Over fifty percent of the people around the world is infected with Helicobacter pylori ( H. pylori ), which is the main cause of gastric diseases such as chronic gastritis and stomach cancer. H. pylori adhesin A (HpaA), which is a surface-located lipoprotein, is essential for bacterial colonization in the gastric mucosa. HpaA had been proposed to be a promising vaccine candidate against H. pylori infection. However, the effect of non-lipidated recombinant HpaA (rHpaA) to stimulate immune response was not very ideal, and the protective effect against H. pylori infection was also limited. Here, we hypothesized that low immunogenicity of rHpaA may attribute to lacking the immunostimulatory properties endowed by the lipid moiety. In this study, two novel lipopeptides, LP1 and LP2, which mimic the terminal structure of the native HpaA (nHpaA), were synthesized and TLR2 activation activity was confirmed in vitro . To investigate whether two novel lipopeptides could improve the protective effect of rHpaA against the infection of H. pylori , groups of mice were immunized either intramuscularly or intranasally with rHpaA together with LP1 or LP2. Compared with rHpaA alone, the bacterial colonization of the mice immunized with rHpaA plus LP2 via intranasal route was significantly decreased and the expression levels of serum IgG2a, IFN-γ, and IL-17 cytokines in spleen lymphocyte culture supernatant increased obviously, indicating that the enhanced protection of LP2 may be associated with elevated specific Th1 and Th17 responses. In conclusion, LP2 has been shown to improve the protective effect of rHpaA against H. pylori infection, which may be closely related to its ability in activating TLR2 by mimicking the terminal structure of nHpaA.
Background: Because there is an urgent need to develop antibacterial therapies other than antibiotics, research has increasingly focused on the high-temperature-requirement protein A (HtrA) family proteases, which have both serine protease and chaperone activities.Objectives: The research progresses of the role of HtrA family proteases in the pathogenesis of bacterial infections are summarized, and the pros and cons of exploiting HtrA inhibitors in antibacterial drug development are proposed. Sources: A search of PubMed was performed to identify relevant studies. Content: HtrA is essential for bacteria to survive in harsh environments, based on the degradation and refolding of misfolded proteins. Moreover, HtrA family protease can lyse the epithelial cell barrier to promote invasion and can also act as or assist virulence factors to enhance pathogenicity. On the other hand, HtrA secreted by certain bacteria can also affect intra-and interspecies biofilm formation (the mechanism of its promotion or inhibition has not yet been proven). Overall, in view of the role of the HtrA family in promoting bacterial pathogenicity, effective HtrA inhibitors may be an exciting direction for drug development. Therefore, the research progress regarding HtrA inhibitors are summarized and the risks of their application are discussed. Implications: This review will be useful both for investigators involved in the HtrA field as well as those wishing to acquire a basic understanding of the role and potential implementations of HtrA. Ruo-Yi Xue,
Transmissible gastroenteritis virus (TGEV) causes great economic loss to swine industry worldwide. Vaccination is an important method to control the TGEV infection. In this study, a TGEV oral vaccine was generated by transferring a eukaryotic expression recombinant plasmid carrying the S AD (A and D antigenic sites of the S protein) epitope of TGEV into a swine-origin Lactobacillus acidophilus (L. acidophilus).In orally immunized BALB/c mice, the TGEV L. acidophilus oral vaccine induced significantly higher level of SIgA antibodies specific to TGEV compared with the mice immunized with a commercial inactivated TGEV vaccine and similar levels of IgG specific to TGEV as the inactivated vaccine. Furthermore, the TGEV L. acidophilus oral vaccine induced higher levels of IFN-γ, which suggested that the vaccine was able to induce immune response. In brief, this novel TGEV L. acidophilus oral vaccine could induce high levels of both mucosal and humoral immune responses, which has a potential to be used in the pig industries in the future.
As TLR2 agonists, several lipopeptides had been proved to be candidate vaccine adjuvants. In our previous study, lipopeptides mimicking N-terminal structures of the bacterial lipoproteins were also able to promote antigen-specific immune response. However, the structure-activity relationship of lipopeptides as TLR2 agonists is still unclear. Here, 23 synthetic lipopeptides with the same lipid moiety but different peptide sequences were synthesized, and their TLR2 activities in vitro and mucosal adjuvant effects to OVA were evaluated. LP1-14, LP1-30, LP1-34 and LP2-2 exhibited significantly lower cytotoxicity and stronger TLR2 activity compared with Pam2CSK4, the latter being one of the most potent TLR2 agonists. LP1-34 and LP2-2 assisted OVA to induce more profound specific IgG in sera or sIgA in BALF than Pam2CSK4. Furthermore, the possibility of LP1-34, LP2-2 and Pam2CSK4 as the mucosal adjuvant for the SARS-CoV-2 recombinant RBD (rRBD) was investigated. Intranasally immunized with rRBD plus either the novel lipopeptide or Pam2CSK4 significantly increased the levels of specific serum and respiratory mucosal IgG and IgA, while rRBD alone failed to induce specific immune response due to its low immunogenicity. The novel lipopeptides, especially LP2-2, significantly increased levels of rRBD-induced SARS-CoV-2 neutralizing antibody in sera, BALF and nasal wash. Finally, Support vector machine (SVM) results suggested that charged residues in lipopeptides might be beneficial to the agonist activity, while lipophilic residues might adversely affect the agonistic activity. Figuring out the relationship between peptide sequence in the lipopeptide and its TLR2 activity may lay the foundation for the rational design of novel lipopeptide adjuvant for COVID-19 vaccine.
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