bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nanoparticle vaccines enhance humoral responses to a malaria antigen by expanding Tfh cells and inducing germinal center formation (166.10)
Authors: Moon James , Suh Heikyung , Li Adrienne , Yadava Anjali , Irvine Darrell 
Published: January 2023

Abstract
Nanoparticles (NP) are promising delivery vehicles for vaccines that promote humoral and cellular immunity in concert. We recently developed a novel lipid-based NP vaccine system, termed interbilayer-crosslinked multilamellar vesicles (ICMVs). ICMVs efficiently entrap and co-deliver antigens and molecular adjuvants to lymphoid tissues, initiating potent cellular and humoral immune responses. ICMVs were synthesized by fusing liposomes containing antigen into multilamellar vesicles, followed by bilayer-to-bilayer crosslinking of lipid bilayers within the vesicle walls to stabilize the particles. ICMVs carrying ovalbumin and the TLR agonist MPLA induced robust cytotoxic T lymphocyte responses in mice, achieving a peak ~30% tetramer+ cells in the CD8+ T-cell population after 3 immunizations. Mice vaccinated with ICMVs containing a candidate Plasmodium vivax antigen raised high-titer, high-avidity antibody responses against the antigen lasting &gt; 1 yr, at 10-fold lower dose of antigen than conventional adjuvants such as alum or Montanide. Compared to vaccination with alum, immunization with ICMVs prolonged antigen accumulation at the draining lymph nodes, enhanced germinal center formation, and increased the expansion of antigen-specific follicular helper T-cells, partially explaining the enhanced antibody response. These results suggest that antigen/adjuvant-carrying ICMVs may serve as a platform to elicit potent cellular and humoral immune responses against infectious pathogens.
Generation of the Recombinant M. smegmatis and M. bovis (BCG) Vaccine with genes of Enteropathogenic E. coli bfpA and intimin. Dias da Silva, W, 1, 3, Vasconcellos, H.L.F. 1,2,3 ; Scaramuzzi, K.1,3; Rodriguez, D.2 ; Nascimento, I.P.2; 1 Laboratório de Imunoquímica, Instituto Butantan São Paulo, SP, Brazi. 2 Laboratório de Biotecnologia, Instituto Butantan São Paulo, SP, Brazil. 3 Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, SP, Brazil. (166.15)
Authors: daSilva Wilmar , Vasconcelos Halyka , Scaramuzzi Karina , Nascimento Ivan , Junior Jorge , Pizza Rochane , Kipnis André 
Published: January 2023

Abstract
Escherichia coli (EPEC) is important cause of diarrhea in children. EPEC adhere the intestinal epithelium causing the attaching and effacing (A/E) lesions. Recombinant M. smegmatis (MS) and BCG were constructed to express bfpA or intimin. Briefly, the whole bfpA gene and the intimin portion were amplified by PCR primers from genomic DNA (EPEC), and inserted into pMIP12 at the BamH I/KpnI sites. The vectors pMIP_bfpA and pMIP _intim were introduced separately into MS and BCG. Recombinants clones were selected based on resistance to kanamycin and named rSmeg_pMIP_(bfpA or intimin) and rBCG_pMIP_(bfpA or intimin). The expression of bfpA and intimin were detected by Western blotting using polyclonal anti-BfpA or anti-Intimin as first antibodies. The immunogenicity of these proteins was assessed in C57BL/6 mice. IgA and IgG antibodies anti-BfpA and anti-Intimin were detected in feces or in serum. TNF-α and INF-γ were produced in vitro by spleen cells from mice immunized with recombinant BfpA and recombinant Intimin. Adhesion of EPEC (E2348/69) on Hep-2 target cells was blocked by IgA or IgG from mice immunized with recombinant BfpA or Intimin, but not by non-immune antibodíes. Immunogenic non-infective vectors containing relevant EPEC virulence genes are promising vaccines.
Enhancement of the long term efficacy of BCG vaccine against experimental tuberculosis in mice through rapamycin induced modulation of CD4 and CD8 T cell functions (166.17)
Authors: Bakhru Pearl , Soudani Emily , Khan Arshad , Yuan Daniel , Lewis Dorothy , Hunter Robert , Jagannath Chinnaswamy 
Published: January 2023

