bluuebunny/crossref_metadata_2025_split huggingface dataset:
Proteolytic processing of TNF-α by influenza-specific CD8+ T cells is required for alveolar epithelial cell MIP-2 production and severe lung injury in a transgenic mouse model of influenza infection (67.3)
Authors: DeBerge Matthew , Enelow Richard 
Published: January 2023

Abstract
Adoptive transfer of influenza hemagglutinin (HA)-specific CD8+ T cells into transgenic mice expressing influenza HA on the alveolar epithelium results in epithelial cell production of monocyte chemotactic protein (MCP)-1 and macrophage inflammatory protein (MIP)-2, the subsequent mononuclear cell infiltration and diffuse alveolar damage. The lung injury observed in this model is mediated by CD8+ T cell production of tumor necrosis factor (TNF)-α. TNF-α is expressed as a transmembrane (tm) protein that is proteolytically processed to produce soluble (s) TNF-α. To determine the roles of tmTNF-α and sTNF-α in CD8+ T cell mediated lung injury, we generated HA-specific CD8+ T cells that only express a noncleavable tmTNF-α (TM). We found that proteolytic processing of tmTNF-α to sTNF-α was required for alveolar epithelial cell production of MIP-2 but not MCP-1 in vitro. Furthermore, this epithelial cell production of MIP-2 required ERK activation that was dependent on TNF-α signaling through TNF-α receptor II. Finally, we adoptively transferred HA-specific TM CD8+ T cells into HA transgenic mice and found that TM CD8+ T cells failed to induce alveolar epithelial cell MIP-2 production and neutrophil infiltration, and produced milder lung injury than transferred wild-type CD8+ T cells. Taken together, these findings suggest that proteolytic processing of tmTNF-α to sTNF-α is a critical event regulating CD8+ T cell mediated injury in a transgenic mouse model of influenza infection.
Evaluation of specific antibodies against prM DENV in Mexican endemic area by using a recombinant protein (67.6)
Authors: Ramírez-Hernández Liliana , García-Cordero Julio , Vivanco-Cid Héctor , Bravo-Maceda Laura , Cedillo-Barrón Leticia 
Published: January 2023

Abstract
Dengue virus (DENV) includes four serotypes, all of them are able to cause DF and DHF. Recently it has described that the antibody response to the prM protein of DENV may plays an important role in both protection from and enhancement of disease. At this respect it has reported that prM-antibodies are highly cross-reactive among the four DENV serotypes and, interestingly at high concentrations, this antibodies do not neutralize infection but potently promote Antibody-Dependent Enhancement (ADE). The production of recombinant proteins rises as feasible alternative to evaluate massively the immunological status against different proteins in ELISA conventional assay. The aim of this work is the cloning and production of prM recombinant protein to evaluate the specific antibody response against this protein, in Mexican endemic areas. The recombinant protein was expressed in a bacterial system of E. coli and subsequently purifies and quantified to use as antigen in ELISA indirect assay. Sera from healthy volunteers and sera from Dengue confirmed donors classified as DF or DHF according with the WHO criteria were tested. Our results confirm that an elevated titters of specific antibodies to the prM protein, seems to associate with a secondary infection and DHF development. The production of this recombinant antigen may be useful, cheap and reliable to evaluate massively the immune response in endemic areas.
Detection of RSV F-specific human mucosal IgA antibody titers utilizing a sensitive electrochemiluminescence platform (67.8)
Authors: Patton Kathryn , Zuo Fengrong , Cherukuri Anu 
Published: January 2023

Abstract
It has been previously shown that mucosal immune responses play a significant role in mediating protection against respiratory viral infections. Respiratory Syncytial Virus (RSV) is a persistent respiratory virus which infects humans throughout life and can cause severe lower respiratory tract infections, particularly in the elderly. Establishing key biomarkers of vaccine-induced immune response is essential to the development of a successful vaccine. In this study, thirty healthy human donors separated into two age cohorts were evaluated: Young Adult (20 to 30 yrs, n=10) and Elderly (65 to 85 yrs, n=20). Plasma samples from the 30 donors were evaluated for neutralizing antibody titers against wild-type (wt) RSV A2 using a micro-neutralization assay and results showed an average titer of ~10.5+2.2 log2 in both age cohorts. In an effort to investigate additional biomarkers, we evaluated nasal wash samples from these donors for wt RSV A2 and RSV-F specific IgA antibody titers. We utilized both a conventional ELISA and a novel Electrochemiluminescence technology to detect the antigen-specific IgA titers. Results from these studies identified the Electrochemiluminescence platform as being a highly sensitive and powerful technology with a wide enough dynamic range to discern subtle differences in mucosal IgA antibody titers. Utilizing such an approach to detect critical biomarkers in dilute nasal wash samples should benefit clinical vaccine development.
Dynamic of T regulatory, Th17, and Tc17 cells and their related cytokines during Nocardia brasiliensis infection in BALB/c mice (99.1)
Authors: Rosas-Taraco Adrian , Perez-Liñan Amira , Perez-Rivera Luz , Salinas-Carmona Mario 
Published: January 2023

