bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immune complex-induced enhancement on presentation of bacterial antigens by dendritic cells is mediated by activating Fcγ receptor III (43.36)
Authors: Herrada Andres Alonso , Contreras Francisco , Tobar Jaime , Pacheco Rodrigo , Kalergis Alexis 
Published: January 2023

Abstract
Dendritic cells (DCs) are capable of initiating adaptive immune responses against infectious agents by presenting pathogen-derived antigens on MHC molecules to naïve T cells. We have previously shown that Salmonella enterica serovar Typhimurium (S. Typhimurium), is able to survive inside DCs and interfere with their function by avoiding activation of bacteria-specific T cells. In contrast, when S. Typhimurium is targeted to Fcγ receptors on the DC surface, bacteria are degraded and their antigens presented to T cells. However, the specific Fcγ receptor responsible of restoring presentation of antigens remains unknown. Here we show that IgG-coated S. Typhimurium was targeted to lysosomes, degraded and its antigens presented on MHC molecules only when the low affinity activating FcγRIII was expressed on DCs. FcγRIII-mediated enhancement of Ag presentationled to a robust activation of T cells specific for bacteria-expressed antigens. Laser confocal and electron microscopy analyses revealed that IgG-coated S. Typhimurium was rerouted to the lysosomal pathway through a FcγRIII-dependent mechanism. Our data support the notion that the capacity of enhancing priming of bacteria-specific T cells by DCs can be attributed as a novel function for the activating FcγRIII.
This work was supported by grants FONDECYT 1030557 and 1050979, FONDEF D04I1075 and Millennium Nucleus on Immunology and Immunotherapy.
Lung resident memory CD4 T cells provide optimal protective immunity to influenza challenge (43.4)
Authors: Teijaro John , Ndjembi Modesta P , Lorenzo Lani , Chandran smita , Farber Donna 
Published: January 2023

Abstract
Diverse subsets of CD4 memory T cells in lymphoid and non-lymphoid tissue are known to persist after infection; however, the ability of these subsets to mediate protective immunity against viral challenge is not known. We previously showed that a population of influenza hemagglutinin (HA)-specific memory CD4 T cells exhibits diverse migration properties with spleen and lung-derived memory CD4 T cells exhibiting tissue-specific homing. Here, we examined the ability of purified lung and spleen-resident HA-specific memory CD4 T cells to mediate protection upon influenza challenge. We found that lung-derived memory CD4 T cells facilitated more rapid clearance of virus from infected lung compared to equal numbers of spleen-derived memory T cells. Moreover, viral clearance in mice receiving lung memory occurred with reduced weight loss pathology, whereas naive mice or mice receiving splenic HA-specific memory T cells displayed precipitous weight loss and ruffled appearance. We found intrinsic functional differences in proliferation and effector capacity of lung compared to spleen-derived memory cells, including reduced overall expansion and IL-2 production from lung versus spleen subsets. Our results demonstrate an enhanced ability of lung-derived memory CD4 T cells to mediate protective responses with minimal pathology compared to lymphoid memory T cells, with important implications for vaccine design.
Supported by NIH-AI-50632
Catalytic Antibodies to Staphylococcus aureus (43.41)
Authors: Brown Eric Luis , Smith Keri , Paul Sudhir , Duncan Katherine 
Published: January 2023

