Immunoglobulin Glycosylation - An Unexploited Potential for Immunomodulatory Strategies in Farm Animals.

The function of antibodies, namely the identification and neutralization of pathogens, is mediated by their antigen binding site (Fab). In contrast, the subsequent signal transduction for activation of the immune system is mediated by the fragment crystallizable (Fc) region, which interacts with receptors or other components of the immune system, such as the complement system. This aspect of binding and interaction is more precise, readjusted by covalently attached glycan structures close to the hinge region of immunoglobulins (Ig). This fine-tuning of Ig and its actual state of knowledge is the topic of this review. It describes the function of glycosylation at Ig in general and the associated changes due to corresponding glycan structures. We discuss the functionality of IgG glycosylation during different physiological statuses, like aging, lactation and pathophysiological processes. Further, we point out what is known to date about Ig glycosylation in farm animals and how new achievements in vaccination may contribute to improved animal welfare.

Susceptibility of Four Abalone Species, Haliotis gigantea, Haliotis discus discus, Haliotis discus hannai and Haliotis diversicolor, to Abalone asfa-like Virus.

Abalone amyotrophia is a viral disease that causes mass mortality of juvenile Haliotis discus and H. madaka. Although the cause of this disease has yet to be identified, we had previously postulated a novel virus with partial genome sequence similarity to that of African swine fever virus is the causative agent and proposed abalone asfa-like virus (AbALV) as a provisional name. In this study, three species of juvenile abalone (H. gigantea, H. discus discus, and H. diversicolor) and four species of adult abalone (the above three species plus H. discus hannai) were experimentally infected, and their susceptibility to AbALV was investigated by recording mortality, quantitatively determining viral load by PCR, and conducting immunohistological studies. In the infection test using 7-month-old animals, H. gigantea, which was previously reported to be insusceptible to the disease, showed multiplication of the virus to the same extent as in H. discus discus, resulting in mass mortality. H. discus discus at 7 months old showed abnormal cell masses, notches in the edge of the shell and brown pigmentation inside of the shell, which are histopathological and external features of this disease, while H. gigantea did not show any of these characteristics despite suffering high mortality. Adult abalones had low mortality and viral replication in all species; however, all three species, except H. diversicolor, became carriers of the virus. In immunohistological observations, cells positive for viral antigens were detected predominantly in the gills of juvenile H. discus discus and H. gigantea, and mass mortality was observed in these species. In H. diversicolor, neither juvenile nor adult mortality from infection occurred, and the AbALV genome was not increased by experimental infection through cohabitation or injection. Our results suggest that H. gigantea, H. discus discus and H. discus hannai are susceptible to AbALV, while H. diversicolor is not. These results confirmed that AbALV is the etiological agent of abalone amyotrophia.

Exchange of C-Terminal Variable Sequences within Morbillivirus Nucleocapsid Protein Are Tolerated: Development and Evaluation of Two Marker (DIVA) Vaccines (Sungri/96 DIVA, Nigeria/75/1 DIVA) against PPR.

Across Africa, the Middle East, and Asia, peste des petits ruminants virus (PPRV) places a huge disease burden on agriculture, affecting, in particular, small ruminant production. The recent PPR outbreaks in Northern Africa, the European part of Turkey, and Bulgaria represent a significant threat to mainland Europe, as a source of disease. Although two safe and efficacious live attenuated vaccines (Sungri/96 and Nigeria/75/1) are available for the control of PPR, current serological tests do not enable the differentiation between naturally infected and vaccinated animals (DIVA). The vaccinated animals develop a full range of immune responses to viral proteins and, therefore, cannot be distinguished serologically from those that have recovered from a natural infection. This poses a serious problem for the post-vaccinal sero-surveillance during the ongoing PPR eradication program. Furthermore, during the latter stages of any eradication program, vaccination is only possible if the vaccine used is fully DIVA compliant. Using reverse genetics, we have developed two live attenuated PPR DIVA vaccines (Sungri/96 DIVA and Nigeria/75/1 DIVA), in which the C-terminal variable region of the PPRV N-protein has been replaced with dolphin morbillivirus (DMV). As a proof of principle, both the DIVA vaccines were evaluated in goats in pilot studies for safety and efficacy, and all the animals were clinically protected against the intranasal virulent virus challenge, similar to the parent vaccines. Furthermore, it is possible to differentiate between infected animals and vaccinated animals using two newly developed ELISAs. Therefore, these DIVA vaccines and associated tests can facilitate the sero-monitoring process and speed up the implementation of global PPR eradication through vaccination.