Abstract
BCG vaccine protects children but does not induce long-term immunity against tuberculosis. Rapamycin has been found to directly act on MTOR of T cells and extend the longevity of CD8 T cell response to viral infection in mice. We hypothesized that rapamycin co-administration during BCG vaccination may alter the quality of CD8 function to enable long-term immunity. Methods: C57Bl/6 mice were given one dose of BCG vaccine (1 million per mouse; s.c.) or BCG with doses of rapamycin (75 microgram/mg given daily for 30 days) followed by aerosol infection with virulent Mycobacterium tuberculosis (Mtb). At 4 and 8 weeks, antigen specific CD8 T cells, memory specific markers and tetramers specific for Mtb antigens-ESAT6 and TB10.4 were analysed using flow cytometry. Log10 decline of Mtb counts in lungs was determined to correlate T cell phenotype with protection after vaccination. Results: Rapamycin coadministration with BCG enhanced the expansion of antigen-specific CD8 T cells in mice that correlated with a decline in the counts of Mtb in lungs and spleens of mice. Rapamycin increased both CD8 and CD4 T cells in the lungs and spleens and enhanced central memory (Tcm) CD8 T cells in lymphoid organs. Tcm levels, in turn, correlated with an increase in expression of Eomes transcription factor by CD8 T cells. Since Eomes is a determinant of Tcm lineage, we suggest that the long-term efficacy of BCG vaccine can be enhanced through modulation of MTOR dependent pathways of T cells.
Protective B cell epitopes of Francisella tularensis O-polysaccharide targeted by mouse and human antibodies (166.22)
Authors: Lu Zhaohua , Rynkiewicz Michael , Madico Guillermo , Roche Marly , Wang Qi , Hui Julia , Perkins Hillary , Seaton Barbara , Zaia Joseph , Costello Catherine , Sharon Jacqueline 
Published: January 2023

Abstract
Francisella tularensis (Ft), the gram-negative bacterium that causes tularemia, is considered a potential bioterrorism agent. Antibodies to Ft lipopolysaccharide (LPS) are protective against respiratory tularemia in mouse models, and we have previously described mouse monoclonal antibodies (MAbs) to non-overlapping terminal and internal epitopes of the Ft LPS O-polysaccharide (OAg). In the current study, we used competition ELISA with oligosaccharides of defined OAg repeat length, x-ray crystallography and docking studies to map the epitope of the terminal-binding MAb FB11 to one OAg tetrasaccharide repeat at the non-reducing end, and the epitope of the internal-binding MAb Ab52 to six sugar residues, spanning two OAg repeats, each repeat contributing three residues. Both FB11 and Ab52 conferred or prolonged survival in a mouse model of respiratory tularemia against Ft type B live vaccine strain (LVS) or the highly virulent Ft type A strain SchuS4, respectively. The two MAbs were successfully used as reporters, in competition ELISA, to demonstrate the presence of antibodies to both terminal and internal Ft OAg epitopes in the sera of tularemia patients. These results indicate that two Ft OAg repeats are necessary and sufficient for antibody binding to both terminal and internal protective OAg epitopes, which may inform the design of vaccines for tularemia. Furthermore, the FB11 and Ab52 MAbs could be used to monitor protective B cell responses in tularemia vaccine trials.
Probiotics and lactogenic immune factors affect neonatal B cell responses to rotavirus vaccine (166.26)
Authors: Chattha Kuldeep , Vlasova Anastasia , Esseili Malak , Kandasamy Sukumar , Siegismund Christine , Rajashekara Gireesh , Saif Linda 
Published: January 2023

Abstract
Breast milk (milk/colostrum [cols]) components and gut commensals play important roles in neonatal immune maturation, establishment of gut homeostasis and immune responses to oral vaccines. We investigated the impact of lactic acid bacteria colonization (Lactobacillus rhamnosus strain GG and Bifidobacterium lactis Bb12, probiotics) with/without mother’s milk/cols on B cell responses to an attenuated human rotavirus (RV) vaccine in a neonatal gnotobiotic pig model. Milk/cols did not affect probiotic colonization in RV vaccinated pigs. However unvaccinated pigs fed milk/cols shed higher fecal titers of probiotic bacteria than non-cols/milk fed colonized controls (p&lt;0.05). In RV vaccinated pigs, milk/cols feeding with probiotic treatment resulted in a trend for higher mean serum IgA RV antibody titers and intestinal IgA antibody secreting cell (ASC) numbers compared to milk-fed, non-probiotic colonized pigs. Probiotic colonization alone did not affect IgA RV antibody titers in vaccinated pigs, but serum IgG RV antibody titers (p&lt;0.05) and gut IgG ASC numbers were lower, suggesting that certain probiotics impact RV vaccine responses. In vaccinated pigs, probiotic or milk/cols supplementation did not enhance total intestinal B cell numbers above that induced by attenuated RV vaccine alone. Our findings suggest that probiotics and milk/cols components (soluble mediators), alone or synergistically, modulate neonatal immune responses to oral RV vaccines, requiring further evaluation.
A vaccine formulated with the Chlamydia trachomatis (Ct) recombinant major outer membrane protein (rMOMP) and TLR2 and TLR9 agonists as adjuvants elicits strong protection against an intranasal challenge (166.4)
Authors: Cheng Chunmei , Pal Sukumar , Tifrea Delia , de la Maza Luis 
Published: January 2023