Abstract
Actinomycetoma caused by Nocardia brasiliensis induces an inflammatory response with multiple microabscesses and granuloma formation with abundant large cells and mononuclear infiltration. Th1 and Th2 lymphocytes response have been evaluated in N. brasiliensis infection. T regulatory, Th17, and Tc17 lymphocytes are being studied to evaluate their role in several infectious diseases, but there are not data in N. brasiliensis infection. In this study, we evaluated the levels of Treg, Th17 and Tc17, as well as their related cytokines during N. brasiliensis infection in BALB/c mice. Methodology: Mice infected with N. brasiliensis in the footpad were sacrificed at 0, 3, 7, 15, 30, 60 days after infection and levels of Treg, Th17 and Tc17 cells in footpad and spleen were measured by flow cytometry, and their related cytokines (IL-6, IL-10, IL-17A, IL-23 and TGF-β) in the homogenized tissue were measured by ELISA. Results: In footpad, Th17/Tc17 lymphocytes were increased at day 3 (P&lt;0.01), while Treg cells at day 7 (P&lt;0.01). In spleen, Treg cells reached its peak at day 15 (P&lt;0.01) meanwhile Tc17/Th17 at day 3 (P&lt;0.05). Anti-inflammatory cytokines were higher, TGF-β at day 7 and 30 (P&lt;0.01), while IL-10 at day 15. IL-17A and IL-23 were increased gradually during the infection (P&lt;0.01). Finally, IL-6 was increased at day 3 (P&lt;0.01). In conclusion, there is an imbalance of Treg, Th17 and Tc17 in the early stage of N. brasiliensis that could favor chronic disease.
Th17 stimulation and IL17A play critical roles in the Staphylococcus aureus iron regulated surface determinant B (IsdB) mediated protection in a disseminated challenge model. (99.11)
Authors: Joshi Amita , Pancari Gregory , Cope Leslie , Bowman Eddie , Cua Dan , McNeely Tessie 
Published: January 2023

Abstract
We have previously shown that IsdB, a conserved protein expressed by Staphylococcus aureus, induces a robust antibody response which correlates with protection in a murine challenge model. Here we looked at IsdB mediated cellular immune response. First the importance of lymphocytes was examined. Using CB-17 SCID mice we noted that lymphocytes were essential in protection against disseminated S. aureus infection. Neither active nor passive IsdB immunization of CB-17 SCID mice conferred protection against a lethal challenge of S. aureus. Adoptive transfer of CD3+ plus B19+ cells conferred protection in CB-17 SCID immunized mice but not controls. Evaluation of lymphocyte subsets indicated that T cells but not B cells conferred protection. CD3+ or CD4+ T cells conferred protection, whereas CD8+ cells were less active. Neither CD19+ B cells nor CD138highB220intCD19lo plasma cells were protective. Supportive of this data, IsdB immunized Jh mice (IgH chain deficient) were protected against lethal challenge, while nude (T cell deficient) mice were not. In vitro assays indicated that isolated IsdB immune splenocytes produced abundant IL-17A, but not IFN-γ after in vitro stimulation with IsdB peptides. These findings suggest a role for Th 17 cells in IsdB mediated defense against invasive S. aureus infection.
Major histocompatibility complex class II gene diversity and tolerance to avian malaria in Hawaiian honeycreepers (Drepanidinae) (99.15)
Authors: Jarvi Susan , Bianchi Kiara , Farias Margaret , Wiegand Kimberly , Skinner Sarah , Asano Ashley , Czerwonka Christopher 
Published: January 2023