The Immune System and the Antiviral Responses in Chinese Giant Salamander, Andrias davidianus.

The Chinese giant salamander, belonging to an ancient amphibian lineage, is the largest amphibian existing in the world, and is also an important animal for artificial cultivation in China. However, some aspects of the innate and adaptive immune system of the Chinese giant salamander are still unknown. The Chinese giant salamander iridovirus (GSIV), a member of the Ranavirus genus (family Iridoviridae), is a prominent pathogen causing high mortality and severe economic losses in Chinese giant salamander aquaculture. As a serious threat to amphibians worldwide, the etiology of ranaviruses has been mainly studied in model organisms, such as the Ambystoma tigrinum and Xenopus. Nevertheless, the immunity to ranavirus in Chinese giant salamander is distinct from other amphibians and less known. We review the unique immune system and antiviral responses of the Chinese giant salamander, in order to establish effective management of virus disease in Chinese giant salamander artificial cultivation.

Effects of dietary quercetin on the innate immune response and resistance to white spot syndrome virus in Procambarusclarkii.

In recent years, the use of natural products with immune-stimulating and antimicrobial properties has attracted increasing attention in aquaculture researches. In our study, the effect of diet supplemented with quercetin, a flavonoid commonly found in some types of plants substance on the innate immune response and disease resistance in crayfish (Procambarus clarkii) against white spot syndrome virus (WSSV) is reported. It was found that dietary 40 mg/kg quercetin significantly reduced the mortality of crayfish and WSSV copy number after WSSV challenge. Dietary quercetin increased catalase (CAT), and lysozyme (LZM) activity in crayfish. Dietary quercetin increased the expression of NF-κB, anti-lipopolysaccharide factor (ALF) and toll-like receptor (TLR) genes in crayfish. The apoptosis rate of hemocyte was increased by quercetin supplement in crayfish. Our results suggest that dietary quercetin may affect the innate immunity of crayfish and protect crayfish from WSSV infection.

Monitoring Natural SARS-CoV-2 Infection in Lions (Panthera leo) at the Barcelona Zoo: Viral Dynamics and Host Responses.

To date, no evidence supports the fact that animals play a role in the epidemiology of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the coronavirus infectious disease 2019 (COVID-19). However, several animal species are naturally susceptible to SARS-CoV-2 infection. Besides pets (cats, dogs, Syrian hamsters, and ferrets) and farm animals (minks), different zoo animal species have tested positive for SARS-CoV-2 (large felids and non-human primates). After the summer of 2020, a second wave of SARS-CoV-2 infection occurred in Barcelona (Spain), reaching a peak of positive cases in November. During that period, four lions (Panthera leo) at the Barcelona Zoo and three caretakers developed respiratory signs and tested positive for the SARS-CoV-2 antigen. Lion infection was monitored for several weeks and nasal, fecal, saliva, and blood samples were taken at different time-points. SARS-CoV-2 RNA was detected in nasal samples from all studied lions and the viral RNA was detected up to two weeks after the initial viral positive test in three out of four animals. The SARS-CoV-2 genome was also detected in the feces of animals at different times. Virus isolation was successful only from respiratory samples of two lions at an early time-point. The four animals developed neutralizing antibodies after the infection that were detectable four months after the initial diagnosis. The partial SARS-CoV-2 genome sequence from one animal caretaker was identical to the sequences obtained from lions. Chronology of the events, the viral dynamics, and the genomic data support human-to-lion transmission as the origin of infection.

Sending Out Alarms: A Perspective on Intercellular Communications in Insect Antiviral Immune Response.

Viral infection triggers insect immune response, including RNA interference, apoptosis and autophagy, and profoundly changes the gene expression profiles in infected cells. Although intracellular degradation is crucial for restricting viral infection, intercellular communication is required to mount a robust systemic immune response. This review focuses on recent advances in understanding the intercellular communications in insect antiviral immunity, including protein-based and virus-derived RNA based cell-cell communications, with emphasis on the signaling pathway that induces the production of the potential cytokines. The prospects and challenges of future work are also discussed.

Avian Influenza A Virus Associations in Wild, Terrestrial Mammals: A Review of Potential Synanthropic Vectors to Poultry Facilities.