Abstract
Of growing concern are the steadily increasing numbers of community-acquired methicillin resistant Staphylococcus aureus infections combined with the need for novel antibiotic independent therapeutic strategies. We propose to test the hypothesis that catabolic antibodies (CABs) may play a role in protecting against S. aureus infections. CABs are immunoglobulins endowed with a capacity to catalyze the hydrolysis of specific antigenic protein/polypeptide substrates. A single molecule of a catabolic antibody can degrade thousands of antigen molecules, therefore, a CAB response against bacterial pathogens would provide a very effective means to control infection. To date, a role for catabolic antibodies in defense against bacterial infections has not been examined. To investigate the role of CABs we focused on the S. aureus extracellular fibrinogen binding protein (Efb) protein, which contributes to virulence in wound infection. We found that polyclonal preparations of normal human IgG and IgM showed significant cleavage of Efb. Of interest, IgG was more potent than IgM at hydrolyzing Efb. Further investigation of the cleavage of Efb by IgG and IgM was conducted throught the analysis of N-terminal sequencing. To test the functionality of the CAB response to Efb, we incubated Efb with normal IgG or IgM, then used the products of this reaction in a complement activation assay. Both IgG and IgM cleavage resulted in the prevention of Efb-induced blocking of the complement cascade. Our results suggest that CAB may play an important role in the immune response against S. aureus infection.
The precarious balance of immune response to Mycobacterium tuberculosis … are T regulatory cells predictive of infection outcome in a non-human primate model of tuberculosis? (43.5)
Authors: Green Angela M. , Bongers Kale S. , Flynn JoAnne L. 
Published: January 2023

Abstract
A majority of persons infected with M.tb contain but do not eliminate the bacteria, while a minority, develop active tuberculosis. Recent studies in humans suggest an increased frequency of CD4+CD25+ Treg cells in peripheral blood correlates with active TB. To determine whether an increased frequency of CD4+FoxP3+ Treg cells in the periphery is predictive of active disease, we used the non-human primate model of TB, the only animal model that mimics both human latent infection and active disease. Cynomolgus macaques (24) were infected with low dose M.tb and followed until disease state (active or latent) was declared (6–8 months). All animals demonstrated a decrease in the frequency of Tregs following infection until ~ 2 months p.i. without a change in frequency of total CD4+ T cells. Concurrently, the frequency of Tregs and total CD4 T cells in the airways increased up to ~ 2 months p.i. Prior to and 8 weeks p.i., monkeys that eventually presented as latently infected had a significantly higher frequency of Tregs within the CD4 compartment (p&lt; 0.05 and p&lt; 0.005 respectively) than monkeys that eventually had active disease. Between 12–20 weeks, there was a trend toward a higher frequency of Tregs in the monkeys with active disease. Our results suggest frequency of Treg in the periphery may predict or serve as a marker for infection outcome, depending on the stage of infection. NIH grant: RO1 AI50732-01
Expression of PD1 Differs on T Cells from a Pathogenic Versus Nonpathogenic Primate Models of AIDS (43.50)
Authors: Rogers Kenneth , Onlamoon N , Hudson K , Bryan P , Mayne A E , Mori K , Pattanapanyasat K , Villinger F , Ansari A A 
Published: January 2023

Abstract
In most chronic infections antigen specific memory T cells experience a progressive immune exhaustion. Recent reports of HIV infection demonstrate increased expression of PD1 on exhausted T cells correlating with viral loads, and in vitro restoration of function by blockade of PD1 interactions with its ligands. We characterized PD1 in a rhesus macaque model of SIV infection where AIDS develops versus an asymptomatic natural host, sooty mangabeys. Infected animals of both species showed an increase in frequency of total PD1+ CD4+ cells, but not CD8+, which correlated with viral loads in macaques, but not in mangabeys. Furthermore this increase was noted in naïve mangabey CD4+ cells, but central memory macaque CD4+ cells. In macaques, antigen specific CD8+ T cells had increased PD1 expression (MFI) that was reduced with antiviral therapy. While the blockade of PD1-PDL1 interactions in vitro enhanced overall SIV antigen specific responses, individual responses to specific peptides were found enhanced, unchanged or even diminished. These data support a potential for role PD1 in the phenomena of “immune exhaustion” and a rationale for its study using monkey models of AIDS.
B7-H1 Expression on Gastric Epithelial Cells Induces Development of T Regulatory Cells during Helicobacter pylori Infection (43.52)
Authors: Beswick Ellen J , Pinchuk Irina V , Das Soumita , Reyes Victor E 
Published: January 2023

