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Olfactory dysfunction (OD) is a debilitating symptom frequently reported by patients with chronic rhinosinusitis (CRS) and it is associated with a dysregulated sinonasal inflammation. However, little information is available about the effect of the inflammation-related nasal microbiota and related metabolites on the olfactory function in these patients. Therefore, the current study aimed to investigate the nasal microbiota-metabolites-immune interactions and their role in the pathogenesis of OD in CRS patients. 23 and 19 CRS patients with and without OD, respectively, were enrolled in the present study. The \"Sniffin' Sticks\" was used to measure the olfactory function, while the metagenomic shotgun sequencing and the untargeted metabolite profiling were performed to assess the differences in terms of the nasal microbiome and metabolome between the two groups. The levels of nasal mucus inflammatory mediators were investigated by a multiplex flow Cytometric Bead Array (CBA). A decreased diversity in the nasal microbiome from the OD group compared to the NOD group was evidenced. The metagenomic analysis revealed a significant enrichment of in the OD group, while , , and were significantly less represented (LDA value > 3, p < 0.05). The nasal metabolome profiles were significantly different between the OD and NOD groups ( < 0.05). The purine metabolism was the most significantly enriched metabolic subpathway in OD patients compared with NOD patients ( < 0.001). The expressions of IL-5, IL-8, MIP-1α, MCP-1, and TNF were statistically and significantly increased in the OD group ( < 0.05). All these data, including the dysregulation of the nasal microbiota, differential metabolites, and elevated inflammatory mediators in OD patients demonstrated a clear interaction relationship. The disturbed nasal microbiota-metabolite-immune interaction networks may be implicated in the pathogenesis of OD in CRS patients and the underlying pathophysiological mechanisms need to be further investigated in future studies.

► Immunization of mice with gD plus IC31® elicits serum antibodies with HSV-2 neutralizing activity. ► Skin and nasomucosal immunization induce gD-specific antibodies in vaginas of mice immunized with IC31®-adjuvanted gD. ► Intradermal immunization with gD plus IC31® induces strong splenic lymphoproliferative and IFN-γ responses. ► Immunization of mice with gD plus IC31® confers significant protection against a lethal vaginal HSV-2 challenge. Genital herpes caused by herpes simplex virus type 2 (HSV-2) remains the leading cause of genital ulcers worldwide. Given the disappointing results of the recent genital herpes vaccine trials in humans, development of novel vaccine strategies capable of eliciting protective mucosal and systemic immune responses to HSV-2 is urgently required. Here we tested the ability of the adjuvant IC31® in combination with HSV-2 glycoprotein D (gD) used through intranasal (i.n.), intradermal (i.d.), or subcutaneous (s.c.) immunization routes for induction of protective immunity against genital herpes infection in C57BL/6 mice. Immunization with gD plus IC31® through all three routes of immunization developed elevated gD-specific serum antibody responses with HSV-2 neutralizing activity. Whereas the skin routes promoted the induction of a mixed IgG2c/IgG1 isotype profile, the i.n. route only elicited IgG1 antibodies. All immunization routes were able to induce gD-specific IgG antibody responses in the vaginas of mice immunized with IC31®-adjuvanted gD. Although specific lymphoproliferative responses were observed in splenocytes from mice of most groups vaccinated with IC31®-adjuvanted gD, only i.d. immunization resulted in a significant splenic IFN-γ response. Further, immunization with gD plus IC31® conferred 80–100% protection against an otherwise lethal vaginal HSV-2 challenge with amelioration of viral replication and disease severity in the vagina. These results warrant further exploration of IC31® for induction of protective immunity against genital herpes and other sexually transmitted infections.

► Higher doses of the rOmpA anti-Acinetobacter baumannii vaccine induced higher vaccine titers. ► Higher dose of the rOmpA vaccine induced more polarized Type 2 immune response. ► Distinct rOmpA peptides preferentially induced IFN-γ or IL-4T cell responses. ► Higher vaccine dose induced epitope spreading for IL-4 producing lymphocytes. ► Higher vaccine dose induced epitope restriction for IFN-γ producing lymphocytes. The rOmpA vaccine has been shown to protect mice from lethal infection caused by extreme-drug-resistant (XDR) Acinetobacter baumannii. The role of dose in immunology of the rOmpA vaccine was explored. Mice were vaccinated with various doses of rOmpA plus aluminum hydroxide (Al(OH)3) adjuvant. The impact of dose on antibody titers, cytokine production, and immunodominant epitopes was defined. Anti-rOmpA IgG and IgG subtype titers were higher at larger vaccine doses (30 and 100μg vs. 3μg). The 3μg dose induced a balanced IFN-γ–IL-4 immune response while the 100μg dose induced a polarized IL-4/Type 2 response. Epitope mapping revealed distinct T cell epitopes that activated IFN-γ-, IL-4-, and IL-17-producing splenocytes. Vaccination with the 100μg dose caused epitope spreading among IL-4-producing splenocytes, while it induced fewer reactive epitopes among IFN-γ-producing splenocytes. Vaccine dose escalation resulted in an enhanced Type 2 immune response, accompanied by substantial IL-4-inducing T cell epitope spreading and restricted IFN-γ-inducing epitopes. These results inform continued development of the rOmpA vaccine against A. baumannii, and also are of general importance in that they indicate that immune polarization and epitope selectivity can be modulated by altering vaccine dose.