The potential role of wild mammals in the epidemiology of influenza A viruses (IAVs) at the farm-side level has gained increasing consideration over the past two decades. In some instances, select mammals may be more likely to visit riparian areas (both close and distant to farms) as well as poultry farms, as compared to traditional reservoir hosts, such as waterfowl. Of significance, many mammalian species can successfully replicate and shed multiple avian IAVs to high titers without prior virus adaptation and often can shed virus in greater quantities than synanthropic avian species. Within this review, we summarize and discuss the potential risks that synanthropic mammals could pose by trafficking IAVs to poultry operations based on current and historic literature.

Subolesin vaccination inhibits blood feeding and reproduction of Haemaphysalis longicornis in rabbits.

BACKGROUND: Ticks can transmit numerous tick-borne pathogens and cause a huge economic loss to the livestock industry. Tick vaccines can contribute to the prevention of tick-borne diseases by inhibiting tick infestation or reproduction. Subolesin is an antigenic molecule proven to be a potential tick vaccine against different tick species and even some tick-borne pathogens. However, its effectivity has not been verified in Haemaphysalis longicornis, which is a widely distributed tick species, especially in East Asian countries. Therefore, the purpose of this study was to evaluate the effectivity of subolesin vaccination against H. longicornis in a rabbit model. METHODS: Haemaphysalis longicornis (Okayama strain, female, adult, parthenogenetic strain) and Japanese white rabbits were used as the model tick and animal, respectively. The whole open reading frame of H. longicornis subolesin (HlSu) was identified and expressed as a recombinant protein using E. coli. The expression was verified using sodium dodecyl sulfate polyacrylamide gel electrophoresis, and the immunogenicity of rHlSu against anti-H. longicornis rabbit serum was confirmed using Western blotting. After vaccination of rHlSu in rabbits, experimental infestation of H. longicornis was performed. Variables related to blood-feeding periods, pre-oviposition periods, body weight at engorgement, egg mass, egg mass to body weight ratio, and egg-hatching periods were measured to evaluate the effectiveness of subolesin vaccination. RESULTS: The whole open reading frame of HlSu was 540 bp, and it was expressed as a recombinant protein. Vaccination with rHlSu stimulated an immune response in rabbits. In the rHlSu-vaccinated group, body weight at engorgement, egg mass, and egg mass to body weight ratio were statistically significantly lower than those in the control group. Besides, egg-hatching periods were extended significantly. Blood-feeding periods and pre-oviposition periods were not different between the two groups. In total, the calculated vaccine efficacy was 37.4%. CONCLUSIONS: Vaccination of rabbits with rHlSu significantly affected the blood-feeding and reproduction in H. longicornis. Combined with findings from previous studies, our findings suggest subolesin has the potential to be used as a universal tick vaccine.

High housing density increases stress hormone- or disease-associated fecal microbiota in male Brandt's voles (Lasiopodomys brandtii).

Density-dependence is an important mechanism in the population regulation of small mammals. Stressors induced by high-density (e.g., crowding and aggression) can cause physiological and neurological disorders, and are hypothesized to be associated with alterations in gut microbiota, which may in turn reduce the fitness of animals by increasing stress- or disease-associated microbes. In this study, we examined the effects of housing density on the hormone levels, immunity, and composition of gut microbiota in male Brandt's voles (Lasiopodomys brandtii) by conducting two specific housing density experiments with or without physical contact between voles. Voles in high density groups exhibited higher serum corticosterone (CORT), serotonin (5-HT), and immunoglobulin G (IgG) levels, as well as higher testosterone (T) levels only in the experiment with physical contact. Meanwhile, high-density treatments induced significant changes in the composition of gut microbiota by increasing disease-associated microbes. The levels of hormones and immunity (i.e., CORT, 5-HT, and IgG) elevated by the high density treatment were significantly correlated with some specific microbes. These results imply that high-density-induced stress may shape the fitness of animals under natural conditions by altering their gut microbiota. Our study provides novel insights into the potential roles of gut microbiota in the density-dependent population regulation of small rodents as well as the potential mechanisms underlying psychological disorders in humans and animals under crowded conditions.

Linking longitudinal and cross-sectional biomarker data to understand host-pathogen dynamics: Leptospira in California sea lions (Zalophus californianus) as a case study.