Abstract
During H. pylori infection, T cells are recruited to the gastric mucosa, but the host response is unable to clear the infection. We have previously shown that during infection H. pylori induces B7-H1 on the gastric epithelium, and interacting T cells are thus anegized. Recently, T regulatory cells (Treg) with a CD4+ CD25high FoxP3+ phenotype were found at an increased frequency in the H. pylori-infected gastric mucosa. Since B7-H1 promotes T cell anergy during H. pylori infection and Treg cells are present in the infected gastric mucosa, we hypothesized that B7-H1 expression by gastric epithelial cells during H. pylori infection promotes development of T regulatory cells. In order to investigate this, we examined by flow cytometry the induction of the Treg phenotype when naïve T cells were incubated with H. pylori-exposed gastric epithelial cells. The number of CD4+CD25+FoxP3+ cells increased together with the production of IL-10 and TGF-β in the cultures. The frequency of Treg cells along with IL-10 and TGF-β production was markedly decreased when B7-H1 was blocked with monoclonal antibodies. The function of these Treg cells was investigated by sorting them for use in co-cultures with activated T cells, which effectively decreased proliferation of the activated T cells. B7-H1 may thereby play a crucial role in the development of CD4+CD25+FoxP3+ Treg cells and the inadequate T cell response leading to chronic infection.
Helminth secretory product Ribonuclease T2 is a Th2-inducing agent (43.8)
Authors: Jankovic Dragana , Steinfelder Svenja , Andersen John F. , Sher Alan 
Published: January 2023

Abstract
Helminth-induced Th2 polarization is associated with down-regulated dendritic cell (DC) function but the underlying molecular mechanism remains elusive due to the poor characterization of helminth molecules with Th2-inducing activity. During Schistosoma mansoni infection egg, but not worm, Ag are a target of a strong Th2 response. Moreover, when injected in naïve mice schistosome eggs or water-soluble egg extract (SEA) have an intrinsic ability to promote development of Th2 cells. Using as a read-out an in vitro model of CD4+ T cell priming with CD11c+ splenic DC we demonstrated that SEA fractions containing molecule(s) with an approximate MW of 30 kD selectively promote Th2 polarization and down-regulate DC functions. Moreover, similar positive fractions were isolated from preparations containing egg excretory/secretory molecules. The N-terminal sequence of the latter identified the S. mansoni enzyme Ribonuclease T2 as the active component and this was further confirmed with the recombinant protein. S. mansoni ribonuclease is the first chemically defined protein with Th2-promoting activity known to act on dendritic cells.
Association between TLR4 SNPs (Asp299Gly/Thr399Ile) and non-IgE mediated food allergy (NFA) with or without recurrent otitis media (OM) and chronic rhinosinusitis (CRS). (44.25)
Authors: Jyonouchi Harumi , Geng Lee , Cushing-Ruby Agnes , Cheongeun Oh , Hester Jeff D 
Published: January 2023

Abstract
Co-segragating missense mutations of Asp299Gly and Thr399Ile in TLR4 are found in 10% of general population. Heterozygousity of these mutations is implicated with hyporesponsiveness to a TLR4 agonist (LPS). This study addressed the association between heterozygousity of these TLR4 alleles and NFA with or without recurrent OM/CRS. The study included 203 children: inflammatory bowel disease (IBD; N=11 median 14.5 y), OM/CRS/no NFA (N=21, median 7.3 y), NFA alone (N=64, median 3.8 y), OM/CRS+NFA (N=30, median 5.5 y) and controls (N=78, median 6.9 y). Production of proinflammatory cytokines (TNF-α, IL-1ß, IL-6, and IL-12) by peripheral blood mononuclear cells and TLR2 Arg753Gln allele were also assessed. In this study, 20/203 (9.85%) and 7/203 (3.4%) subjects were heterozygous for TLR4 Asp299Gly/Thr399Ile and TLR2 Arg753Gln alleles, respectively. Heterozygousity of these TLR4 alleles were associated with OM/CRS+NFA (57.1% vs 9.7%, p&lt;0.00001), IgE mediated FA (p&lt;0.001), and atopy (p&lt;0.02) but not with OM/CRS/no NFA or IBD. Such an association was not found in TLR2 Arg753Gln allele. LPS responses did not differ irrespective with these TLR2/4 mutated alleles. Among 21 children with OM/CRS/no NFA, 16 revealed other immunodeficiencies. Thus individuals heterozygous for TLR4 Asp299Gly/Thr399Ile alleles may be predisposed to OM/CRS/NFA and possibly IgE mediated FA.
Funded by Jonty Foundation.
Innate responses at the DC level determine the outcome of Leishmania infections (44.28)
Authors: Vargas-Inchaustegui Diego Antonio , Xin Lijun , Eaves-Pyles Tonyia , Soong Lynn 
Published: January 2023

