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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the coronavirus disease-19 (COVID-19). More than 143 million cases of COVID-19 have been reported to date, with the global death rate at 2.13%. Currently, there are no licensed therapeutics for controlling SARS-CoV-2 infection. The antiviral effects of heme oxygenase-1 (HO-1), a cytoprotective enzyme that inhibits the inflammatory response and reduces oxidative stress, have been investigated in several viral infections. To confirm whether HO-1 suppresses SARS-CoV-2 infection, we assessed the antiviral activity of hemin, an effective and safe HO-1 inducer, in SARS-CoV-2 infection. We found that treatment with hemin efficiently suppressed SARS-CoV-2 replication (selectivity index: 249.7012). Besides, the transient expression of HO-1 using an expression vector also suppressed the growth of the virus in cells. Free iron and biliverdin, which are metabolic byproducts of heme catalysis by HO-1, also suppressed the viral infection. Additionally, hemin indirectly increased the expression of interferon-stimulated proteins known to restrict SARS-CoV-2 replication. Overall, the findings suggested that HO-1, induced by hemin, effectively suppressed SARS-CoV-2 in vitro. Therefore, HO-1 could be potential therapeutic candidate for COVID-19.

SARS-CoV-2 induces illness and death in humans by causing systemic infections. Evidence suggests that SARS-CoV-2 can induce brain pathology in humans and other hosts. In this study, we used a canine transmission model to examine histopathologic changes in the brains of dogs infected with SARS-CoV-2. We observed substantial brain pathology in SARS-CoV-2-infected dogs, particularly involving blood-brain barrier damage resembling small vessel disease, including changes in tight junction proteins, reduced laminin levels, and decreased pericyte coverage. Furthermore, we detected phosphorylated tau, a marker of neurodegenerative disease, indicating a potential link between SARS-CoV-2-associated small vessel disease and neurodegeneration. Our findings of degenerative changes in the dog brain during SARS-CoV-2 infection emphasize the potential for transmission to other hosts and induction of similar signs and symptoms. The dynamic brain changes in dogs highlight that even asymptomatic individuals infected with SARS-CoV-2 may develop neuropathologic changes in the brain.

•A nanogel vaccine encapsulating rabbit HEV capsid protein was developed.•The nanogel vaccine induced anti-HEV antibodies, IL-12, and IFN-γ.•The nanogel vaccine completely protected rabbits from HEV infection. Infection with hepatitis E virus (HEV) has raised serious public health concerns worldwide. In this study, a nanogel-based vaccine encapsulating the capsid protein of rabbit HEV was developed and its protective efficacy was compared with a subunit vaccine. A total of 23 rabbits were divided into 5 groups: (1) negative control (n = 4), (2) positive control (n = 4), (3) nanogel control (n = 5), (4) nanogel vaccine (n = 5), and (5) subunit vaccine (n = 5). Rabbits were vaccinated two times, at weeks 0 and 1, with nanogel and subunit vaccines, respectively, and challenged with rabbit HEV at week 4. By week 11, rabbits vaccinated with the nanogel vaccine produced higher antibodies than those vaccinated with the subunit vaccine. Fecal viral shedding and viremia were identified in rabbits of the positive and nanogel control groups at weeks 6–10. However, there was no viral shedding and viremia in rabbits immunized with both the nanogel and subunit vaccines. Alanine aminotransferase and aspartate aminotransferase levels were not elevated in any rabbit. However, histopathological examination revealed much less hepatic inflammation in rabbits of the nanogel vaccine group compared to the positive and nanogel control groups. Significant increases in IL-12 and IFN–γlevels were identified from rabbits immunized with the nanogel vaccine. Collectively, these results indicate that the newly developed nanogel vaccine induced sufficient immunity leading to complete protection from HEV infection in rabbits. Application of this vaccine should be considered as a preventive measure against HEV infection in other animal species and humans.

Equine parvovirus-hepatitis (EqPV-H) is a newly identified etiologic agent of Theiler’s disease (TD). We present a case of EqPV-H-related fulminant hepatitis in a 14-year-old thoroughbred mare in Korea. The mare had acute hepatopathy and gastrointestinal symptoms, with abnormal liver-related blood parameters. The horse was born in the USA and imported to Korea in 2017, with no history of administration of equine biological products after entry into Korea. The horse was diagnosed with EqPV-H-associated hepatitis after abdominal ultrasonography, laparotomy, and nested polymerase chain reaction (PCR) and in situ hybridization (ISH) assays. The serum, nasal swab, oral swab, and liver biopsy were positive for EqPV-H according to the PCR assay. Genetic analysis of the partial NS1 gene of EqPV-H showed a unique nucleotide substitution, distinct from that in previously deposited strains. EqPV-H DNA was found not only in hepatocytes but also in bile duct epithelium and Kupffer cells, particularly via ISH. To the best of our knowledge, this is the first case of EqPV-H-associated TD in Asia, providing the first clinical evidence for viral shedding from the mouth and nose, and identification of EqPV-H in the liver. This study contributes to a better understanding of the pathological features of EqPV-H-associated TD.

