bluuebunny/crossref_metadata_2025_split huggingface dataset:
A critical functional role for neuroimmune semaphorin 4A in asthma severity (103.7)
Authors: Nkyimbeng-Takwi EusebiusHenry , Shanks Kathleeen , Smith Elizabeth , Lipsky Michael , DeTolla Louis , Keegan Achsah , Chapoval Svetlana 
Published: January 2023

Abstract
Semaphorin 4A belongs to a family of secreted and membrane-bound glycoproteins which were originally found to be expressed in the nervous system and function as axon guidance molecules. Recent studies identified Sema4A to be expressed and function in the immune system. An abundant Sema4A expression was found on APC but not on resting T cells. The expression was upregulated with corresponding cell activation. Sema4A on APC has been reported to enhance activation and differentiation of T cells in vitro and generation of Ag-specific T cells in vivo. We hypothesized that Sema4A plays a critical regulatory role in allergic airway response. To test our hypothesis, we employed Sema4A-/- and WT mice in the well-defined mouse model of OVA-induced experimental asthma. We observed a significant increase in eosinophilic airway infiltration accompanied by bronchial epithelial cell hyperplasia in allergen-treated Sema4A-/- mice as compared to similarly treated WT mice. This enhanced inflammatory response was associated with a selective increase in BAL IL-13 content. Surprisingly, an augmented AHR was detected in both PBS- and OVA-treated Sema4A-/- mice versus similarly treated WT mice. Allergic response was downregulated by re-introduction of recombinant Sema4A protein. However, the in vitro recall T cell response to OVA was not affected by Sema4A deficiency. These data provide a new insight into Sema4A biology and defines it as a critical regulator of Th2-driven lung pathophysiology.
Alterations in pulmonary immunity in response to vaccinia virus (103.8)
Authors: Walline Crystal , Benson Heather , Sehra Sarita , Mwanthi Muithi , Fisher Amanda , Clapp D. Wade , Brutkiewicz Randy , Kaplan Mark , Wilkes David , Blum Janice 
Published: January 2023

Abstract
Vaccinia virus (VV) infection in mice is an accepted model to study the pathogenesis of variola virus, the causative agent of human smallpox. Although the lung is a key site of poxvirus infection, there is little known about the local immune response to intrapulmonary VV infection. Additionally, because vaccination with VV is contraindicated in patients with atopic allergic skin conditions it is very important to determine the role of atopic lung disease on local vaccinia immunity. We have found that established allergic lung disease results in significantly increased numbers of eosinophils, myeloid dendritic cells (mDCs) and alveolar macrophages. Interestingly, an intrapulmonary VV infection in mice with allergic lung disease does not further increase the number of mDCs or alveolar macrophages, but does trigger a significant increase in plasmacytoid DCs (pDCs) and a significant decrease in eosinophils. Moreover, pulmonary eosinophils, mDCs and macrophages from mice with allergic lung disease were less susceptible to an in vitro VV infection than the respective cells from naïve mice. Whereas pulmonary pDCs and B cells from mice with allergic lung disease were more susceptible to an in vitro VV infection. Alterations in antigen presentation were also observed using splenocytes from animals with induced hypersensitivity. Taken together, these studies strongly suggest that the allergic lung microenvironment may influence anti-viral immunity to an intrapulmonary VV infection.
Optical marking of migrating lymphocytes by two-photon photoconversion for single cell tracking and fate mapping (104.22)
Authors: Phan Tri , Hampton Henry , Tomura Michio , Kanagawa Osami , Mackay Charles , Brink Robert , Chtanova Tatyana 
Published: January 2023

Abstract
We present a method for localised two-photon photoconversion of fluorescent cells within distinct microanatomical compartments in intact lymph nodes. This method allows efficient photoconversion of whole cell populations as well as of single cells while preserving cell viability and motility. Moreover, the combination of high-speed image acquisition and real-time display permits us to target and lock-on to individual cells for photoconversion as they migrate within the lymph node. Optical cell marking makes it possible to differentiate otherwise homogenous responding cells based on their microanatomical location. It also enables discontinuous in vivo tracking of cell fates to distal sites after extended time intervals.
Human influenza-specific effector and memory CD8 T cells from older adults show signs of terminal differentiation and senescence (104.3)
Authors: Wagar Lisa , McElhaney Janet , Watts Tania 
Published: January 2023

