The occurrence of preterm birth is associated with multiple factors including bleeding, infection and inflammation. Platelets are mediators of hemostasis and can modulate inflammation through interactions with leukocytes. TREM like Transcript 1 (TLT-1) is a type 1 single Ig domain receptor on activated platelets. In adults, it plays a protective role by dampening the inflammatory response and facilitating platelet aggregation at sites of vascular injury. TLT-1 is expressed in human placenta and found in cord blood. We thus hypothesized that TLT-1 deficiency is associated with prematurity and fetal inflammation.
To test this hypothesis, we examined cord blood levels of soluble TLT-1 (sTLT) in premature and term infants and compared the inflammatory response in C57BL/6 (WT) and TLT-1-/- (treml1-/- , KO) mice given intraperitoneal LPS mid-gestation RESULTS: The preterm infant cord blood level of sTLT was significantly lower than that found at term. On exposure to LPS, histology of KO (as compared to WT) placenta and decidua showed increased hemorrhage, and KO decidual RNA expression of IL-10 was significantly lower. KO fetal interface tissues (placenta, membranes, amniotic fluid) over time showed increased expression of inflammatory cytokines such as IL-6, IFN-γ, and TNF, but not MCP-1. However, fetal organs showed similar levels.
There is a potential association between insufficient TLT-1 expression and increased fetal inflammatory responses in the setting of prematurity. The data support further study of TLT-1 in the mechanistic link between bleeding, inflammation and preterm birth, and perhaps as a biomarker in human pregnancy.
© 2023 The Authors. American Journal of Reproductive Immunology published by John Wiley & Sons Ltd.

In previous studies, we determined that the F-box protein Fbp1, a subunit of the SCF(Fbp1) E3 ligase in Cryptococcus neoformans, is essential for fungal pathogenesis. Heat-killed fbp1Δ cells (HK-fbp1) can confer vaccine-induced immunity against lethal challenge with clinically important invasive fungal pathogens, e.g., C. neoformans, C. gattii, and Aspergillus fumigatus. In this study, we found that either CD4+ T cells or CD8+ T cells were sufficient to confer protection against lethal challenge by C. neoformans in HK-fbp1-induced immunity. Given the potent effect of HK-fbp1 as a preventative vaccine, we further tested the potential efficacy of administering HK-fbp1 cells as a therapeutic agent for treating animals after infection. Remarkably, administration of HK-fbp1 provided robust host protection against preexisting C. neoformans infection. The mice infected with wild-type H99 cells and then treated with HK-fbp1 showed significant reduction of fungal burden in the infected lung and no dissemination of fungal cells to the brain and spleen. We find that early treatment is critical for the effective use of HK-fbp1 as a therapeutic agent. Immune analysis revealed that early treatment with HK-fbp1 cells elicited Th1-biased protective immune responses that help block fungal dissemination and promote better host protection. Our data thus suggest that HK-fbp1 is both an effective prophylactic vaccine candidate against C. neoformans infection in both immunocompetent and immunocompromised populations and a potential novel therapeutic strategy to treat early-stage cryptococcosis. IMPORTANCE Invasive fungal infections, e.g., cryptococcosis, are often life threatening and difficult to treat with very limited therapeutic options. There is no vaccine available in clinical use to prevent or treat fungal infections. Our previous studies demonstrated that heat-killed fbp1Δ cells (HK-fbp1) in Cryptococcus neoformans can be harnessed to confer protection against a challenge by the virulent parental strain, even in immunocompromised animals, such as ones lacking CD4+ T cells. In this study, we further determined that T cells are required for vaccine-induced protection against homologous challenge and that either CD4+ or CD8+ cells are sufficient. This finding is particularly important for the potential utility of this vaccine candidate in the context of HIV/AIDS-induced immune deficiency, the main risk factor for cryptococcosis in humans. Furthermore, in addition to the utility of HK-fbp1 as a prophylactic vaccine, we found that HK-fbp1 administration can inhibit disease dissemination when animals are treated at an early stage during Cryptococcus infection. Our findings could significantly expand the utility of HK-fbp1 not only as a prophylactic vaccine but also as a novel therapy against cryptococcosis. In all, our studies showed that the HK-fbp1 strain can be used both preventively and therapeutically to elicit robust host protection against cryptococcosis.