Abstract
Ct is the most common sexually transmitted bacterial pathogen in the World and there is an urgent need for a vaccine to prevent these infections. To enhance the immunogenicity of a vaccine formulated with the Ct mouse pneumonitis rMOMP, we used combinations of Pam2CSK4 (TLR2) + CpG1826 (TLR9) and Montanide ISA 720 + CpG1826 as adjuvants. Neisseria gonorrhoeae recombinant porin B was used as antigen control with the same adjuvants. Female BALB/c mice were primed twice in the nares (i.n.) or in the colon (cl.) and were boosted twice by the intramuscular plus subcutaneous (i.m.+s.c.) routes. Based on the IgG2a/IgG1 ratio in sera, mice immunized with rMOMP+Pam2CSK4+CpG1826 showed a strong Th2 response while animals vaccinated with rMOMP+Montanide+CpG1826 had a Th1 response. These mice also developed robust Ct-specific T cell proliferation and high levels of IFN-γ. Four weeks after the last immunization, the mice were challenged i.n. with 104 inclusion-forming units (IFU) of Ct. Using changes in body weight, weight of the lungs and number of IFU recovered from the lungs at 10 days post-challenge as parameters of protection, the mice immunized i.n.+i.m.+s.c. with rMOMP+Pam2CSK4+CpG1826 were better protected against the i.n. chlamydial infection than the other groups. In conclusion, a combination of Pam2CSK+CpG1826 elicits strong humoral and cellular immune responses and enhances the protective ability of a Ct-rMOMP vaccine delivered by the mucosal and systemic routes.
Role of Dectin-2 in the serotype-specific antibody production and host protection against Streptococcus pneumoniae infection caused by pneumococcal polysaccharide vaccine (166.8)
Authors: Miyasaka Tomomitsu , Akahori Yukiko , Miyamura Namiko , Toyama Masahiko , Saijo Shinobu , Iwakura Yoichiro , Kinjo Yuki , Oishi Kazunori , Kawakami Kazuyoshi 
Published: January 2023

Abstract
Anti-pneumococcal polysaccharide vaccine (PPV) induces the production of serotype-specific Ab including IgG2 in spite of its feature of thymus-independent antigen. It remains to be clarified how PPV causes a class-switching from IgM to IgG. Recently, C-type lectin receptors (CLR) sensing polysaccharides have garnered much attention in the host defense to fungal infection. In our recent study, Dectin-2, a CLR involved in the recognition of mannose-rich polysaccharides, has been found to play an important role in the host defense to pneumococcal infection. Therefore, in this study, we addressed how Dectin-2 was involved in the vaccine effect of PPV using a mouse model. The serum levels of anti-serotype 3 pneumococcal capsular polysaccharide (PPS-3) two weeks after vaccination were significantly reduced in Dectin-2 knockout (KO) mice compared to wild-type (WT) mice. Weight loss and hypothermia of mice caused by infection with Streptococcus pneumoniae (URF918) were improved in WT mice transferred with spleen cells from vaccinated WT mice compared to those from vaccinated Dectin-2KO mice. Similar tendency was observed in the survival of infected mice. In in vitro experiments, IL-12p40, TNF-α and IL-6 production by bone marrow-derived dendritic cells (BM-DCs) stimulated with PPV was abrogated in Dectin-2KO. These results suggest that Dectin-2 is involved in the PPV-induced serotype-specific Ab production and host protection through sensing the pneumococcal polysaccharide antigens.
Modulation of immune cell function by an early life experience (167.11)
Authors: Smith Susan , Williamson Lauren , Sholar Paige , Bilbo Staci 
Published: January 2023