Abstract
Little is known about normal human aging and its effects on the function of T cells specific for acutely infecting pathogens. To address this issue, we conducted a multicolour flow cytometry study of older persons’ responses to influenza virus challenge ex vivo. Young and elderly donors were recruited in the fall of 2008. PBMCs were stained directly ex vivo or stimulated with A/Puerto Rico/8/34 (PR8) for 18 hours and assessed for functional markers. The data show that most donors have pre-existing influenza-specific T cells (measured by IFNγ) that are reactivated by PR8, although older donors had smaller pre-vaccination populations of flu-responsive T cells. Effector cells identified upon restimulation with influenza displayed a more terminally differentiated phenotype in older compared to younger adults. This phenotype did not change post-vaccination with trivalent inactivated vaccine, which lacks significant internal viral proteins and is a poor inducer of CD8 T cell responses. For HLA-A2+ donors, it was determined by tetramer staining that elderly influenza-specific CD8 T cells express higher levels of senescence markers KLRG1 and CD57 compared to young controls. Our study shows that influenza specific effector and memory T cells from older individuals show signs of terminal differentiation and senescence. Thus, as has been shown for persistent life-long infections, memory CD8 T cells to an acutely infecting pathogen show signs of deterioration with age.
Identification of a genomic region within MCMV critical for the export of m4/Kb complexes (105.17)
Authors: O'Neill Gabriela , Lu Xiuju , Hill Ann 
Published: January 2023

Abstract
The murine cytomegalovirus (MCMV) protein m4/gp34 binds to major histocompatibility complex (MHC) class I molecules in the endoplasmic reticulum (ER), and this stable m4/gp34-MHC class I complex is then exported to the cell surface. m4/gp34 can impact antigen presentation to CD8 T cells either positively or negatively. However, its main role may be to interact with natural killer (NK) cells. Recent evidence indicates that m4/gp34 in combination with the MHC class I molecule H-2Dk stimulates the activating NK receptor Ly49P. m4/gp34 is retained in the ER unless it binds to MHC class I. The goal of this study was to understand the molecular basis for export of the m4/gp34-MHC class I complex. We found that when m4/gp34 was expressed in a gutless adenovirus vector, it readily formed complexes with MHC class I. However, the complexes were retained in the ER. Superinfection with MCMV lacking m4 restored the export of m4/gp34-Kb complexes. Screening a panel of virus mutants revealed that a region of the MCMV genome containing open reading frames (ORFs) m166-m170 was needed for efficient export of m4/gp-34-Kb complexes. We will present data describing the impact of individual ORFs within this region on the export of m4/gp34-Kb complexes and on the biological function of m4/gp34.
Transition from inflammatory to anti-inflammatory immune responses in deer mice infected with Sin Nombre virus (105.20)
Authors: Schountz Tony , Acuna-Retamar Mariana , Torres Perez Fernando , Kedmi Shira , Prescott Joseph , Peters Staci , Hjelle Brian 
Published: January 2023

Abstract
Hantavirus cardiopulmonary syndrome (HCPS) is characterized by pronounced inflammation that is thought to contribute to its pathogenesis. Deer mice (Peromyscus maniculatus) are the principal reservoir hosts of Sin Nombre virus (SNV), the etiologic agent of the great majority of HCPS cases in North America. Deer mice have life-long apathogenic persistence with periods of viral shedding in excrement. Virus-specific CD4+ T cells from deer mice possess features of regulatory T cells at persistence. We examined the post-infection kinetics of viral load and immune gene expression in deer mice on days 2, 5, 7, 10, 15 and 20. Viral RNA peaked on day 10 in the lungs and day 15 in the heart, with decreased RNA correlating with the appearance of IgG on day 15. In spleens, Ccl3 and Ccl5 expression was elevated on day 2, while Ccl2 expression was elevated on days 7-15. Several inflammatory cytokine genes were elevated on days 5 and 7, including IL-12p35, IL-21 and IL-23, but then declined. TGFβ1 expression occurred early in infection, but markedly declined and reappeared on days 15 and 20. CD4 expression was elevated on day 7 while CD8 and TCRβ expression were elevated on days 7 and 10, perhaps reflecting a stalled antiviral T cell response. These data suggest that early in infection an inflammatory immune response occurs, but it transitions to an anti-inflammatory response. This switch may interfere with viral clearance and contribute to the persistence and ecology of SNV.
Identification of H-2d-restricted, NS3-specific CD4 and CD8 T-cell epitopes in Japanese encephalitis virus infected mice (105.25)
Authors: Pan Chien-Hsiung , Wei Wen-Min , Wu Sze-Hsien , Hu Hui-mei 
Published: January 2023