Confronted with the challenge of understanding population-level processes, disease ecologists and epidemiologists often simplify quantitative data into distinct physiological states (e.g. susceptible, exposed, infected, recovered). However, data defining these states often fall along a spectrum rather than into clear categories. Hence, the host-pathogen relationship is more accurately defined using quantitative data, often integrating multiple diagnostic measures, just as clinicians do to assess their patients. We use quantitative data on a major neglected tropical disease (Leptospira interrogans) in California sea lions (Zalophus californianus) to improve individual-level and population-level understanding of this Leptospira reservoir system. We create a "host-pathogen space" by mapping multiple biomarkers of infection (e.g. serum antibodies, pathogen DNA) and disease state (e.g. serum chemistry values) from 13 longitudinally sampled, severely ill individuals to characterize changes in these values through time. Data from these individuals describe a clear, unidirectional trajectory of disease and recovery within this host-pathogen space. Remarkably, this trajectory also captures the broad patterns in larger cross-sectional datasets of 1456 wild sea lions in all states of health but sampled only once. Our framework enables us to determine an individual's location in their time-course since initial infection, and to visualize the full range of clinical states and antibody responses induced by pathogen exposure. We identify predictive relationships between biomarkers and outcomes such as survival and pathogen shedding, and use these to impute values for missing data, thus increasing the size of the useable dataset. Mapping the host-pathogen space using quantitative biomarker data enables more nuanced understanding of an individual's time course of infection, duration of immunity, and probability of being infectious. Such maps also make efficient use of limited data for rare or poorly understood diseases, by providing a means to rapidly assess the range and extent of potential clinical and immunological profiles. These approaches yield benefits for clinicians needing to triage patients, prevent transmission, and assess immunity, and for disease ecologists or epidemiologists working to develop appropriate risk management strategies to reduce transmission risk on a population scale (e.g. model parameterization using more accurate estimates of duration of immunity and infectiousness) and to assess health impacts on a population scale.

A novel ß-catenin from Apostichopus japonicus mediates Vibrio splendidus-induced inflammatory-like response.

ß-catenin, an adaptor molecule in Wnt/ß-catenin signaling pathway, is associated with different physiological processes such as intestinal immune, apoptosis, and inflammation-associated response. However, the function of ß-catenin is still largely unknown in Apostichopus japonicus. In the present study, we cloned and characterized ß-catenin gene from A. japonicus by RNA-seq and RACE approaches. The complete sequence of Ajß-catenin consisted of a 5' UTR of 166 bp, a 3' UTR of 501 bp and an ORF of 2433 bp encoding a protein of 810 amino acids. Ajß-catenin has a GSK-ß consensus phosphorylation site of 21 amino acids located at N-terminal region and twelve Armadillo/ß-catenin-like repeat (ARM) domains from 145 to 671 aa. Spatial expression analysis revealed that Ajß-catenin mRNA levels displayed higher abundance in intestine. For Vibrio splendidus challenged sea cucumber, Ajß-catenin transcripts reached their peak at 6 h and remained at higher levels until 24 h post infection in comparison with that of the control group. GSK-3ß inhibitor treatment could induce both Ajß-catenin and the inflammatory factors expression. Ajß-catenin silencing could also down-regulate inflammatory factors expression. These results collectively suggested that Ajß-catenin was a novel molecule mediate V. splendidus-induced immune response of A. japonicus via regulating the inflammatory factors expression.

The economic value of R0 for selective breeding against microparasitic diseases.