Abstract
Pro-inflammatory IL-1 beta cytokine production within the hippocampus (HP) is required for normal learning. However, excessive IL-1 beta levels in the brain can interfere with memory consolidation, resulting in cognitive deficits and neurodegeneration. We have identified the cellular source of IL-1 beta during learning as microglia, a CNS-resident macrophage cell type. Intriguingly, microglia from adult rats that suffered an immune challenge early in life are “primed” for exaggerated IL-1 beta responses, which is maladaptive because it can interfere with normal learning and memory. Similar to control cells, primed microglia do not produce cytokines constitutively. Rather, exaggerated cytokine responses in primed microglia likely result from an altered pattern of transcriptional regulation that was initiated during an early life infection and is propagated into adulthood via specific epigenetic markings. We have found that HP microglia from neonatally infected rats have a global reduction in dimethylated histone H3K9 compared to control (mock-infected) rats. The specific gene loci involved in the regulation of microglial cytokine expression from primed and control rats are now under investigation. Thus, our model of early life infection demonstrates a role for brain-resident immune cells in mediating the “programming” of a later cognitive dysfunction via intrinsic differences in their epigenetic status.
The role of splenic CD103+CD8α+cDCs in the induction of CTL responses during respiratory virus infection (168.11)
Authors: Morimoto Junko , Nakayama Yosuke , Danzaki Keiko , Kajino Kiichi , Uede Toshimitsu 
Published: January 2023

Abstract
We have previously reported that large numbers of virus-specific CD8+ T cells were detected in the spleen following intranasal influenza virus infection. This finding does not seem simply due to the migration of cells from the draining mediastinal lymph nodes (mLN), but rather indicates that spleen can be a site for the induction of primary CTL responses. Although the integrin αEβ7 (CD103)+ migratory DCs have been known as a major DC subset which prime naïve influenza virus-specific CD8+ T cells in the mLN, what kind of DC subset is responsible for the induction of CTL responses in the spleen remains unclear. In this study, we found that increased numbers of CD103+DCs were detectable in the spleen following influenza virus infection, and the majority of CD103+DCs expressed CD8α. Although both CD103+CD11chi DCs (CD103+DCs) and CD103-CD11chi DCs (CD103-DCs) showed activated phenotype evidenced by the expression of co-stimulatory molecules at 9 days post infection, PDL-1 expression pattern was different between these two subsets. Immunohistochemical analysis showed that CD103+DCs localized in the T cell area (also in the B cell area) and purified CD103+DCs produced large amounts of IL-12p40 compared with CD103-DCs. These data suggest that splenic CD103+DCs may play a critical role in the development of CTL responses during influenza virus infection. We are currently investigating how efficiently splenic CD103+DCs act as antigen presenting cells.
Effects of zidovudine on murine viral infection-induced peripheral neuropathy and cytokine responses (168.12)
Authors: Cao Ling , Butler Michael , Draleau Kyle 
Published: January 2023

Abstract
LP-BM5, a murine retroviral isolate, causes a severe acquired immunodeficiency syndrome in C57BL/6 mice, similar to that caused by HIV infection, thus the term murine AIDS (MAIDS). Previously, we have shown that C57BL/6 mice infected with LP-BM5 developed significant hind paw mechanical hypersensitivity, behavioral sign of peripheral neuropathy. To test whether profound inflammatory responses in the nervous system contribute to the development of LP-BM5-induced peripheral neuropathy, we first determined the levels of selected cytokines (IL-1β, IL-6, TNFα, IFNγ, and IL-12) in the lumbar spinal cord and dorsal root ganglia (DRG) by qRT-PCR and in the hind paw skin with FlowCytomix multiplex assay post-LP-BM5 infection (p.i.). In the lumbar spinal cord, mRNA levels of all these cytokines trended upwards over time p.i., whereas in the DRG, IL-1β and IFNγ mRNA levels elevated throughout the time p.i. In the hind paw skin, all cytokines measured (except TNFα that was not detectable) increased transiently and peaked at 4-6 weeks p.i.. Further, administration of the anti-retroviral agent zidovudine (AZT) via drinking water (0.2 mg/ml) significantly reduced LP-BM5-induced mechanical hypersensitivity and cytokine responses in the lumbar spinal cord and DRG at 12 weeks p.i.. Altogether, data indicate that tissue-specific cytokine responses are associated with the development of LP-BM5-induced peripheral neuropathy and these responses can be inhibited by AZT treatment.
Limited Type I IFNs Play a Role in the Pathogenesis of Respiratory Syncytial Virus in Neonatal Mice (168.17)
Authors: You Dahui , Lee Greg , Shrestha Bishwas , Shen Li , Cormier Stephania 
Published: January 2023