Abstract
Japanese encephalitis virus (JEV) is the agent to cause the disorder of central nervous system (CNS) or even death. Neutralizing antibodies is believed to play a major role to prevent JEV entry to CNS. The importance of T-cell responses in the control of JEV infection is not clear. In addition, the presence of heterologous suboptimal neutralizing antibodies among between JEV and other flaviviuses may enhance viral infection. A peptide vaccine constituted with both CD4 and CD8 T cell epitopes to elicit a Th1-type response can provide an alternative solution to reduce the impact of heterologous suboptimal neutralizing antibodies. Total 40 and 31 of MHC-I and II peptides were predicted and used in these study. Spleen cells harvested from NS3 DNA vaccinated or JEV-infected BALB/c mice were stimulated and the IFN-gamma production was detected by ELISPOT assay. The mixture of Kd and Ld-restricted peptides showed the stronger ability to stimulate IFN-gamma production than Dd. Four individual MHC-I restricted peptides were identified. To prove the peptide is CD4 or CD8-dependent, different cell populations were depleted by magnetic beads before performing ELISPOT assay, and all 4 peptides showed a CD8-dependent pattern. For MHC-II, a similar strategy was used and three IFN-gamma stimulating Ad-restricted peptides were mapped. A peptide based JEV vaccine based on this study will be used to test the immunogenicity and protection in a mouse model.
Fc gamma receptors are important for protection from Cytomegalovirus infection (105.28)
Authors: Bootz Anna , Winkler Thomas , Mach Michael 
Published: January 2023

Abstract
Cytomegalovirus is a clinically important pathogen. Previously we could show using murine cytomegalovirus (MCMV) that the adoptive transfer of memory B lymphocytes from immune donors into B- and T-cell immunodeficient RAG-/- mice completely protected from MCMV-induced morbidity and mortality. The protection is correlated with production of protective antibodies. Antibodies can act by neutralization of extracellular virus and/or antibody-dependent cellular cytotoxicity (ADCC) via Fc receptor-mediated effector functions. To investigate the role of Fc receptors for protection we adoptively transferred immune serum from infected donor mice into recipients that were deficient for the expression of Fcγ-receptors. First we used mice lacking the γ-chain (FcRγxRAG-/-), which is the accessory chain of the activating murine IgG receptors FcγRI, FcγRIII, and FcγRIV. FcRγxRAG-/- mice developed severe disease with high viral titers and had a significantly shorter survival compared to the RAG-/- control animals. Essentially no difference was seen between mice lacking the FcγRI and RAG-/- animals. Mice lacking the FcγRIII receptor were significantly less susceptible to MCMV infection than FcRγxRAG-/-, indicating that NK cells were not the major effector cell type involved, since FcγRIII is the only activating Fc-receptor on NK cells. Thus, although Fcγ-receptors are essential for antibody mediated protection from MCMV, NK cells seem not to be the crucial cell type involved.
Enhancing MCMV-specific T cell responses by blocking viral replication (105.44)
Authors: Loo Christopher , Snyder Christopher , Hill Ann 
Published: January 2023

