affecting Transmission

LACV is primarily transmitted to humans and animals through the bite of Aedes triseriatus. Research indicates that Ae. triseriatus is a competent vector for LACV, as it can both acquire the virus from an infected host and transmit it to a new host (Paulson and Grimstad, 1989). Additionally, LACV has been detected in other Aedes species, such as Ae. albopictus and Ae. japonicus, suggesting a potential for broader vector diversity (Sardelis et al., 2002; Westby et al., 2015). The primary transmission hosts of LACV are small mammals such as chipmunks and squirrels (Patrican et al., 1985b; Thompson and Beaty, 1977). Humans, however, are considered “dead-end” hosts because they do not produce a sufficient viral load to continue transmitting the virus. While oral transmission is often the primary mode for the rapid spread of mosquito-borne diseases, other methods such as venereal and transovarial transmission also play significant roles in the persistence and maintenance of these diseases in ecosystems (Fig. 1). Transovarial transmission is particularly important for the persistence of LACV in nature, allowing the virus to remain in mosquito populations and environments even under unfavorable conditions (Darby et al., 2023; Watts et al., 1973). This mode of transmission enables the virus to bypass the need for an external host, which is crucial for its survival when suitable hosts are scarce. Additionally, venereal transmission of LACV has been reported in Ae. triseriatus mosquitoes, providing another route for the virus to spread within mosquito populations (Thompson and Beaty, 1977). Although less common, this mode of transmission can introduce the virus into new mosquito populations or help maintain it in areas where oral transmission is less prevalent. Understanding these diverse transmission methods is essential for developing comprehensive disease control strategies.

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FIG. 1.

La Crosse virus natural cycle.

The dissemination of LACV is significantly influenced by external factors such as climate change, land use, and biological interactions (Fig. 2) (Leisnham and Juliano, 2012). LACV transmission tends to peak during warmer months due to increased mosquito activity (Harding et al., 2018). Research has assessed the capability of various mosquitoes to transmit LACV, with Ae. triseriatus and Ae. albopictus being prime subjects due to their geographic distribution and ecological niches (Hughes et al., 2006; Westby et al., 2015). Mosquito larvae require specific temperature ranges for development. Ae. albopictus generally needs higher temperatures compared to Ae. triseriatus to complete larval development (Teng and Apperson, 2000). Current climatic conditions are restricting the northern distribution of Ae. albopictus, but climate models suggest that by 2040, the species might establish itself in southern Canada (Lowe et al., 2021). Climate warming is projected to increase average temperatures and result in milder winters across much of North America (Estrada et al., 2013). Winter temperatures in the northeastern United States are expected to rise by 1.7°C to 5.4°C this century, which may promote the northward spread of Aedes mosquitoes (Hayhoe et al., 2007). However, while winter temperature is important, it alone may not define the range of Ae. albopictus (Rochlin et al., 2013). Research indicates that appropriate snowfall and rainfall can enhance the number of Ae. albopictus (Alto and Juliano, 2001; Rochlin et al., 2013). A recent study evaluated Ae. albopictus’s climate adaptability in North America by analyzing three climate indicators: wintering conditions (OW), a combination of OW and annual temperature, and a linear index of precipitation and temperature suitability (SIG) (Ogden et al., 2014). Nonetheless, due to uncertainties about which climate indicator best predicts adaptability, further field research is needed. Land use changes, such as the conversion of forests into peripheral habitats, can increase the number of artificial water storage containers, which are insulated from cold temperatures and thus enhance the overwintering success of warm-loving mosquitoes like Ae. albopictus (Tamini et al., 2021). Ae. triseriatus mosquitoes, which prefer to inhabit tree cavities, might have expanded into the Appalachian region due to human encroachment into hardwood forests, potentially spreading LACV (Day et al., 2023). Competition, predation, and parasitism also influence the role of mosquito vectors in disease transmission. Mosquito species often compete for survival within the same habitat. Although laboratory and field studies suggest that Ae. albopictus outcompetes Ae. triseriatus for resources, evidence of competitive exclusion is limited (Bevins, 2008; Juliano and Lounibos, 2005). Common parasitoids, Ascogregarina taiwanensis and Ascogregarina barretti, target Ae. albopictus and Ae. triseriatus, respectively, shifting the competitive balance between these species (Tseng, 2007). Generally, Ae. albopictus has a competitive advantage over Ae. triseriatus, but increased parasitism by Ascogregarina taiwanensis can reduce this edge, improving the survival rates of Ae. triseriatus (Stump et al., 2021). In addition, heightened parasitism of Ae. triseriatus might increase the proportion of Ae. albopictus in the population, although its effect on overall ecological dynamics appears minimal. Predation also plays a significant role in regulating mosquito populations. Ae. triseriatus larvae prey on newly hatched Ae. albopictus larvae, while the latter are less susceptible to such predation (Edgerly et al., 1999). In addition to intraguild predation, top-down predation by major predators such as Toxorhynchites rutilus and Corethrella appendiculata in forested areas can limit the spread of Ae. albopictus. Habitat loss may reduce predation pressure, potentially facilitating the spread of Ae. albopictus (Kesavaraju et al., 2008; Kesavaraju and Juliano, 2004; Lounibos et al., 2001).