BACKGROUND: Microparasitic diseases are caused by bacteria and viruses. Genetic improvement of resistance to microparasitic diseases in breeding programs is desirable and should aim at reducing the basic reproduction ratio [Formula: see text]. Recently, we developed a method to derive the economic value of [Formula: see text] for macroparasitic diseases. In epidemiological models for microparasitic diseases, an animal's disease status is treated as infected or not infected, resulting in a definition of [Formula: see text] that differs from that for macroparasitic diseases. Here, we extend the method for the derivation of the economic value of [Formula: see text] to microparasitic diseases. METHODS: When [Formula: see text], the economic value of [Formula: see text] is zero because the disease is very rare. When [Formula: see text]. is higher than 1, genetic improvement of [Formula: see text] can reduce expenditures on vaccination if vaccination induces herd immunity, or it can reduce production losses due to disease. When vaccination is used to achieve herd immunity, expenditures are proportional to the critical vaccination coverage, which decreases with [Formula: see text]. The effect of [Formula: see text] on losses is considered separately for epidemic and endemic disease. Losses for epidemic diseases are proportional to the probability and size of major epidemics. Losses for endemic diseases are proportional to the infected fraction of the population at the endemic equilibrium. RESULTS: When genetic improvement reduces expenditures on vaccination, expenditures decrease with [Formula: see text] at an increasing rate. When genetic improvement reduces losses in epidemic or endemic diseases, losses decrease with [Formula: see text] at an increasing rate. Hence, in all cases, the economic value of [Formula: see text] increases as [Formula: see text] decreases towards 1. DISCUSSION: [Formula: see text] and its economic value are more informative for potential benefits of genetic improvement than heritability estimates for survival after a disease challenge. In livestock, the potential for genetic improvement is small for epidemic microparasitic diseases, where disease control measures limit possibilities for phenotyping. This is not an issue in aquaculture, where controlled challenge tests are performed in dedicated facilities. If genetic evaluations include infectivity, genetic gain in [Formula: see text] can be accelerated but this would require different testing designs. CONCLUSIONS: When [Formula: see text], its economic value is zero. The economic value of [Formula: see text] is highest at low values of [Formula: see text] and approaches zero at high values of [Formula: see text].

Drosophila immunity against natural and nonnatural viral pathogens.

The fruit fly Drosophila melanogaster is extensively used as a model species for molecular biology and genetics. It is also widely studied for its innate immune system to expand our understanding of immune host defenses against numerous pathogens. More precisely, studies using both natural and nonnatural Drosophila pathogens have provided a better perspective of viral infection strategies and immunity processes than any other invertebrate. This has made significant advances in identifying and characterizing the innate immune mechanisms by which hosts can combat viral pathogens. However, in-depth studies on antiviral immunity are still lacking due in part to the narrow research focus on the evolution and conservation of antiviral strategies to combat infections caused by both natural and nonnatural viruses. In this review, we will cover three major areas. First, we will describe the well-characterized antiviral immune mechanisms in Drosophila. Second, we will survey the specific pathways induced by natural viruses that have been studied in Drosophila. Finally, we will discuss the pathways activated by nonnatural viruses, drawing comparisons to natural viruses and giving an unprecedented insight into the virus community of Drosophila that is necessary to understand the evolutionary and immune context needed to develop Drosophila as a model for virus research.

Adjuvants: What a Difference 15 Years Makes!

Vaccination is a critical tool in modern animal production and key to maintaining animal health. Adjuvants affect the immune response by increasing the rate, quantity, or quality of the protective response generated by the target antigens. Although adjuvant technology dates back to the nineteenth century, there was relatively little improvement in adjuvant technology before the late twentieth century. With the discovery of molecular pathways that regulate the timing, quantity, and quality of the immune response, new technologies are focused on bringing safer, more effective, and inexpensive adjuvants to commercial use.

The Enhanced Immune Protection in Chinese Mitten Crab Eriocheir sinensis Against the Second Exposure to Bacteria Aeromonas hydrophila.

Accumulating evidences suggest that the enhanced immune responses and increased protection against bacteria-induced mortality can be initiated after the primary exposure to various microbial communities and their components in various organisms including commercially valuable crustaceans. In the present study, the survival rate and immune responses of Chinese mitten crab Eriocheir sinensis were determined after an immune priming (IP) with formalin-killed Aeromonas hydrophila and an immune challenge (ICH) with the same but live pathogen (Ah group). A group in which the animals received a salt injection prior to challenge was maintained as control (Ns group). In the present study, it was shown that an IP with killed A. hydrophila can significantly protect the crabs against the ICH with a lethal dose of the live pathogen. The increased survival was associated with elevated rate and duration of phagocytosis. The antibacterial activity of the serum was significantly increased in Ah group compared to that in Ns group. Significant changes of phenoloxidase (PO) activities were also found between Ah and Ns group but not in Ah group between IP and ICH. No significant changes of lysozyme were found in Ah and NS group during the whole experiment except 3 h after IP. In addition, the levels of transcripts and protein of Dscam were increased in hemocytes of the crabs from Ah group. All the results suggested that a primary immune priming with a particular killed pathogen could induce an enhanced immunity in crabs when they were encountered secondly with the same live pathogen. The evidences of elevated immune protections in crabs would contribute to better understand the mechanism of immune priming in invertebrates.

