A broad-spectrum pneumococcal vaccine induces mucosal immunity and protects against lethal Streptococcus pneumoniae challenge.

Pneumococcal disease is a major threat to public health globally, impacting individuals across all age groups, particularly infants and elderly individuals. The use of current vaccines has led to unintended consequences, including serotype replacement, leading to a need for a new approach to combat pneumococcal disease. A promising solution is the development of a broad-spectrum pneumococcal vaccine. In this study, we present the development of a broad-spectrum protein-based pneumococcal vaccine that contains three pneumococcal virulence factors: rlipo-PsaA (lipidated form), rPspAΔC (truncated form), and rPspCΔC (truncated form). Intranasal immunization with rlipo-PsaA, rPspAΔC, and rPspCΔC (LAAC) resulted in significantly higher IgG titres than those induced by administration of nonlipidated rPsaA, rPspAΔC, and rPspCΔC (AAC). Furthermore, LAAC immunization induced the production of higher IgA titres in vaginal washes, feces, and sera in mice, indicating that LAAC can induce systemic mucosal immunity. In addition, administration of LAAC also induced Th1/Th17-biased immune responses and promoted opsonic phagocytosis of Streptococcus pneumoniae strains of various serotypes, implying that the immunogenicity of LAAC immunization provides a protective effect against pneumococcal infection. Importantly, challenge data showed that the LAAC-immunized mice had a reduced bacterial load not only for several serotypes of the 13-valent conjugate pneumococcal vaccine (PCV13) but also for selected non-PCV13 serotypes. Consistently, LAAC immunization increased the survival rate of mice after bacterial challenge with both PCV13 and non-PCV13 serotypes. In conclusion, our protein-based pneumococcal vaccine provides protective effects against a broad spectrum of Streptococcus pneumoniae serotypes.

Recombinant lipidated FLIPr effectively enhances mucosal and systemic immune responses for various vaccine types.

Formyl peptide receptor-like 1 inhibitor protein (FLIPr) is an immune evasion protein produced by Staphylococcus aureus, and FLIPr is a potential vaccine candidate for reducing Staphylococcus aureus virulence and biofilm formation. We produced recombinant lipidated FLIPr (rLF) to increase the immunogenicity of FLIPr and showed that rLF alone elicited potent anti-FLIPr antibody responses to overcome the FLIPr-mediated inhibition of phagocytosis. In addition, rLF has potent immunostimulatory properties. We demonstrated that rLF is an effective adjuvant. When an antigen is formulated with rLF, it can induce long-lasting antigen-specific immune responses and enhance mucosal and systemic antibody responses as well as broad-spectrum T-cell responses in mice. These findings support further exploration of rLF in the clinic as an adjuvant for various vaccine types with extra benefits to abolish FLIPr-mediated immunosuppressive effects.

Intranasal Vaccination With Recombinant Antigen-FLIPr Fusion Protein Alone Induces Long-Lasting Systemic Antibody Responses and Broad T Cell Responses.

A simple formulation is urgently needed for mucosal vaccine development. We employed formyl peptide receptor-like 1 inhibitory protein (FLIPr), an FcγR antagonist secreted by Staphylococcus aureus, as a vector to target ovalbumin (OVA) to dendritic cells (DCs) via intranasal administration. Our results demonstrate that intranasal administration of recombinant OVA-FLIPr fusion protein (rOVA-FLIPr) alone efficiently delivers OVA to DCs in nasal lymphoid tissue. Subsequently, OVA-specific IgG and IgA antibodies in the circulatory system and IgA antibodies in mucosal tissue were detected. Importantly, activation of OVA-specific CD4+ and CD8+ T cells and induction of a broad-spectrum cytokine secretion profile were detected after intranasal administration of rOVA-FLIPr alone in immunocompetent C57BL/6 mice. Furthermore, we employed immunodeficient AG129 mice as a Zika virus infection model and demonstrated that intranasal administration of recombinant Zika virus envelope protein domain III-FLIPr fusion protein induced protective immune responses against the Zika virus. These results suggest that antigen-FLIPr fusion protein alone via intranasal administration can be applied to mucosal vaccine development.

The effects of dopaminergic medication on dynamic decision making in Parkinson's disease.

In the present study we address the following questions: (1) How is performance affected when patients with Parkinson's Disease (PD) perform a dynamic decision making task? (2) Does dopaminergic medication differentially affect dynamic decision making? To address these questions participants were trained with different goals during learning: either they made intervention-based decisions or prediction-based decisions during learning. The findings show that overall there is an advantage for those trained to intervene over those trained to predict. In addition, the results are the first demonstration that PD patients 'ON' (N=20) compared to 'OFF' L-Dopa (N=15) medication and also relative to healthy age matched controls (N=16) showed lower levels of relative improvement in the accuracy of their decisions in a dynamic decision making task, and tended to use sub-optimal strategies. These findings provide support for the 'Dopamine Overdose' hypothesis using a novel decision making task, and suggest that executive functions such as decision making can be adversely affected by dopaminergic medication in PD.

(1)H-NMR spectroscopy revealed Mycobacterium tuberculosis caused abnormal serum metabolic profile of cattle.