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FIG. 2.

Factors affecting mosquito vector transmission.

Several intrinsic factors of mosquitoes significantly impact the transmission of LACV (Fig. 2). Firstly, the nutritional status of mosquito larvae can affect both the susceptibility of adult mosquitoes to LACV infection and their ability to transmit the virus (Grimstad and Walker, 1991). Generally, nutritional deprivation in Ae. triseriatus larvae leads to notable changes in their transmission capabilities, with smaller females transmitting LACV at significantly higher rates compared to larger females (Grimstad and Haramis, 1984; Patrican et al., 1985a). Further research suggests that nutritional deficiencies can cause thinning of the intestinal basement membrane, which facilitates a faster release of LACV into the blood cavity, thereby enhancing the vectorial capacity of the mosquito (Grimstad and Walker, 1991). Secondly, genetic factors in mosquitoes also influence their ability to transmit LACV. Specifically, the eastern tree-hole mosquito, Aedes triseriatus, possesses quantitative trait loci that regulate its capacity for LACV transoviposition (Graham et al., 2003). In addition, the level of viremia in the host affects the likelihood of virus transmission. Experimental evidence shows that chipmunks with viremia levels exceeding 3.2 log10 SMICLD50/0.025 mL are more likely to transmit LACV to over 50% of Ae. triseriatus mosquitoes (Patrican et al., 1985b). Moreover, while white-tailed deer are a primary blood source for Ae. triseriatus, high prevalence of JC antibodies in deer populations may antagonize LACV transmission (Osorio et al., 1996). Considering these factors is crucial for developing disease control strategies that address the multifaceted nature of LACV transmission. Such strategies should incorporate ecological, environmental, and human dimensions to ensure a comprehensive approach.

Geographic Distribution and Phylogenetic Analysis

Since the first isolation of LACV in the 1960s, the majority of reported neuroinvasive diseases caused by LACV have been historically associated with the Midwestern United States (Thompson et al., 1965). However, human infections with LACV have also been reported in the Eastern United States (Vahey et al., 2021). In the 1990s, the disease emerged in the Appalachian region. By the early 2000s, the states with the highest average annual incidence rates were West Virginia, eastern Tennessee, western North Carolina, and central and southern Ohio (Harding et al., 2018). A study revealed that between 2003 and 2012, nearly 81 percent of pediatric cases of La Crosse virus occurred in Ohio, North Carolina, West Virginia, and Tennessee (Byrd, 2016). Interestingly, human seropositivity rates can vary widely between counties and even communities, suggesting that endemicity may be highly localized (Vahey et al., 2021). To date, LACV has only been identified in the United States, likely due to the limited presence of suitable mosquito vectors (Harding et al., 2018). However, as LACV-carrying mosquito species may expand northward, it is anticipated that LACV could be found in Canada and other parts of the Americas (Drebot, 2015; Ogden et al., 2014).