Abstract
Although Leishmania braziliensis (Lb) and L. amazonensis (La) are endemic in the same geographic regions in South America, their infections can lead to very different clinical manifestations. Given the important role of dendritic cells (DCs) in leishmanial infections and activation of parasite-specific CD4 T cells, we hypothesize that Lb infection efficiently triggers innate responses in DCs and macrophages and that this innate immunity, in conjunction with the subsequent Th1 responses, leads to rapid killing of parasites in the local tissue. To test this hypothesis, we infected murine bone marrow-derived DCs, as well as murine and human macrophages, with Lb and La and measured infection rate, cell activation status, cytokine secretion, and activation of the JAK/STAT signaling pathway. Our key findings are:
although both species of parasites were comparable in infecting mouse DCs and human and mouse macrophages, La parasites tended to have prolonged survival within the cell;Lb-infected DCs displayed an activated phenotype (CD11chighCD45RB−CD83+CD40+CD80+), while La-infected cells showed a “semi-activation” status, with much lower numbers of activated DCs;Lb-infected DCs produced 3-fold higher levels of IL-12p40 and were more potent in priming naïve CD4+ T cells when compared to La-infected counterparts;although IL-10 production was detectable in Lb-infected DCs, its level was considerably lower than that of IL-12p40, suggesting the potential of Lb-infected DCs in activating Th1-type responses;microarray analysis revealed up-regulation of several genes (e.g., IFN-g and IFN regulatory factors) in Lb-infected DCs.
Collectively, study indicates that innate responses at the DC level determine the outcome of Leishmania infections.
Ribosomal protein L22 inhibits induction of type I IFN and faciliates the replication of VSV (44.33)
Authors: yang eunjung , Choi In-Hong 
Published: January 2023

Abstract
L22 is a 14.8-kDa protein constituent of the large ribosomal subunit, which is not conserved in prokaryotes and does not share RNA binding motifs with any other known protein such as PKR and RIG-I/Mda5. L22 associates with human telomerase, the small viral RNA HVP-1 in Herpesvirus papio–infected baboon cells, the 39X region within the 39-untranslated region (UTR) of the human Hepatitis C virus (HCV) genomic RNA, poly (ADPribose) polymerase in Drosophila melanogaster, and the Herpes simplex–infected cell proteins (ICP) 4 and ICP 22 in human cells. In uninfected human B cells, L22 is located in the nucleoli and cytoplasm, whereas following EBV infection, L22 is found in the nucleoplasm. In transformed B cells, EBER 1 is quantitatively bound by L22 (&gt;95%), whereas only 30%–50% of the L22 protein associates with this RNA and inhibits regulation of cellular activities by the Epstein-Barr virus small RNA EBER-1. However, the function of L22 both in the ribosome and in these several RNP complexes remains unknown.
Here we investigated whether L22 has an effect on antiviral response; the replication of VSV and activation of eIF2. First, the replication of VSV was evaluated after transfection of L22 in A549 cells. When the cells were infected with VSV (MOI =1), a significant enhancement of replication of virus was detected. The phosphorylation of the α subunit of eIF2 complex was inhibited by transfection of L22, which is usually followed by VSV infection through PKR activation. Our data also showed L22 inhibited phosphorylation of IRF3 and STAT1. Therefore, we suggest that ribosomal protein L22 negatively regulates type I IFN response in VSV infection model, which facilitates the replication of VSV.
This study was supported by Brain Korea 21 Project for Medical Science, Yonsei University.
AGE AND GENDER-RELATED SPONTANEOUS BACTERIAL KERATITIS IN CD36KO MICE (44.40)
Authors: Barcia Rita N , Whiston Emily , Lee Karen , Heimer Susan , Masli Sharmila , Marshak-Rothstein Ann , Gregory Meredith , Ksander Bruce R 
Published: January 2023