In previous studies we determined that the F-box protein Fbp1, a subunit of the SCF(Fbp1) E3 ligase in Cryptococcus neoformans , is essential for fungal pathogenesis. Heat-killed fbp1 Δ cells (HK-fbp1) can confer vaccine-induced immunity against lethal challenge with clinically important invasive fungal pathogens, e.g., C. neoformans, C. gattii , and Aspergillus fumigatus . In this study, we found that either CD4 + T cells or CD8 + T cells are sufficient to confer protection against lethal challenge of C. neoformans in HK-fbp1 induced-immunity. Given the potent effect of HK-fbp1 as a preventative vaccine, we further tested the potential efficacy of administering HK-fbp1 cells as a therapeutic agent for treating animals after infection. Remarkably, administration of HK-fbp1 provided robust host protection against pre-existing C. neoformans infection. The mice infected with wild type H99 cells and then treated with HK-fbp1 showed significant reduction of fungal CFU in the infected lung, and no dissemination of fungal cells to the brain and spleen. we find that early treatment is critical for the effective use of HK-fbp1 as a therapeutic agent. Immune analysis revealed that early treatment with HK-fbp1 cells elicited Th1 biased protective immune responses that help block fungal dissemination and promote better host protection. Our data thus suggest that HK-fbp1 is both an effective prophylactic vaccine candidate against C. neoformans infection in both immunocompetent and immunocompromised populations, as well as a potential novel therapeutic strategy to treat early stage cryptococcosis. Importance Invasive fungal infections, e.g., cryptococcosis, are often life threatening and difficult to treat with very limited therapeutic options. There is no vaccine available in clinical use to prevent or treat fungal infections. Our previous studies demonstrated that heat-killed fbp1 Δ cells (HK-fbp1) in Cryptococcus neoformans can be harnessed to confer protection against a challenge by the virulent parental strain, even in immunocompromised animals, such as the ones lacking CD4 + T cells. In this study, we further determined that T cells are required for vaccine-induced protection against homologous challenge and that either CD4 + or CD8 + cells are sufficient. This finding is particularly important for the potential utility of this vaccine candidate in the context of HIV/AIDS-induced immune deficiency, the main risk factor for cryptococcosis in humans. Furthermore, in addition to the utility of HK-fbp1 as a prophylactic vaccine, we found that HK-fbp1 administration can inhibit disease dissemination when animals are treated at an early-stage during Cryptococcus infection. Our findings could significantly expand the utility of HK-fbp1 not only as prophylactic vaccine but also as a novel therapy against cryptococcosis. Conceptually, therapeutic administration of HK-fbp1 could have an advantage over small molecule antifungal drugs in that it is expected to have minimal side effects and lower cost. In all, our studies showed that HK-fbp1 strain can be used both preventively and therapeutically to elicit robust host protection against cryptococcosis.

The current asthma therapies are inadequate for many patients with severe asthma. Pyrroloquinoline quinone (PQQ) is a naturally-occurring redox cofactor and nutrient that can exert a multitude of physiological effects, including anti-inflammatory and antioxidative effects. We sought to explore the effects of PQQ on allergic airway inflammation and reveal the underlying mechanisms. In vitro, the effects of PQQ on the secretion of epithelial-derived cytokines by house dust mite- (HDM-) incubated 16-HBE cells and on the differentiation potential of CD4+ T cells were investigated. In vivo, PQQ was administered to mice with ovalbumin- (OVA-) induced asthma, and lung pathology and inflammatory cell infiltration were assessed. The changes in T cell subsets and signal transducers and activators of transcription (STATs) were evaluated by flow cytometry. Pretreatment with PQQ significantly decreased HDM-stimulated thymic stromal lymphopoietin (TSLP) production in a dose-dependent manner in 16-HBE cells and inhibited Th2 cell differentiation in vitro. Treatment with PQQ significantly reduced bronchoalveolar lavage fluid (BALF) inflammatory cell counts in the OVA-induced mouse model. PQQ administration also changed the secretion of IFN-γ and IL-4 as well as the percentages of Th1, Th2, Th17, and Treg cells in the peripheral blood and lung tissues, along with inhibition the phosphorylation of STAT1, STAT3, and STAT6 while promoting that of STAT4 in allergic airway inflammation model mice. PQQ can alleviate allergic airway inflammation in mice by improving the immune microenvironment and regulating the JAK-STAT signaling pathway. Our findings suggest that PQQ has great potential as a novel therapeutic agent for inflammatory diseases, including asthma.
Copyright © 2022 Zhihui Min et al.

The success of using immune checkpoint inhibitors to treat cancers implies that inhibiting an immunosuppressive cytokine, such as TGF-β2, could be a strategy to develop novel adjuvants for microbial vaccines. To develop nucleic acid based TGF-β2 inhibitors, we designed three antisense oligonucleotides, designated as TIO1, TIO2, and TIO3, targeting the conserve regions identical in human and mouse TGF-β2 mRNA 3'-untranslated region. In cultured immune cells, TIO3 and TIO1 significantly reduced the TGF-β2 mRNA expression and protein production. In mice, the TIO3 and TIO1, when formulated in various microbial vaccines, significantly enhanced the antibody response to the vaccines, and the TIO3-adjuvanted influenza virus vaccine induced effective protection against the influenza virus challenge. In the immunized mice, TIO3 formulated in microbial vaccines dramatically reduced surface-bound TGF-β2 expression on CD4+ T cells and CD19+ B cells in the lymph node (LN) cells and spleen cells; up-regulated the expression of CD40, CD80, CD86, and MHC II molecules on CD19+ B cells and CD11c+ dendritic cells; and promoted IFN-γ production in CD4+ T cells and CD8+ T cells in the LN cells. Overall, TIO3 or TIO1 could be used as a novel type of adjuvant for facilitating the microbial vaccines to elicit more vigorous and persistent antibody response by interfering with TGF-β2 expression.
©2020 Society for Leukocyte Biology.