Neonates are highly susceptible to infectious diseases and, in general, respond poorly to conventional vaccines due to immaturity of the immune system. In the present study, we hypothesized that the anti-tetanus toxoid (TT) vaccine response of neonatal mice could be enhanced by retinoic acid (RA), a bioactive retinoid, and polyriboinosinic:polyribocytidylic acid (PIC), an inducer of IFN. Early-life treatments with RA and/or PIC were well tolerated and stimulated both primary anti-TT IgG production in infancy and the memory response in adulthood. TT-specific lymphocyte proliferation and type 1/type 2 cytokine production were also significantly augmented. In addition, RA and PIC modulated the maturation and/or differentiation of neonatal B cells, natural killer (NK)/NKT cells, and antigen-presenting cells. Although RA alone increased the neonatal anti-TT antibody response, it selectively increased anti-TT IgG1 and IL-5, resulting in a skewed type 2 response. PIC, a potent adjuvant in adult mice, elevated neonatal anti-TT IgG as well as all IgG isotypes (IgG1, IgG2a, and IgG2b) and induced TT-specific IFN-γ, an important type 1 cytokine; however, PIC alone failed to benefit the memory response. The combination of RA plus PIC was more potent than either agent alone in elevating primary and secondary anti-TT IgG responses as well as IgG isotypes. Moreover, RA plus PIC increased TT-specific IFN-γ and IL-5, suggesting the combination effectively promoted both type 1 and type 2 responses in neonatal mice. Thus, RA combined with PIC, a nutritional-immunological intervention, seems promising as an adjuvant for early-life vaccination.

Typically, neonates exhibit decreased or aberrant cellular immune responses when compared to adults, resulting in increased susceptibility to infection. However, it is clear that newborns are able to generate adult-like protective T cell responses under certain conditions. The focus of our research is to understand the deficiencies within the neonatal immune system that lead to improper cellular responses and how priming conditions can be altered to elicit the appropriate T cell response necessary to protect against development of pathogen-induced disease. With these goals in mind, we are exploring the attributes of neonatal T cells and their development, as well as the conditions during priming that influence the resulting response to immune challenge during the neonatal period.

One of the major lessons we learned from the radiation-attenuated cercariae vaccine studies is that protective immunity against schistosomiasis is dependent on the induction of T helper (Th)1-/Th2-related immune responses. Since most schistosome larval and adult-worm-derived molecules used for vaccination uniformly induce a polarized Th1 response, it was essential to include a type 2 immune response-inducing molecule, such as cysteine peptidases, in the vaccine formula. Here, we demonstrate that a single subcutaneous injection of Syrian hamsters with 200 μg active papain, 1 h before percutaneous exposure to 150 cercariae of Schistosoma haematobium, led to highly significant (P < 0.005) reduction of >50% in worm burden and worm egg counts in intestine. Immunization of hamsters with 20 μg recombinant glyceraldehyde 3-phosphate dehydrogenase (rSG3PDH) and 20 μg 2-cys peroxiredoxin-derived peptide in a multiple antigen peptide construct (PRX MAP) together with papain (20 μg/hamster), as adjuvant led to considerable (64%) protection against challenge S. haematobium infection, similar to the levels reported with irradiated cercariae. Cysteine peptidases-based vaccination was also effective in protecting outbred mice against a percutaneous challenge infection with S. haematobium cercariae. In two experiments, a mixture of Schistosoma mansoni cathepsin B1 (SmCB1) and Fasciola hepatica cathepsin L1 (FhCL1) led to highly significant (P < 0.005) reduction of 70% in challenge S. haematobium worm burden and 60% reduction in liver egg counts. Mice vaccinated with SmCB1/FhCL1/rSG3PDH mixture and challenged with S. haematobium cercariae 3 weeks after the second immunization displayed highly significant (P < 0.005) reduction of 72% in challenge worm burden and no eggs in liver of 8-10 mice/group, as compared to unimmunized mice, associated with production of a mixture of type 1- and type 2-related cytokines and antibody responses.