In our study, we collected and analyzed the complete genome sequences of all reported LACV and related CSG representative members using MEGA 5.1. Pairwise distance analysis indicated that the known LACV sequences shared 86.47–99.69% nucleotide identity and had >95.98% amino acid identity with each other, suggesting that LACV viruses are evolutionarily conserved (Putkuri et al., 2014). In addition, most LACV strains were closely related to SSHV and CHATV, with amino acid sequence similarities exceeding 86.69% and 79.35%, respectively, demonstrating a close evolutionary relationship among these viruses.

Phylogenetic trees were constructed using a neighbor-joining (NJ) approach based on the amino acid sequences of LACV, along with corresponding CSG sequences retrieved from GenBank (Fig. 3). Phylogenetic trees based on three segments revealed that all LACV-related sequences could be roughly divided into three major phylogenetic groups (Evans and Peterson, 2019). The Trivittatus virus belongs to the TVTV group. All LACV strains clustered with Lumbo virus, San Angelo virus, Tahyna virus, California encephalitis virus, Chatanga virus, and Snowshoe hare virus, forming the CEV group. In contrast, Melao virus, Serra do Navio virus, KEYV, South River virus, Jerry Slough virus, Jamestown Canyon virus, and Inkoo virus formed the MELV group. The figure illustrates that while LACV is generally evolutionarily conserved, some variation exists among LACV strains isolated in different years within the same region of the United States. Although current evidence does not suggest extensive recent recombination events, the phylogenetic analysis opens the possibility of potential recombination in LACV segments in the future. This insight is valuable for monitoring LACV evolution and understanding its implications for disease emergence and vector control strategies.

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FIG. 3.

Phylogenetic analysis of the amino acid sequences of representative LACV and other CSG members. (A) segment L, (B) segment M, and (C) segment S encoding nucleoprotein. The LACV sequences in the current study were marked black with a rhombus. The phylogenetic trees were constructed via the NJ method using MEGA 5.1, with 1,000 replicates and bootstrap values of 70% being regarded as significant. The numbers above the branches indicate the bootstrap values.

Clinical Manifestations and Neuropathogenesis

LACV infections are frequently asymptomatic or result in only mild febrile illness. However, in some cases, particularly among children, LACV can progress to a severe neurological disorder known as La Crosse encephalitis. In severe cases, particularly in children, the infection can lead to encephalitis characterized by seizures, coma, and focal neurological deficits (Ouellette, 2024). An electroencephalogram pattern known as periodic lateralized epileptiform discharges (PLEDs) has been associated with severe LACV infections and may indicate a more concerning subgroup of patients at higher risk for long-term neurological outcomes (de los Reyes et al., 2008). Children with La Crosse virus encephalitis complicated by PLEDs tend to experience more severe disease and potentially worse prognoses. PLEDs typically occur during the acute phase of the disease, with 60% of cases appearing within the first 2 days following a clinical seizure (Snodgrass et al., 1989). A study of 127 patients with La Crosse encephalitis admitted from 1987 to 1996 found that the average duration of hospitalization was 6 days, with fever onset usually occurring on the third day of hospitalization (McJunkin et al., 2001). Although less common, LACV infection in adults has also been documented. In a case series, adults with La Crosse encephalitis presented with symptoms such as fever, headache, nausea, vomiting, and altered mental status. Some patients also exhibited neurological signs, including tremors, nystagmus, and cranial nerve palsies (Teleron et al., 2016). While the overall mortality rate for La Crosse encephalitis is less than 1%, survivors may face long-term effects such as seizures, cognitive impairment, poor academic performance, attention deficit hyperactivity disorder, personality disorders, and delayed neuromotor development (Balkhy and Schreiber, 2000; Byrd, 2016; Haddow and Haddow, 2009; McJunkin et al., 2011). In addition, LACV infection has been associated with acute flaccid paralysis, a polio-like illness characterized by sudden limb weakness (Hennessey et al., 2017).