Abstract
Susceptibility to avian malaria differs both within and between species of Hawaiian honeycreepers. Due to their critical function in adaptive immunity, proteins encoded by Mhc genes may be key in the development of tolerance to Plasmodium relictum in low elevation populations of `amakihi (Hemignathus virens). To evaluate gene copy number, 263 Mhc class II peptide-binding region clones were sequenced from a captive family of `amakihi. Phylogenetic analysis suggests a minimum of 10 Mhc class II genes with detection of 35 unique alleles. Species comparisons (total 503 clones, eight birds/species) reveal that Mhc diversity is highest in `amakihi [d = 0.085(0.015)] with 98 distinct alleles detected (average 13.5/bird), followed by `apapane (Himatione sanguinea) [d = 0.068(0.012)] with 66 distinct alleles detected (average 11/bird) and in a highly susceptible species, the i`iwi (Vestiaria coccinea) diversity appears lowest with d = 0.057(0.011) and 66 distinct alleles detected (average 10.6/bird). Within `amakihi, Mhc sequences from birds from low elevation (56 distinct alleles, average 14.25 alleles/bird) and high elevation (50 distinct alleles, average 12.75 alleles/bird) subpopulations appear distinct with detection of only one shared allele. Microarray-based population level analysis (~1,000 individuals) of Mhc diversity in `amakihi detected at least one allele with a significantly higher frequency in low elevation populations than mid or high elevation subpopulations.
Route of Francisella tularensis infection shapes the subsequent immune response (99.2)
Authors: Barrigan Lydia , Steele Shaun , Tuladhar Shraddha , Woolard Matthew , Kawula Thomas , Frelinger Jeffrey 
Published: January 2023

Abstract
The bacterium Francisella tularensis is the causative agent of tularemia. F. tularensis induces a host response that is dependent on the route of infection. Intranasal (i.n.) inoculations are more virulent and require fewer bacteria to produce a lethal infection than intradermal (i.d.) inoculations (10^3 organisms i.n. versus 10^6 i.d.). Interestingly, one day post infection, the bacterial loads are similar in the spleen and lung regardless of the route of infection. We also found that i.d. inoculation resulted in IFN-γ+ T cells in the lung whereas i.n. inoculation produced very few IFN-γ+ T cells and instead many IL-17+ T cells in the lung. Due to the similar bacterial loads systemically after 1 day, but very different host responses, we hypothesize that the adaptive immune response is influenced by local events at the site of infection immediately following inoculation. To test this hypothesis, we infected C57Bl/6 mice i.n. or i.d. and identified cytokine production in the lung and tail at four hours post-infection. Additionally, we have identified alveolar macrophages as the primary cell type infected four hours post-infection, to the exclusion of other myeloid cells and lung parenchyma. Furthermore, we have identified cytokines produced by alveolar macrophages when cultured ex vivo and infected with F. tularensis. These data will help us further understand how the adaptive immune response to F. tularensis is shaped early after infection.
Identification of a putative IgM memory B cell population during bacterial infection (99.31)
Authors: Yates Jennifer , Racine Rachael , McLaughlin Maura , Wittmer Susan , Winslow Gary 
Published: January 2023

Abstract
Humoral immunity and B cell memory are essential components of the adaptive immune response. These elements of immunity have remained largely unexplored in intracellular bacterial infections. Ehrlichia muris is an obligate intracellular bacterium that generates a chronic infection in immunocompetent mice. Chronic infection with E. muris is characterized by long-term IgM production that confers antibody-mediated protection against virulent ehrlichial challenge. We have identified a novel CD19+ B cell population in the spleens of chronically infected mice based on the expression of the cell surface markers CD11c, CD73, and PD-L2. As determined by fluorescence microscopy, these cells are localized in germinal centers of the spleen. Upon stimulation with LPS in vitro, the CD11c+/CD73+/PD-L2+ B cells proliferated and produced antigen specific IgM. BrdU incorporation studies revealed that the population is largely quiescent, and new cells were not recruited to this population during chronic infection. We propose that the CD11c+/CD73+/PD-L2+ B cells we have identified during chronic infection, are long-lived effector/memory cells responsible for the maintenance of long-term immunity during chronic ehrlichial infection.
Immunodominance of the Sm-p40 antigen contributes to the development of severe schistosomiasis mansoni (99.5)
Authors: Finger Eduardo , Finardi de Souza Alessandra , Galante Coimbra Thaissa , dos Santos Daniel 
Published: January 2023

