Mucosal vaccine development for respiratory viral infections

Mucosal vaccines have risen to prominence in the corona virus disease 2019(COVID-19)pandemic due to their ability to elicit both local antibody and tissue-resident T cell responses,affording a dual-layered defense against infection and transmission at respiratory entry sites.While intramuscular vaccines predominantly focus on systemic immunity,mucosal vaccines offer a more nuanced,site-specific approach.However,the field faces a dearth of mucosal vaccine options for respiratory diseases,starkly contrasting to the extensive array of well-characterized injectable vaccines.The unique features of mucosal surfaces necessitate specialized adjuvants and delivery systems,adding complexity to adapting injectable vaccine technologies for mucosal applications.Here,we review the recent insights into the specificities of respiratory mucosal immunology that provide a foundation for future innovations besides the emerging vaccine platforms,newly discovered adjuvants,and vaccine delivery systems,which may open promising avenues for developing mucosal vaccines targeting respiratory pathogens.

Molecular mechanism of action of anti-tumor necrosis factor antibodies in inflammatory bowel diseases

Anti-tumor necrosis factor(TNF) antibodies are successfully used in the therapy of inflammatory bowel diseases(IBD). However, the molecular mechanism of action of these agents is still a matter of debate. Apart from neutralization of TNF, influence on the intestinal barrier function, induction of apoptosis in mucosal immune cells, formation of regulatory macrophages as well as other immune modulating properties have been discussed as central features. Nevertheless, clinically effective anti-TNF antibodies were shown to differ in their mode-of-action in vivo and in vitro. Furthermore, the anti-TNF agent etanercept is effective in the treatment of rheumatoid arthritis but failed to induce clinical response in Crohn's disease patients, suggesting different contributions of TNF in the pathogenesis of these inflammatory diseases. In the following, we will review different aspects regarding the mechanism of action of anti-TNF agents in general and analyze comparatively different effects of each antiTNF agent such as TNF neutralization, modulation of the immune system, reverse signaling and induction of apoptosis. We discuss the relevance of the membranebound form of TNF compared to the soluble form for the immunopathogenesis of IBD. Furthermore, we review reports that could lead to personalized medicine approaches regarding treatment with antiTNF antibodies in chronic intestinal inflammation, by predicting response to therapy.

Changes of the immunological barrier of intestina mucosa in rats with sepsis

BACKGROUND： Sepsis has become the greatest threat to in-patients, with a mortality of over 25%.The dysfunction of gut barrier, especially the immunological barrier, plays an important role in the development of sepsis. This dysfunction occurs after surgery, but the magnitude of change does not differentiate patients with sepsis from those without sepsis. Increased intestinal permeability before surgery is of no value in predicating sepsis. The present study aimed to observe the changes of intestinal mucosal immunologic barrier in rat models of sepsis induced by cecal ligation and puncture.METHODS： Sixty Sprague-Dawley rats were randomly divided into a sepsis group （n=45） and a control group （n=15）. The rats in the sepsis group were subjected to cecal ligation and puncture （CLP）, whereas the rats in the control group underwent a sham operation. The ileac mucosa and segments were harvested 3, 6 and 12 hours after CLP, and blood samples were collected. Pathological changes, protein levels of defensin-5 （RD-5） and trefoil factor-3 （TFF3） mRNA, and lymphocytes apoptosis in the intestinal mucosa were determined. In an additional experiment, the gut-origin bacterial DNA in blood was detected.RESULTS： The intestinal mucosa showed marked injury with loss of ileal villi, desquamation of epithelium, detachment of lamina propria, hemorrhage and ulceration in the sepsis group. The expression of TFF3 mRNA and level of RD-5 protein were decreased and the apoptosis of mucosal lymphocyte increased （P〈0.05） in the sepsis group compared with the control group. Significant differences were observed in RD-5 and TFF3 mRNA 3 hours after CLP and they were progressively increased 6 and 12 hours after CLP in the sepsis group compared with the control group （P〈0.05, RD-5 F=11.76, TFF3 F=16.86 and apoptosis F=122.52）. In addition, the gut-origin bacterial DNA detected in plasma was positive in the sepsis group.CONCLUSION： The immunological function of the intestinal mucosa was impaired in septic rats and further deteriorated in the course of sepsis.

Olfactory immune response to SARS-CoV-2

Numerous pathogens can infect the olfactory tract,yet the pandemic caused by SARS-CoV-2 has strongly emphasized the importance of the olfactory mucosa as an immune barrier.Situated in the nasal passages,the olfactory mucosa is directly exposed to the environment to sense airborne odorants;however,this also means it can serve as a direct route of entry from the outside world into the brain.As a result,olfactotropic infections can have serious consequences,including dysfunction of the olfactory system,CNS invasion,dissemination to the lower respiratory tract,and transmission between individuals.Recent research has shown that a distinctive immune response is needed to protect this neuronal and mucosal tissue.A better understanding of innate,adaptive,and structural immune barriers in the olfactory mucosa is needed to develop effective therapeutics and vaccines against olfactotropic microbes such as SARS-CoV-2.Here,we summarize the ramifications of SARS-CoV-2 infection of the olfactory mucosa,review the subsequent immune response,and discuss important areas of future research for olfactory immunity to infectious disease.

Microbial sensing in the intestine

The gut microbiota plays a key role in host health and disease,particularly through their interactions with the immune system.Intestinal homeostasis is dependent on the symbiotic relationships between the host and the diverse gut microbiota,which is influenced by the highly co-evolved immune-microbiota interactions.The first step of the interaction between the host and the gut microbiota is the sensing of the gut microbes by the host immune system.In this review,we describe the cells of the host immune system and the proteins that sense the components and metabolites of the gut microbes.We further highlight the essential roles of pattern recognition receptors(PRRs),the G protein-coupled receptors(GPCRs),aryl hydrocarbon receptor(AHR)and the nuclear receptors expressed in the intestinal epithelial cells(IECs)and the intestine-resident immune cells.We also discuss the mechanisms by which the disruption of microbial sensing because of genetic or environmental factors causes human diseases such as the inflammatory bowel disease(IBD).