The neuropathogenesis of LACV and other California serogroup orthobunyaviruses is not fully understood but is thought to involve direct viral invasion of the central nervous system (CNS), immune-mediated damage, and disruption of the blood–brain barrier (BBB) (Evans and Peterson, 2019). Studies on the pathogenesis of neuroinvasive LACV infections have focused on the type I interferon (IFN) response. Correlative studies in mouse models have shown that mice lacking type I IFN receptor 1 are more susceptible to LACV-induced neurological disease compared with normal mice (Evans et al., 2019). LACV infection induces RIG-I to bind to mitochondrial antiviral signaling proteins (MAVS), which activates signaling molecules, such as IRF3, IRF7, and NF-κB, leading to type I interferon production. Defects in IRF3 and IRF7 are associated with an early onset of LACV-induced neurological disease (Taylor et al., 2014). The olfactory nerve has been proposed as a potential route for LACV and other viruses to access the CNS, which may explain the neurological symptoms observed in LACV infections (van Riel et al., 2015). Notably, LACV exhibits a particular tropism for neuronal cells, contributing to its neuroinvasive potential. Recent studies have shown that neuronal maturation reduces the type I interferon response to LACV infection, leading to increased apoptosis and exacerbated disease in human neurons (Winkler et al., 2019). In addition, LACV infects brain capillary endothelial cells, which are crucial for maintaining the BBB. It has been demonstrated that LACV enters the CNS through leakage from olfactory bulb capillaries, resulting in rupture of the BBB and allowing LACV to enter the brain via the hematogenous route (Winkler et al., 2015). Once in the CNS, LACV primarily infects neurons and induces the upregulation of Sarm1, which triggers a pro-inflammatory cytokine response, leading to neuronal damage, cell death, and subsequent neurological disorders (Mukherjee et al., 2013). The type and mechanism of cellular infiltrates in the brain may also be crucial for understanding the pathogenesis of LACV infection in the CNS. Recent studies suggest that LACV infections transmitted by insect bites can spread through human keratinocytes to other tissues and eventually reach the nervous system, causing disease (Westby et al., 2015). In addition, age affects the susceptibility of cerebral capillary endothelial cells to LACV infection and cell death, with younger cells showing higher susceptibility due to lower type I IFN production, which may partly explain the higher incidence of severe disease in children (Basu et al., 2021).

Diagnosis

Early and accurate diagnosis of LACV infection is crucial for effective patient care and public health intervention. Diagnosing LACV infection requires a combination of clinical presentation and laboratory testing. In patients suspected of having active viral replication, the diagnosis can be confirmed through direct serologic testing, detection of pathogen nucleic acids in affected tissues, or virus culture (Piantadosi and Kanjilal, 2020). Serologic diagnosis is the mainstay for detecting arboviruses. Since the 1990s, several serological tests have been used to diagnose LACV, including the IgM antibody capture enzyme-linked immunosorbent assay (MAC-ELISA), IgG ELISA, hemagglutination inhibition (HI), complement fixation assay (CF), neutralization tests (NT), and indirect fluorescent antibody tests (Calisher et al., 1986). A survey demonstrated that IgM antibodies were detected in 177 (96%) of 184 sera from LACV-infected patients using MAC-ELISA, highlighting the high sensitivity of this method for detecting LACV antibodies (Powers et al., 2023). Therefore, MAC-ELISA is the most commonly used first-line serologic surveillance method. It is a sensitive and specific assay that minimizes competition from IgG and reduces the risk of non-specific antibody binding (Martin et al., 2000). In addition, indirect fluorescent antibody (IFA) assays have proven useful for detecting antibodies in the acute phase of LACV infection. The IFA assay detects all antibody groups and is known for being a rapid, reliable, and sensitive test (Beaty et al., 1982). Recent advances have introduced the microsphere immunoassay (MIA) as a new generation of antibody testing methods (Basile et al., 2013; Johnson et al., 2007). Combining individual enzyme-linked immunosorbent assays with MIA allows for simultaneous detection of IgM and IgG, covering a broad range of arbovirus infections (Basile et al., 2013). Despite these advancements, LACV’s cross-reactivity necessitates validation with more specific methods such as the plaque reduction neutralization test (PRNT), HI, or CF to confirm results (Beaty et al., 1983).