To re-evaluate virulence of Mycobacterium tuberculosis (M. tb) in cattle, we experimentally infected calves with M. tb andMycobacterium bovisvia intratracheal injection at a dose of 2.0×10(7) CFU and observed the animals for 33 weeks. The intradermal tuberculin test and IFN-γin vitro release assay showed that both M. tb and M. bovis induced similar responses. Immunohistochemical staining of pulmonary lymph nodes indicated that the antigen MPB83 of both M. tb and M. bovis were similarly distributed in the tissue samples. Histological examinations showed all of the infected groups exhibited neutrophil infiltration to similar extents. Although the infected cattle did not develop granulomatous inflammation, the metabolic profiles changed significantly, which were characterized by a change in energy production pathways and increased concentrations of N-acetyl glycoproteins. Glycolysis was induced in the infected cattle by decreased glucose and increased lactate content, and enhanced fatty acid ß-oxidation was induced by decreased TG content, and decreased gluconeogenesis indicated by the decreased concentration of glucogenic and ketogenic amino acids promoted utilization of substances other than glucose as energy sources. In addition, an increase in acute phase reactive serum glycoproteins, together with neutrophil infiltration and increased of IL-1ß production indicated an early inflammatory response before granuloma formation. In conclusion, this study indicated that both M. tb and M.bovis were virulent to cattle. Therefore, it is likely that cattle with M. tb infections would be critical to tuberculosis transmission from cattle to humans. Nuclear magnetic resonance was demonstrated to be an efficient method to systematically evaluate M. tb and M. bovi sinfection in cattle.

[Comparison of skin sympathetic reaction in patients with generalized anxiety disorder and with major depression disorder].

OBJECTIVE: To compare skin sympathetic response(SSR) between patients with generalized anxiety disorder(GAD) and patients with major depression disorder(MDD). METHODS: The latency and amplitude of SSR wave were measured in 30 GAD patients and 30 MDD patients, before and after 8-week treatment of anti-anxiety or anti-depression drugs. Thirty age and sex-matched healthy subjects served as healthy controls (HC). RESULTS: Before the treatment, the latency of SSR in GAD patients was significantly shorter than that in HC group, while the amplitude was significantly higher than that in the HC (P<0.05). In MDD group, the latency before the treatment was significantly longer than that in the HC,while the amplitude was significantly lower than that in the HC (P <0.05). After treatment,the latency of SSR in GAD group was extended compared to the baseline level, and close to the level of the HC. The amplitude of SSR in GAD group became lower after treatment, but still higher than that of control group. The latency of SSR in MDD patients was significantly shorter after treatment compared to baseline level (P <0.05). In addition, the latency of SSR in MDD group was still longer than that in GAD group (P<0.05); meanwhile,the amplitude of SSR in MDD group was significantly lower that in GAD group (P<0.001). SSR parameters were positively correlated with HAMA and HAMD scores with a correlation coefficient of 0.57 and 0.73, respectively. CONCLUSION: There are significant differences in SSR parameters between patients with GAD and patients with MDD,indicating that SSR can be used as an objective index to distinguish anxiety from depression.

[Effects of secondary structure of the leader peptide on modification and processing of bovicin HJ50].

OBJECTIVE: Elucidating the correlation between the secondary structure of the leader peptide of lantibiotic bovicin HJ50 and its modification and processing. METHODS: The variants with mutated leader peptide were synthesized by semi-in vitro biosynthesis, and their modification pattern were then analyzed by MALDI-TOF MS. At the same time, the effect of leader peptide mutants on processing the modified propeptide was examined by HPLC and antimicrobial activity. RESULTS: We constructed 6 mutants (F-16A, V-15E, E-14L, E-8P, L-7D, L-4K) involved in forming secondary structure of the bovicin HJ50 leader peptide. F-16A, V-15E, L-4K showed very little effect on modification and processing whereas E-14L and E-8P caused changes in modification. In addition, we found that L-7D strongly affected the processing. CONCLUSION: The conserved helix structure in the leader peptide of bovicin HJ50 was closely related to the activity of BovM and BovT150, and the presence of secondary structure was very important to modification and processing of bovicin HJ50.

FimH alleles direct preferential binding of Salmonella to distinct mammalian cells or to avian cells.

This study aimed to determine whether allelic variants of the FimH adhesin from Salmonella enterica confer differential bacterial binding to different types of mammalian cells [murine bone marrow-derived dendritic cells (DCs) and HEp-2 cells] and chicken leukocytes. Although the type 1 fimbriated S. enterica serovar Typhimurium strains AJB3 (SR-11 derivative) and SL1344 both aggregated yeast cells, only the former bound efficiently to DCs and HEp-2 cells. Type 1 fimbriae-mediated binding to DCs having previously been shown to require the FimH adhesin and to be inhibited by mannose, FimH sequences from strains SL1344 and AJB3 were compared and found to differ by only one residue, asparagine 158 in SL1344 being replaced by a tyrosine in AJB3. The importance of residue 158 for FimH-mediated binding was further confirmed in recombinant Escherichia coli expressing S. enterica type 1 fimbriae with a variety of substitutions engineered at this position. Additional studies with the 'non-adhesive' FimH of a type 2 fimbriated S. enterica serovar Gallinarum showed that this FimH did not mediate bacterial binding to murine DCs or HEp-2 cells. However, the type 2 FimH significantly improved bacterial adhesion to chicken leukocytes, in comparison to the type 1 FimH of strain AJB3, attributing for the first time a function to the type 2 fimbriae of S. enterica. Consequently, our data show that allelic variation of the S. enterica FimH adhesin directs not only host-cell-specific recognition, but also distinctive binding to mammalian or avian receptors. It is most relevant that this allele-specific binding profile parallels the host specificity of the respective FimH-expressing pathogen.