Abstract
In murine schistosomiasis, H-2k CBA and C3H mice develop severe CD4 T cell(CD4) mediated liver pathology(LP) and a high Th1/17 response very focused on a single epitope of the parasite egg antigen Sm-p40(p234-246). Low pathology C57BL/6 mice do not recognize this antigen. A possible reason for this result is that p234-246 exacerbated dominance(ED) polarizes the anti-egg response causing severe LP. To test this hypothesis we: a)analyze the LP of SJL mice whose H-2 haplotype also exhibit ED of a single Sm-p40 epitope and b) analyze the LP of CBA mice whose p234-246 ED was neutralized by an epitope cocktail. Methodology:H-2s Sm-p40 restriction pattern was determined with the rankpep software. SJL LP was documented by comparative liver morphometric analysis(LMA) of infected CBA, C57BL/6 and SJL mice euthanized 7 weeks-post-infection(wpi). The effect of p234-246 ED neutralization was studied by LMA of 3 groups of infected CBA mice euthanized at 7wpi. The 1st group was treated with an emulsion of adjuvant and 4 synthetic epitopes designed to compete for I-Ak with an affinity equal or higher than p234-246, the 2nd was treated with adjuvant alone and the 3rd was not treated. Results:LMA shows that SJL mice develop as severe a LP as CBA mice and that p234-246 ED neutralization prevents development of severe LP. Conclusion:These results show that ED may be pathogenic in CD4 mediated diseases and that its neutralization may be an effective therapeutic strategy that deserves exploration.
Ig G and IgM opsonizing antibodies affect Il-12 and TNF-α cytokine production in macrophages infected with a Nocardia brasiliensis recombinant strain. (99.6)
Authors: Salinas-Carmona Mario , Rocha-Pizaña María , Pérez-Rivera Luz 
Published: January 2023

Abstract
Nocardia brasiliensis is is an intracellular microbe that replicates in host macrophages. We developed an actinomycetoma model in BALB/c mice and showed that IgM but not IgG anti-N. brasiliensis antibodies conferred protection and prevent ed actinomycetoma lesion. The survival or death of the bacterium, once in macrophages, possibly depends on the antibodies used to opsonize N. brasiliensis. We constructed a recombinant strain of N. brasiliensis that produces a green fluorescent protein (GFP) to evaluate virulence and role of IgG and IgM antibodies in cytokine production by macrophages in BALB/c mice. The recombinant N. brasiliensis strain expressing the green fluorescent protein constructed by adding a plasmidic vector containing the GFP gene was used to infect BALB/c mice and macrophages to evaluate phagocytosis and cytokine production with opsonizing IgG and IgM antibodies. N. brasiliensis GFP induces actinomycetoma as well as N. brasiliensis WT. The production of IL-12 with opsonized bacteria increased with IgG and decreased with IgM antibodies. TNF- α production was greater at 24 and 48 hours in non-opsonized bacteria. Opsonized bacteria with IgG and IgM antibodies decreased TNFα production but only IgM isotype antibodies decreased IL-12 production by macrophages. The modified N. brasiliensis strain conserves its property to induce disease.
Human sepsis induces a novel cell exhaustion phenotype in the lung characterized by T cell expression of PD-1 & BTLA and HVEM expression on airway epithelium (99.9)
Authors: Boomer Jonathan , To Kathleen , Bricker Traci , Deppong Christine , Chang Katherine , Walton Andrew , Osborne Dale , Crockford Seth , Swanson Paul , Hotchkiss Richard , Green Jonathan 
Published: January 2023

Abstract
Approximately 200,000 people die annually in the US from sepsis. Sepsis is characterized by an acute “cytokine storm” followed by an immune suppressed state. While apoptosis of innate and adaptive immune cells has been demonstrated, the mechanism for immunosuppression in sepsis is poorly defined. In this study, we analyzed the function and phenotype of cells isolated from lung and spleen of septic patients collected within 120 minutes of death and compared these to cells similarly isolated from non-septic patients. Post-stimulation, splenocytes from septic patients had dramatically reduced secretion of the cytokines IFNγ, TNFα, IL-6 and IL-10. Expression of activating and inhibitory receptors was examined by flow cytometry. Splenic T cells had decreased expression of the IL-7 receptor and elevated expression of CD69. Both lung and splenic T cells had increased expression of the inhibitory receptor PD-1 as well as increased expression of its ligands PDL1 and PDL2 on dendritic cells. BTLA but not CTLA4 expression was detected on the majority of lung T cells from septic and control patients. Interestingly HVEM, the ligand for BTLA, was detected by immunohistochemistry on airway epithelial cells of lungs from septic but not control patients, providing a receptor:ligand interaction with the potential to mediate local immune suppression. These data are consistent with a state of immune cell exhaustion, and provide a novel mechanism for local immunosuppression in the lung.
Interferon-mediated inhibition of T cell proliferation contributes to virus-induced transient immune suppression (105.1)
Authors: Urban Stina , Marshall Heather , Welsh Raymond 
Published: January 2023