For immunocompromised patients or cases with false-negative serology, molecular testing becomes crucial. Techniques such as nucleic acid sequence-based amplification and real-time RT-PCR offer rapid, highly sensitive detection of LACV RNA in mosquito pools and human tissues (Lambert et al., 2005). Furthermore, unbiased metagenomic next-generation sequencing (mNGS) is used when targeted diagnostics fail to identify the pathogen. mNGS can detect both DNA and RNA viruses and has successfully diagnosed various neuroinvasive viral infections, including West Nile virus, St. Louis encephalitis virus, and Powassan virus. It shows promise for diagnosing LACV infection (Ramachandran and Wilson, 2020). Viral culture is another method of detection, similar to PRNT, but requires a higher level of biosafety. However, it is rarely used due to the need for brain tissue biopsy or post-mortem examination (Piantadosi and Kanjilal, 2020).

Treatment

Currently, there are no specific antiviral drugs available for the direct treatment of LACV encephalitis. Consequently, treatment primarily focuses on supportive care to manage symptoms, including adequate rest, hydration, fever control, and pain and headache relief. Severely ill patients may require hospitalization for close monitoring and supportive care (McJunkin et al., 2001). Research is ongoing to develop antiviral drugs for LACV infection (Feracci et al., 2024). While several compounds have shown tentative efficacy against LACV, further research is needed to determine their potential clinical effects. Ribavirin, an antiviral drug, acts against LACV by inhibiting viral replication, enhancing the cellular antiviral response, and modulating the immune response (Cassidy and Patterson, 1989). It affects the RNA-dependent RNA polymerase activity of the LACV replication enzyme, inhibiting early stages of the replication cycle and demonstrating antiviral activity within 6 h of ingestion. Given these effects, intravenous ribavirin is currently under investigation in randomized clinical trials for severe LACV infections (McJunkin et al., 1997). A recent study highlighted that Baloxavir acid (BXA), a nucleic acid endonuclease inhibitor approved for influenza, inhibits Bunyavirus replication in vitro more effectively than ribavirin (Ter Horst et al., 2020). BXA increases the melting temperature of the LACV enzyme and binds to the LACV endonuclease, inhibiting substrate cleavage and demonstrating anti-LACV effects. In addition, BXA combined with ribavirin produced more potent antiviral effects. This suggests that designing efficient and selective nucleic acid endonuclease inhibitors could be a promising approach for anti-LACV drug development. An ideal therapy for LACV infection would inhibit viral activity in vivo without causing neuronal damage. Rottlerin treatment has been shown to significantly reduce viral replication and block the release of replicating virus from Golgi neurons, thereby reducing neuroinflammation and preventing encephalitis (Ojha et al., 2021). Despite its effectiveness in mice, reports on rottlerin crossing the BBB are lacking. However, the potential for rottlerin to cross the BBB, especially after LACV-induced vascular leakage, suggests it may have therapeutic potential for neuroinvasive LACV disease (Winkler et al., 2015). Moreover, targeting polyamine metabolism could be valuable in developing antiviral drugs (Mastrodomenico et al., 2019). Polyamines, present in mammalian cells, play a critical role in viral infection, replication, and reproduction. Depleting polyamines can lead to the formation of non-infectious viral particles, which disrupt replication and stimulate the innate immune response (Huang et al., 2020). Future research should explore whether virus particle-bound polyamines affect infectivity, offering insights into viral mechanisms and potential new therapies.

Interferon also plays a crucial role in resistance to LACV infection in children. Studies targeting interferon production mechanisms may enhance future treatments for childhood encephalitis. Research has shown that myeloid dendritic cells (mDCs) are age-dependent and crucial for protecting against LACV by promoting antiviral cytokine production and activating adaptive immune responses (Taylor et al., 2014). Although mDCs’ ability to produce type I interferons during LACV infection could not be directly detected in vivo, differences in type I interferon responses to Poly(I.C) were noted between juvenile and adult mice. Juvenile mice exhibit a significantly lower response due to fewer mDCs (Sorgeloos et al., 2013). Targeted delivery of pathogen recognition receptor ligands to activate mDCs could potentially protect young mice and offer a future therapeutic strategy for early childhood encephalitis virus infection.