Hepatitis A virus (HAV), the causative pathogen of hepatitis A, induces severe acute liver injuries in humans and is a serious public health concern worldwide. However, appropriate therapeutics have not yet been developed. The enzyme heme oxygenase-1 (HO-1) exerts antiviral activities in cells infected with several viruses including hepatitis B and C viruses. In this study, we demonstrated for the first time the suppression of virus replication by HO-1 in cells infected with HAV. Hemin (HO-1 inducer) induced HO-1 mRNA and protein expression, as expected, and below 50 mM, dose-dependently reduced the viral RNA and proteins in the HAV-infected cells without cytotoxicity. Additionally, HO-1 protein overexpression using a protein expression vector suppressed HAV replication. Although ZnPP-9, an HO-1 inhibitor, did not affect HAV replication, it significantly inhibited hemin-induced antiviral activity in HAV-infected cells. Additionally, FeCl3, CORM-3, biliverdin, and the HO-1 inducers andrographolide and CoPP inhibited HAV replication in the HAV-infected cells; andrographolide and CoPP exhibited a dose-dependent effect. In conclusion, these results suggest that HO-1 effectively suppresses HAV infection in vitro, and its enzymatic products appear to exert antiviral activity. We expect that these results could contribute to the development of a new antiviral drug for HAV.

Here, rabbits were immunized with a virus-like particle (VLP) vaccine prepared by expressing 239 amino acids of the swine hepatitis E virus (HEV)-3 capsid protein using a baculovirus system. Thirty specific-pathogen-free rabbits were divided into five groups (negative and positive control and 10, 50, and 100 μg VLP-vaccinated). Positive control group rabbits showed viremia and fecal viral shedding, whereas rabbits vaccinated with 10 μg VLP showed transient fecal viral shedding, and rabbits vaccinated with 50 and 100 μg VLP did not show viremia or fecal viral shedding. Serum anti-HEV antibody titers increased in a dose-dependent manner. Anti-HEV antibody titers were significantly higher (p < 0.05) in 100 μg VLP-vaccinated rabbits than in the negative control rabbits at week 4. Anti-HEV antibody titers were significantly higher in 50 and 10 μg VLP-vaccinated rabbits than in the negative control rabbits at weeks 8 and 11, respectively. Serum IFN-γ and IL-12 levels were significantly higher (p < 0.01) in rabbits vaccinated with 50 and 100 μg VLP than in the negative control rabbits at weeks 4 and 6. Liver tissues of 50 and 100 μg VLP-vaccinated rabbits displayed significantly less (p < 0.05) fibrosis than those of the positive control rabbits. The prepared VLP vaccine demonstrated dose-dependent immunogenicity sufficient for inducing anti-HEV antibody production, thus protecting rabbits against swine HEV-3.

Hepatitis E virus (HEV) is a quasi-enveloped, positive-sense single stranded RNA virus. HEV continually expands the host ranges across animal species. In this study, the possibility of cross-species infection with swine HEV-3 was investigated using rabbits. A total of fourteen 8-week old, specific pathogen-free rabbits were divided into three experimental groups. Four rabbits were used as negative controls, four rabbits were infected with rabbit HEV as positive controls, and six rabbits were inoculated with swine HEV-3. HEV RNA were detected from serum and fecal samples after viral challenge. The levels of anti-HEV antibodies, pro-inflammatory cytokines (IL-1, IL-6, TNF-α and IFN-α), and liver enzymes (alanine and aspartate aminotransferases) were determined in serum samples. Histopathological lesions were examined in liver tissues. Viral RNA and anti-HEV antibodies were identified in rabbits inoculated with swine HEV-3 demonstrating positive infectivity of the virus. However, pro-inflammatory cytokine and liver enzyme levels in serum were not significantly elevated, and only mild inflammatory lesions were detected in the liver tissues of rabbits infected with swine HEV-3. These results suggest that swine HEV-3 can engage in cross-species transmission to rabbits, but causes only mild inflammation of the liver.