Abstract
Vaccine-induced memory is required for protective immunity to pathogens, but many viruses induce a transient state of immune suppression that may contribute to the reduction of vaccine efficacy. We demonstrate here that the production of type I interferon (IFN) during an acute virus infection contributes to this transient immune suppression. Exposure of T cells to IFN-inducers at the same time as antigen had stimulatory effects, whereas pre-exposure to IFN-inducers was inhibitory, indicating that the timing of type I IFN exposure was of essence. Suppression of transgenic T cell proliferation was validated in two models of virus infection, where CD8 T cell proliferation in response to cognate antigen was inhibited 3-9 days after virus infection. Pre-exposure of T cells to the type I IFN inducer and TLR agonist poly(I:C) also had inhibitory effects on CD8 T cell proliferation, as shown by competition between poly(I:C)-pre-treated and control-treated P14 CD8 T cells during a LCMV infection. Poly(I:C)-induced inhibition of CD8 T cell proliferation was transient. T cells lacking type I IFN receptors were resistant to the suppressive effects of poly(I:C), indicating a direct involvement of IFN. Detection of IFN receptor and phosphorylated STAT molecules was reduced in poly(I:C)-pre-treated naive CD8 T cells. Inhibition of CD8 T cell proliferation by exposure to type I IFN prior to antigen stimulation may thus contribute to virus-induced immune suppression.
Pulmonary immunopathology mediated by proteolytic processing of TNF-α by antiviral CD8+ T cells (105.11)
Authors: DeBerge Matthew , Enelow Richard 
Published: January 2023

Abstract
Infection with influenza virus evokes a potent CD8+ T cell response that may contribute to lung immunopathology. Recognition of alveolar anitgen by CD8+ T cells results in significant injury that is critically dependent on TNF-α expressed by CD8+ T cells and is largely mediated by the secretion of chemokines by alveolar epithelial cells and the subsequent pulmonary infiltration. TNF-α is expressed as a transmembrane (tm) protein that is proteolytically processed by TNF-α converting enzyme (TACE) to produce soluble (s) TNF-α. To determine the roles of tmTNF-α and sTNF-α in CD8+ T cell mediated lung injury, we generated CD8+ T cells that express either a noncleavable tmTNF-α or have a deletion in the catalytic domain of TACE. Both T cells are impaired in sTNF-α production but exhibited no defect in other effector functions. In vitro analysis indicated that proteolytic processing of tmTNF-α to sTNF-α was required to induce alveolar epithelial cell expression of macrophage inflammatory protein-2. Furthermore, inhibition of proteolytic processing of TNF-α resulted in reduced induction of alveolar epithelial cell chemokines, less neutrophil infiltration and milder lung injury, though these T cells exhibited no defect in antiviral activity in vivo. This indicates that proteolytic processing of tmTNF-α to sTNF-α is a critical event in the initiation of CD8+ T cell mediated lung injury and represents a potential mechanism of regulation of immunopathology during an influenza infection.
Increased susceptibility to CD8 T cell mediated killing limits the HIV-1 reservoir in naïve CD4 T cells from elite controllers (105.13)
Authors: Leng Jin , Buzon Maria , Yang Yue , Seiss Katie , Pereyra Florencia , Yu Xu G. , Lichterfeld Mathias 
Published: January 2023

Abstract
Elite controllers are HIV-1 infected persons with undetectable levels of HIV-1 replication in the absence of antiretroviral treatment, for reasons that remain unclear. We used a flow cytometric cytotoxicity assay based on the detection of Annexin V in dying target cells to assess the susceptibility of naïve and memory CD4 T cell subsets from elite controllers, HIV progressors, HAART-treated persons and HIV-1 negative individuals to killing by identical HIV-1-specific CD8 T cells. We found that naïve CD4 T cells from elite controllers showed significantly higher susceptibilities to HIV-1-specific CD8 T cell mediated killing than naïve CD4 T cells from all other reference patient cohorts. This increased susceptibility to CD8 T cell-dependent cytotoxicity was not related to higher baseline activation or apoptosis rates. Levels of integrated HIV-1 DNA were significantly decreased in naïve CD4 T cells from elite controllers compared to the alternative patient cohorts, while integrated HIV-1 DNA in memory cell subsets were not different between the study groups. Our data suggest that a higher susceptibility of naïve CD4 T cells to the cytotoxic activities of HIV-1-specific CD8 T cells reduces the HIV-1 reservoir in naïve T cells from elite controllers, and in this way contributes to low cellular reservoirs for HIV-1 in these patients.