Abstract
Cytomegalovirus (CMV) is a β-herpes virus that is benign in the immunocompetent but can be pathogenic and fatal in the immunocompromised host. Our laboratory investigates murine cytomegalovirus (MCMV) as a model for human CMV. A hallmark of both human and murine CMV infection is the development of a strong cytolytic T cell response (CTL) in the acute phase and a large memory T cell pool in the chronic phase. How the virus initiates both acute and chronic responses in the host are not completely understood. In this study, we investigate the acute CD8 T cell response in the spleen when viral replication is blocked early after infection. Our laboratory has developed a recombinant MCMV that includes the thymidine kinase (TK) gene from HSV-1. In vivo, replication of MCMV-TK can be blocked when mice are administered the drug, Famcyclovir (FVR). Our results show MCMV-TK with FVR, is replication-deficient by undetectable plaque forming units in the spleen at day 3 post-infection. Measurement of peripheral inflammatory cytokines and chemokines are also decreased when viral replication is blocked. However, MCMV-TK infected mice, with FVR treatment, have a greater CTL responses at day seven post-infection. Our goal in this project is to identify the key biological mechanism responsible for this enhanced CD8 T cells response, and contribute to the field of optimal strategies for vaccine development.
FoxP3+ CD4+ cells promote CD8 T cell exhaustion during chronic infection (105.5)
Authors: Penaloza-MacMaster Pablo , Araki Koichi , Kamphorst Alice , Iyer Smita , West Erin , Konieczny Bogna , Freeman Gordon , Rudenski Alexander , Ahmed Rafi 
Published: January 2023

Abstract
Understanding the factors that guide T cell exhaustion may provide opportunities to modulate immune responses during chronic infections. We analyzed the contribution of CD4+ FoxP3+ cells (Tregs), to the process of CD8 T cell exhaustion during chronic lymphocytic choriomeningitis virus (LCMV) infection. Tregs have been shown be the master regulators of immune tolerance. However, a possible suppressive role for these cells during chronic infections is still not very well defined, and most studies show correlations, but not direct causations. Normally, LCMV chronically viremic mice experience a pronounced CD8 T cell exhaustion. We showed for the first time that specific ablation of Tregs (in FoxP3DTR mice) after the onset of a chronic viral infection results in a significant rescue of viral-specific CD8 T cell responses. In addition, PD-1 blockade together with Treg depletion resulted in significant reduction of viral loads, greater than PD-L1 blockade alone. This suggests that Tregs and the PD- pathway control CD8 T cell exhaustion by different mechanisms. The CD8 T cell rescue observed after Treg depletion is dependent on B7 signaling, CD4+ cells, and the presence of viral antigen, suggesting a general role for these factors in maintaining CD8 T cell exhaustion during persistent infections. Our data also indicates a general mechanism that may be used by Tregs to suppress self-specific T cell responses during immune homeostasis.
A cationic lipid/DNA adjuvant enhances the efficacy of an inactivated influenza vaccine against matched and heterosubtypic virus challenge in rhesus macaques. (106.15)
Authors: Carroll Timothy , Matzinger Shannon , Lay Marla , Chang Stella , Fairman Jeffery , Miller Christopher 
Published: January 2023

Abstract
The efficacy of current influenza vaccines depends on eliciting type-specific neutralizing antibodies that do not protect against a range of influenza virus subtypes. To determine if the adjuvant JVRS-100 can enhance vaccine-induced protection against matched and heterosubtyic virus challenge, monkeys were immunized with A/Memphis/7/01 (ΔH1N1) or A/Memphis/1/90 (ΔH3N2); with or without JVRS-100 and challenged with a human seasonal influenza isolate, A/Memphis/7/01. Animals immunized with adjuvant had significantly greater anti-influenza antibody titers than the un-adjuvanted groups (p&lt;0.01). Indeed, ΔH1N1+JVRS100 animals had significantly higher H1 neutralizing titers compared to the un-adjuvanted animals (p&lt;0.001). While only ΔH1N1+JVRS-100 animals had significantly lower levels of virus replication (p&lt;0.01) compared to unimmunized control animals after virus challenge, the ΔH3N2+JVRS-100 animals tended to have less virus replication compared to unimmunized controls. Peak influenza virus replication levels inversely correlated with pre-challenge plasma anti-influenza IgG and H1-neutralizing antibody titers. These results demonstrate that JVRS-100 enhances both matched and heterosubtypic immunity in rhesus monkeys.
Murine dialyzed spleen extract decrease the lesion size of experimental localized cutaneous leishmaniasis (106.25)
Authors: Yam Puc Juan Carlos , Becerril-García Miguel Angel , Estrada-García Iris , Estrada-Parra Sergio , Dumonteil Eric , Pérez-Tapia Sonia Mayra , Limón-Flores Alberto Yairh 
Published: January 2023

