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Transmissible spongiform encephalopathies (TSE) are caused by dietary oral exposure to infectious prion proteins (PrPSc); however, the mechanism behind the uptake of PrPSc in the intestines is poorly understood. In addition, epidemiological studies of BSE showed that most cattle are exposed to the agents in the first 6 months of life, during the suckling and weaning periods. In the present study, to elucidate the enteric invasion mechanism of prions and to investigate the age-dependent transmission mechanism suggested by epidemiological studies, wild-type and SCID mice were orally administered brain homogenate from scrapie (Tsukuba 1)-infected mice during the suckling and weaning stages, before being analyzed histopathologically. PrPSc was found to be incorporated into the villous columnar epithelial cells and was also detected in the villous lacteal of 15-day-old suckling mice. However, no such uptake of PrPSc was observed in the weaned mice at 25-days-old. Four different strains of mice were tested. There was no mouse strain difference in the frequency of PrPSc positive columnar epithelial cells. In addition, the uptake of PrPSc in suckling SCID mice lacking maternal antibodies was significantly lower than that in the wild-type suckling mice, and the uptake of PrPSc was enhanced by dilution with purified IgG. In the present study, it was suggested that the weaning period and maternal immunoglobulin are important risk factors for the oral transmission of PrPSc.

Background: The mucosa serves as the first defence against pathogens and facilitates the surveillance and elimination of symbiotic bacteria by mucosal immunity. Recently, the mRNA vaccine against SARS-CoV-2 has been demonstrated to induce secretory antibodies in the oral and nasal cavities in addition to a systemic immune response. However, the mechanism of induced immune stimulation effect on mucosal immunity and commensal bacteria profile remains unclear. Methods: Here, we longitudinally analysed the changing nasal microbiota and both systemic and nasal immune response upon SARS-CoV-2 mRNA vaccination, and evaluated how mRNA vaccination influenced nasal microbiota in 18 healthy participants who had received the third BNT162b. Results: The nasal S-RBD IgG level correlated significantly with plasma IgG levels until 1 month and the levels were sustained for 3 months post-vaccination. In contrast, nasal S-RBD IgA induction peaked at 1 month, albeit slightly, and correlated only with plasma IgA, but the induction level decreased markedly at 3 months post-vaccination. 16 S rRNA sequencing of the nasal microbiota post-vaccination revealed not an overall change, but a decrease in certain opportunistic bacteria, mainly Fusobacterium. The decrease in these bacteria was more pronounced in those who exhibited nasal S-RBD IgA induction, and those with higher S-RBD IgA induction had lower relative amounts of potentially pathogenic bacteria such as Pseudomonas pre-vaccination. In addition, plasma and mucosal S-RBD IgG levels correlated with decreased commensal pathogens such as Finegoldia. Conclusions: These findings suggest that the third dose of SARS-CoV-2 mRNA vaccination induced S-RBD antibodies in the nasal mucosa and may have stimulated mucosal immunity against opportunistic bacterial pathogens. This effect, albeit probably secondary, may be considered one of the benefits of mRNA vaccination. Furthermore, our data suggest that a cooperative function of mucosal and systemic immunity in the reduction of bacteria and provides a better understanding of the symbiotic relationship between the host and bacteria in the nasal mucosa. [ABSTRACT FROM AUTHOR]

Prion diseases are a family of neurodegenerative zoonotic foodborne disorders. Although prions can be transmitted orally, the mechanism by which prions are incorporated into the intestine remains unclear. Our previous studies have shown that an abnormal isoform of prion protein (PrPSc), which is the main component of prions, was efficiently incorporated into the intestine in suckling mice but not in weaned mice. Furthermore, suckling SCID mice lacking maternal antibodies showed decreased uptake of PrPSc into the intestine compared with suckling wild-type mice, while the lack of PrPSc uptake into the intestine of suckling SCID mice was rescued by the oral administration of IgG. These findings raise the possibility that the neonatal Fc receptor (nFcR), which contributes to the uptake of maternal antibodies into the intestine, plays a role in PrPSc incorporation into the intestine. The present immunohistochemical study further showed that the FcR blocker Z-ϵ- aminocaproic acid (ZAA) inhibited PrPSc incorporation into the intestinal villi of suckling mice, supporting the above mentioned concept. Therefore, our findings provide strong evidence that nFcR and maternal antibodies are involved in PrPSc incorporation into the intestine before the weaning period. [ABSTRACT FROM AUTHOR]

Highly pathogenic avian H5 influenza viruses persist among poultry and wild birds throughout the world. They sometimes cause interspecies transmission between avian and mammalian hosts. H5 viruses possessing the HA of subclade 2.3.4.4, 2.3.2.1, 2.2.1, or 7.2 were detected between 2015 and 2018. To understand the neutralizing epitopes of H5-HA, we characterized 15 human monoclonal antibodies (mAbs) against the HA of H5 viruses, which were obtained from volunteers who received the H5N1 vaccine that contains a subclade 2.2.1 or 2.1.3.2 virus as an antigen. Twelve mAbs were specific for the HA of subclade 2.2.1, two mAbs were specific for the HA of subclade 2.1.3.2, and one mAb was specific for the HA of both. Of the 15 mAbs analyzed, nine, which were specific for the HA of subclade 2.2.1, and shared the VH and VL genes, possessed hemagglutination inhibition and neutralizing activities, whereas the others did not. A single amino acid substitution or insertion at positions 144–147 in antigenic site A conferred resistance against these nine mAbs to the subclade 2.2.1 viruses. The amino acids at positions 144–147 are highly conserved among subclade 2.2.1, but differ from those of other subclades. These results show that the neutralizing epitope including amino acids at positions 144–147 is targeted by human antibodies, and plays a role in the antigenic difference between subclade 2.2.1 and other subclades. [ABSTRACT FROM AUTHOR]

Highlights • Influenza A viruses barely escaped from two mAbs against the HA stem. • Escape from the third anti-HA stem mAb occurred readily. • These three mAbs share an epitope and show similar potency in vitro and in vivo. Abstract Background Broadly protective human monoclonal antibodies that recognize the conserved epitopes in the HA of influenza A virus are being developed as therapeutic agents. Emergence of resistant viruses must always be considered when developing therapeutic agents against influenza. Objectives We examined human hetero-reactive mAbs against the HA stem of influenza A virus for the ease with which escape mutant viruses emerged. Study design We attempted to generate the mutant viruses escaped from the hetero-reactive anti-HA stem antibodies. We also evaluated their protective efficacy, binding affinity, and epitopes. Results We obtained several human monoclonal antibodies (mAbs) that react with the HA of different HA subtypes of influenza A virus belonging to group 1. Upon attempting to generate escape mutant viruses, we found that the ease with which such viruses emerged differed among the mAbs; viruses barely escaped from two of the mAbs (clones S9-3-37 and F20C77), whereas escape from the third mAb (clone F5B7) occurred readily. Comparisons of the mAbs revealed that the HA stem epitopes, in vitro neutralization potency, binding affinity to H1-HA, and protective efficacy against lethal challenge with H1N1pdm09 virus were all comparable. Conclusions These results demonstrate the importance of determining the ease with which escape mutant viruses emerge when evaluating anti-HA stem antibodies as antiviral agents during preclinical testing. [ABSTRACT FROM AUTHOR]