Prevention

Strategies to prevent LACV infection primarily focus on vaccine development, personal protective measures, and vector control. These integrated strategies can reduce the risk of LACV transmission and infection, thus protecting public health. Vaccines are a crucial tool in preventing infectious diseases. Among the most promising approaches for preventing LACV infection is the development of DNA vaccines. Studies have demonstrated the creation of a new animal model for vaccine testing that is not age-dependent: genetically targeted mice lacking a functional interferon type I receptor (IFNAR-1) (Pavlovic et al., 2000). Immunization of IFNAR-1-deficient mice with DNA encoding LACV-specific glycoproteins Gc and Gn elicits an immune response reliant on CD4⁺ T cells and mediated by neutralizing antibodies. This response reduces viral replication and disease severity in the animal model (Schuh et al., 1999). In most experiments, 100% of the DNA-immunized defective mice survived without any clinical signs. DNA vaccines have the advantage of mimicking viral infection by expressing viral antigens in host cells. The development of other vaccines against LACV has not been reported, likely due to the lack of suitable animal models.

Personal protection is also vital in preventing LACV infection. Studies indicate that in LACV-endemic areas, younger age, high outdoor activity, and increased exposure to mosquito bites are associated with a higher likelihood of developing symptomatic LACV infections (Haddow and Odoi, 2009). Therefore, personal protective measures such as using mosquito repellents, wearing long-sleeved clothing, and covering exposed skin are essential to prevent LACV infections. In addition, vector control is a key measure in preventing the spread of LACV. Unlike other mosquito species, Ae. triseriatus larvae breed in tree holes and are most active during the daytime (Watts et al., 1974). Studies also show that Ae. triseriatus, similar to other LACV-transmitting mosquitoes like Ae. albopictus, breeds in man-made containers that collect rainwater, particularly discarded tires (Tamini et al., 2021). Individuals living near numerous such containers are at increased risk of disease. Therefore, reducing mosquito breeding sites by filling tree holes and removing man-made containers can help prevent LACV transmission (Hopkins et al., 2019). Biological control methods, such as introducing natural predators such as predatory insects or fish into breeding sites, can also help manage mosquito populations (Faw et al., 2023).

Monitoring and early warning systems, along with blood transfusion safety measures, also play crucial roles in preventing LACV. Monitoring mosquito populations, testing mosquitoes for the presence of the virus, and conducting epidemiological surveys can help identify areas at risk of infection and enhance public health emergency response capabilities (Trout Fryxell et al., 2022). Despite a multilayered approach to blood safety, the risk of transfusion-associated viral infections persists. Recent studies have shown that a photochemical treatment system using riboflavin and ultraviolet light to inactivate viruses in platelet and plasma products eliminates window-period transmission of screened viruses, prevents transmission of unscreened viruses via transfusion, and protects recipients from LACV infection (Keil et al., 2015).

Conclusions

The LACV remains a significant public health threat, primarily to pediatric populations in the United States. The variation in LACV susceptibility with age and the complex pathogenesis that causes LACV encephalitis highlight the importance of future research on LACV. There is good theoretical support for the possibility of a northward spread of LACV vectors due to climate change, but the specific spread of LACV vectors needs to be further substantiated. More advanced diagnostic techniques are needed to cope with more complex changes. The development of antiviral drugs, which are currently under constant research, still needs to pass clinical trials, and DNA vaccines against LACV have shown promise in animal models, but further development and testing are needed before human use can be considered.

In summary, given that LACV is already endemic in the north-central and eastern United States and is at risk of continuing to expand northward, it is imperative to continue and expand our research endeavors, focusing in real time on the dynamic distribution and pathogenesis of LACV and striving for innovative solutions to improve diagnostics, craft effective treatments, and enhance prevention measures.