Norovirus genogroup II (NoV GII) induces acute gastrointestinal food-borne illness in humans. Because gnotobiotic pigs can be infected with human norovirus (HuNoV) GII, they are frequently used to analyze the associated pathogenic mechanisms and immune responses, which remain poorly understood. Recently, mRNA sequencing analysis (RNA-Seq) has been used to identify cellular responses to viruses. In this study, we investigated the host immune response and possible mechanisms involved in virus evasion in the ileum of gnotobiotic pigs infected with HuNoV by RNA-Seq. HuNoV was detected in the feces, blood, and tissues of the jejunum, ileum, colon, mesenteric lymph node, and spleen of pigs infected with HuNoV. In analysis of mRNA sequencing, expression of anti-viral protein genes such as OAS1, MX1, and MX2 were largely decreased, whereas type I IFN was increased in pigs infected with HuNoV. In addition, expression of TNF and associated anti-inflammatory cytokine genes such as IL10 was increased in HuNoV-infected pigs. Expression of genes related to natural killer (NK) cell cytotoxicity and CD8+ T cell exhaustion was increased, whereas that of MHC class I genes was decreased. Expression profiles of selected genes were further confirmed by qRT-PCR and Western blot. These results suggest that infection with HuNoV induces NK cell-mediated cytotoxicity but suppresses type I IFN- and CD8+ T cell-mediated antiviral responses.

Background Gonadotropin‐releasing hormone (GnRH) plays a pivotal role in regulating the reproductive endocrine system. Objective An immunocontraception vaccine aimed at inhibiting the functions of GnRH is tested as a potential tool for controlling animal populations. Methods We developed a recombinant immunocontraceptive vaccine composed of GnRH‐I and GnRH‐II (GnRH I+II), which was conjugated with Salmonella typhimurium flagellin. Forty‐eight BALB/c mice aged 4 weeks were divided into four groups (each group had n = 12): non‐vaccinated male (NVM), non‐vaccinated female (NVF), vaccinated male (VM), and vaccinated female (VF). Mice in the vaccinated groups were vaccinated twice by intramuscular injection at 0 and 2 weeks with 300 μg of the recombinant GnRH protein complex per mouse. Mice in the non‐vaccinated groups were injected with saline and served as the unimmunized controls. Twenty‐four pairs of male and female mice were mated for 10–12 weeks after initial immunization in four groups: 6 NVF × 6 NVM, 6 VF × 6 NVM, 6 NVF × 6 VM, and 6 VF × 6 VM. Results: An increase (p < 0.001) in antibody titers in VM and VF mice was observed. The testosterone levels and the number of spermatocytes were lower (p < 0.001) in VM mice than those in the control mice. The progesterone levels and the number of corpora lutea were lower (p < 0.001) than those in the control mice. Mating results in both VM and VF mice confirmed a 60% reduction in pregnancy rates and offspring numbers. Conclusions The recombinant GnRH vaccine can be used for birth control in both male and female animals. We developed a new form of immunocontraceptive vaccine composed of GnRH‐I and ‐II complex conjugated with STF‐2. We provide the vaccine efficacies with higher anti‐GnRH antibodies in mice. The vaccine containing the GnRH‐I + II peptide linked to STF‐2 induced the suppression of fertility by inhibiting testicular and ovarian functions and reducing sex hormone levels in both male and female mice. In addition, the effects of fertility reduction were confirmed through mating experiments .

Torque teno canis virus (TTCaV) is an approximately 2.8 kb circular single-stranded DNA virus known to cause infections in dogs. However, its incidence in Republic of Korea remains unknown. In this study, 135 dog fecal samples were collected to determine TTCaV infection status in Republic of Korea. Based on polymerase chain reaction (PCR) analysis, 13 of 135 (9.6%) dogs tested positive for TTCaV. Three full-length genome sequences (GenBank IDs: MZ503910, MZ503911, and MZ503912) were obtained from the positive specimens. Phylogenetic tree construction and sequence identity, similarity plot, and recombination analyses were performed using these three full-length genomic sequences. Among the three full-length genomes, MZ503912 was determined to be a recombinant virus based on analysis with the reference TTCaV strains. This novel virus strain might have been generated by recombination between TTCaV strain KX827768 discovered in China and MZ503910 discovered in Republic of Korea. This is the first report to determine the incidence, genetic variation, and recombination of TTCaV in dogs in Republic of Korea. Further studies are needed to elucidate TTCaV pathogenesis in dogs.