Specificity of serological test for detection of tuberculosis in cattle, goats, sheep and pigs under different epidemiological situations.

BACKGROUND: Serum antibody detection has potential as a complementary diagnostic tool in animal tuberculosis (TB) control, particularly in multi-host systems. The objective of the present study was to assess the specificity (Sp) of an enzyme-linked immunosorbent assay (ELISA) based on the new multiprotein complex P22 for the detection of specific antibodies against the Mycobacterium tuberculosis complex (MTC) in the four most relevant domestic animals acting as MTC hosts: cattle, goat, sheep and pig. We used sera from an officially TB-free (OTF) country, Norway, and from a non-OTF one, Spain. The samples included sera from goats that had been vaccinated against M. avium subsp. paratuberculosis (MAP) and sheep from a herd in which Corynebacterium pseudotuberculosis had been isolated. RESULTS: In cattle, the Sp ranged from 92.5 (IC95% 90.7-94) to 99.4% (IC95% 98.3-99.8) depending on the cut-off used and the origin of the samples (Spain or Norway). Sp in cattle (cut-off point 100) was significantly higher (P < 0.05) for Norwegian samples. By contrast, Sp in goats was consistently low at the 100 cut-off [30.9 (CI95%23.4-39.5)-78% (CI95% 68.9-85)]. A higher cut-off of 150 improved Sp in Norwegian goats [97% (CI95% 91.6-99)], but still yielded a poor Sp of 56.1% (CI95% 47.3-64.6) in Spanish goats. In Norway at the 100 cut-off the Sp was 58.3 (CI95% 42.2-72.9) and 90.6% (CI95% 81-95.6) in MAP vaccinated and non-vaccinated goats, respectively, indicating interference due to MAP vaccination. Sp in sheep was between 94.4 (CI95% 91.7-96.3) and 100% (CI95% 96.3-100) depending on the cut-off and country, and no diagnostic interference due to infection with C. pseudotuberculosis was recorded. Sp in pigs was 100%, regardless the cut-off point applied, and no significant differences were observed between pigs from Norway and from Spain. CONCLUSIONS: Due to its excellent Sp in pigs and acceptable Sp in cattle and sheep, this ELISA may constitute a suitable option for TB screening at herd level, particularly in OTF-countries.

Bubaline alphaherpesvirus 1 induces a latent/reactivable infection in goats.

Latent infection is a common mechanism used by several alphaherpesviruses to persist in their host but it is not clear whether this mechanism is also triggered in heterologous infections. Cross-species infections have been documented repeatedly for alphaherpesviruses of ruminants, a group of closely related viruses. Herewith we report latent infection with bubaline alphaherpesvirus 1 (BuHV-1) in experimentally infected goats and subsequent virus reactivation after treatment with dexamethasone (DMS) at 10 months after infection. After DMS treatment, the virus was isolated in one such animal in the nasal swabs from day 3 to 9 post treatment and in the ocular swabs at day 6. The goat was euthanized 48 days after DMS treatment and viral DNA was detected by PCR in the trigeminal ganglia and in two cervical ganglia. Additionally, BuHV-1 DNA was detected by PCR in the trigeminal ganglia of the other 3 goats.

Facets of Theiler's Murine Encephalomyelitis Virus-Induced Diseases: An Update.

Theiler's murine encephalomyelitis virus (TMEV), a naturally occurring, enteric pathogen of mice is a Cardiovirus of the Picornaviridae family. Low neurovirulent TMEV strains such as BeAn cause a severe demyelinating disease in susceptible SJL mice following intracerebral infection. Furthermore, TMEV infections of C57BL/6 mice cause acute polioencephalitis initiating a process of epileptogenesis that results in spontaneous recurrent epileptic seizures in approximately 50% of affected mice. Moreover, C3H mice develop cardiac lesions after an intraperitoneal high-dose application of TMEV. Consequently, TMEV-induced diseases are widely used as animal models for multiple sclerosis, epilepsy, and myocarditis. The present review summarizes morphological lesions and pathogenic mechanisms triggered by TMEV with a special focus on the development of hippocampal degeneration and seizures in C57BL/6 mice as well as demyelination in the spinal cord in SJL mice. Furthermore, a detailed description of innate and adaptive immune responses is given. TMEV studies provide novel insights into the complexity of organ- and mouse strain-specific immunopathology and help to identify factors critical for virus persistence.