Abstract
Respiratory syncytial virus (RSV) remains a major cause of bronchiolitis in infants. Infants developing severe RSV disease have increased risk of developing asthma; the causes of which are unknown. We and others have previously demonstrated that RSV infection results in a skewed Th2 response, which may be responsible for this phenomenon. Here, we show that neonatal mice (&lt; 7 d) expressed limited amounts of type I IFNs in the lung, which was associated with low numbers of pulmonary plasmacytoid dendritic cells (pDCs; a major source of type I IFNs during viral infections) following RSV infection. When neonatal mice were pre-treated with IFNa, the typical Th2 skewed response was decreased compared to untreated control mice. Neonatal mice treated with IFNa demonstrated decreased pulmonary Th2 (IFNg+CD3+CD4+) and Tc2 (IFNg+CD3+CD8+) cells, decreased eosinophils and mucus hyperproduction in the airways, and decreased inflammation in the lung parenchyma upon reinfection. More importantly, pulmonary function of the IFNa treated mice was significantly improved compared to the control mice. We conclude that the limited amount of type I IFNs in the neonates, possibly due to an inchoate pulmonary pDC response, may be partially responsible for the Th2 skewed immune response resulting from neonatal RSV infection. Our study pinpoints IFNa as a possible therapeutic target during infant RSV infection.
Changing expression of and access to STATs in NK cells during viral infections (168.2)
Authors: Kallal Lara , Biron Christine 
Published: January 2023

Abstract
NK cells can respond to viral infections with heightened killing, cytokine production, and proliferation. These functions are influenced by cytokines produced during infections that signal through STAT molecules. The laboratory has previously shown that NK cells express high basal levels of STAT4 and that type 1 IFNs can access STAT4 under these conditions. However, during infections of mice with lymphocytic choriomeningitis virus (LCMV), high STAT1 expression is induced to result in type 1 IFN signaling through STAT1 over STAT4 and subsequent immunoregulatory effects. Here, studies were extended to include STAT3, a known pro-survival and pro-proliferative molecule, and infections with murine cytomegalovirus (MCMV). In contrast to LCMV, MCMV elicits a more complex innate response with high induction of IL-12 as well as type 1 IFN. STAT1 and STAT4 levels were similar in NK cells between both infections, but NK cell STAT3 was increased earlier following MCMV infection. This difference had consequences for NK cell access to the STATs. During both MCMV and LCMV infections, IFN-alpha could activate STAT1, and IL-12 could activate both STAT3 and STAT4. However, IFN-alpha could access STAT3 only during MCMV infection. Ongoing studies are characterizing the pathway to STAT3 induction and the role for this molecule in shaping NK cells during viral infections. Overall, the work is elucidating the pathways for conditioning innate immune responses.
Toll-like receptor 3 signaling inhibits double-stranded RNA-induced apoptosis of macrophages (168.21)
Authors: Ge Baoxue , Chen Jian-Xia , Liu Haipeng , Deubel Vincent , Si-Tahar Mustapha , Alexopoulou Lena , Qin Chengfeng , Liang Guo-Dong , Flavell Richard 
Published: January 2023

Abstract
Most viruses produce dsRNA during their infection. Recognition of dsRNA by TLR3, PKR, RIG-I, or MDA-5 initiates innate immune responses, RIG-I and MDA-5 are sensors for dsRNA to induce proinflammatory cytokines or type I interferon, whereas PKR mediates dsRNA-induced apoptosis. Here, we reported that TLR3 deficiency enhances apoptosis of macrophages in response to poly(I:C) as well as Japanese encephalitis virus (JEV). Unexpectedly, TLR3 deficiency markedly increased the phosphorylation of PKR, and inhibition of PKR by RNAi or a PKR-specific inhibitory oligonucleotide (ION) reduced poly(I:C)-induced apoptosis of TLR3-/- macrophages. Stimulation of TLR3 by poly(I:C) activates PI3K and NF-κB signaling pathways, and inhibition of either PI3K or NF-κB enhanced the poly(I:C)-induced apoptosis of macrophages. Further analysis revealed that TLR3 deficiency, as well as inhibition of PI3K or NF-κB, markedly induced p58IPK, a PKR inhibitor, and inhibition of p58IPK by RNAi reduced the apoptosis of poly(I:C)-induced TLR3-/- macrophages. Lastly, TLR3-/- mice are more resistant to JEV infection, but inhibition of apoptosis by caspase inhibitors reduces their resistance to lethal poly(I:C) stimulation or JEV infection. Together, our findings suggest that stimulation of TLR3 by viral dsRNA may activate PI3K and NF-κB, which induces the p58IPK to suppress the phosphorylation of PKR, thus protecting dsRNA-stimulated or virus-infected cells from apoptosis to facilitate the virus propagation.