Abstract
Leishmaniasis affects 12 millions people in the world and localized cutaneous leishmaniasis (LCL) prevails in México. Drugs used to treat leishmaniasis are not effective and they present side effects. Dialyzable Spleen Extracts (DSE) are a mixture of molecules with the with the ability to regulate immune responses. in this work we determine the effect of DSE administration on a experimental leishmaniasis. First an experimental model for LCL was established in BALB/c mice using intradermal immunization of Leishmania mexicana. In this model lesions show a progressive pattern, with inflammation, follow by ulceration and necrosis. Once LCL was established, different DSE concentrations were used to treat it. Intramuscular administration of 0.1pg of DSE daily for 7 days followed by every third day until 45 day, showed a reduction in lesion size, parasite counts and number of infected macrophages. Combined treatment of DSE with tamoxifen (TAM) had a synergistic effect, decreasing further lesion size than DSE or TAM alone. This experimental model has show to be reproducible, and may be used to assess other anti-leishmania drugs, and it also offers a model to describe the immunological mechanisms underlying DSE effects.
A cationic lipid/DNA adjuvant enhances the effectiveness of Fluzone® in immunosenescent elderly rhesus macaques. (106.30)
Authors: Carroll Timothy , Matzinger Shannon , Genesca Meritxell , Lay Marla , Chang Stella , Fairman Jeffery , Miller Christopher 
Published: January 2023

Abstract
The decline in immunity in older adult humans results in a reduction of influenza vaccine efficacy. Elderly macaques (&gt; 18 years old) have similar declines in immunity as indicated by significantly lower levels of circulating naïve CD4+ T cells, naïve CD8+ T cells and B cells and declines in pDC function compared to juvenile monkeys. To determine if the adjuvant activity of JVRS-100 can improve the efficacy of the inactivated influenza vaccine, Fluzone®, elderly monkeys were immunized with Fluzone® with or without JVRS-100 and challenged with a human seasonal influenza isolate, A/Memphis/7/2001 (H1N1). On the day of challenge, Fluzone®+JVRS-100 immunized animals had significantly higher plasma anti-influenza IgG (p&lt;0.04) and IgA (p&lt;0.01) titers than the un-adjuvanted immunized monkeys. After virus challenge, only the Fluzone®+JVRS-100 immunized animals had a significantly lower level of virus replication (p&lt;0.05) relative to the unimmunized control animals. There were significant inverse correlations between peak influenza virus replication levels in the respiratory tract and plasma and tracheal anti-influenza IgG and IgA antibody titers prior to challenge. These results demonstrate that JVRS-100 enhances the immunogenicity and efficacy of a licensed inactivated influenza vaccine in an immunosenescent elderly monkey population.
Immunotherapy with leishmanial antigen versus immunochemotherapy in murine visceral leishmaniasis (106.7)
Authors: Afrin Farhat , Chouhan Garima , Islamuddin Mohammad , Priya Yadav , Ahmad Farnaz , Want Muzamil 
Published: January 2023

Abstract
Despite significant advances in the treatment of visceral leishmaniasis (VL), conventional chemotherapy (CT) has considerable toxicities and relapses. Immunotherapeutic strategies, aimed to amplify Leishmania-specific immune response prior to or in synergy with CT may lower the required dose or duration of treatment and hence toxicity, improving chemotherapy's overall efficacy, reduce emergence of drug resistant strains, and circumvent the problems of treatment in immunocompromised hosts. Effective antileishmanial intervention blending antigen-based therapy may result in therapeutic harness of cellular immune protection. In the present work, we compared the therapeutic efficacy of leishmanial antigen (freeze-thawed, FT and autoclaved, ALD) when administered alone (immunotherapy, IT) or in combination with pentamidine (immunochemotherapy, ICT) in Leishmania donovani infected mice. FT vaccine administered with pentamidine cleared the splenic and hepatic parasite burden, eliciting Leishmania-specific delayed-type hypersensitivity (DTH) responses and elevated IgG2a levels in contrast to chemo- or immuno-therapy alone. Gamma-IFN and interleukin-4 expression in liver of treated mice and hepatic granuloma formation with associated immune cell recruitment as correlates of cell-mediated immunity are being explored. Our findings underscore the chemo-immunotherapeutic potential of FT antigen that may be extended to drug-nonresponsive VL patients and warrant further investigation.