Abstract
Purpose: CD36 is a scavenger receptor with many ligands such as fatty acids, phospholipids, and TSP-1. While its main function is to clear apoptotic cells, CD36 is also required for full activation of TLR 2 triggered by Staphylococcus aureus. Although S. aureus is found in the normal flora of the ocular surface, mice do not spontaneously develop bacterial keratitis. Since both TLR 2 and CD36 are expressed in the cornea, we hypothesize that CD36 is required to prevent S. aureus keratitis.
Methods: Corneas of CD36KO and wild-type C57BL/6 mice were screened via slit lamp. Corneas containing lesions were sectioned, stained, and examined microscopically. Bacterial load in corneal tissue was determined and Staphylococcus was identified by gram stain and ChromAgar. Serum was collected and analyzed for ANA (anti-nuclear antibodies).
Results: CD36KO mice displayed spontaneous corneal lesions that increased in frequency and severity with age. High levels of Staphylococcus were found in corneas with severe lesions, and not controls. Severe corneal lesions showed a massive CD45+ infiltrate in the anterior part of the cornea. The frequency of corneal lesions in the colony was 74% (female) and only 26% (males). ANAs were found in the serum of older female mice with corneal lesions, but not in the controls.
Conclusion: CD36KO mice develop spontaneous bacterial keratitis. The infection may be secondary to autoimmunity since the highest frequency of keratitis occurred in older female mice with ANA. This is the first report of a spontaneous bacterial keratitis in mice.
Adaptive development of catalytic antibodies to the gp120 superantigenic site in lupus and HIV infected patients (44.43)
Authors: Planque Stephanie , Peng Xiaochang , Karle Sangeeta , Nishiyama Yasuhiro , Mitsuda Yukie , Taguchi Hiroaki , Smith Keri C. , Salas Maria , Hanson Carl , Sheppard Haynes W. , Paul Sudhir 
Published: January 2023

Abstract
The B cell superantigenic site of the HIV protein gp120 (gp120SAg) is important in viral entry into host cells and gp120SAg binding IgG in the preimmune repertoire reduce the risk of infection. Like the gp120SAg binding function, the innate catalytic function of antibody (Ab) variable domains is subject to deterioration during B cell maturation, and gp120SAg binding Abs are not produced appreciably following infection. We report the selection of catalytic single chain Fv (scFv) and light chain (L chain) clones from the Ab repertoire of patients with lupus, a condition involving increased production of gp120SAg binding Abs. The Ab fragments were isolated by covalent phage selection using electrophilic gp120 analogs. Several selected fragments cleaved gp120 via a nucleophilic mechanism coordinated with noncovalent recognition of gp120(421–433), determined by electrophoretic assays. Certain clones neutralized HIV infection in cultured peripheral blood mononuclear cells (low μg/ml potency), including two scFv clones that neutralized primary clade B, C and D strains. In contrast to lupus patients, studies on polyclonal IgG and IgA from HIV infected patients did not support the presence of an amplified Ab response to gp120SAg. IgAs from a minority of infected subjects with no progression to AIDS 5.5 years following seroconversion displayed increased gp120 hydrolysis compared to rapid progressors (P&lt;0.0001). These data suggest catalytic Abs as a protective anti-viral mechanism and open the way to considerations of immunogens that stimulate catalytic immunity as candidate vaccines.
Inhibition of Toll-like receptor and Fc receptor responses in macrophages by TREM-2 and DAP12 (44.7)
Authors: Hamerman Jessica A , Jarjoura Jessica R , Tchao Nadia K , Humphrey Mary Beth , Nakamura Mary C , Lowell Clifford A , Seaman William E , Lanier Lewis L 
Published: January 2023

Abstract
DAP12 is a transmembrane signaling adapter that contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain and is expressed in myeloid cells and natural killer cells. DAP12 associates with receptors that do not have intrinsic signaling ability and therefore use DAP12 to propagate signals. We examined the inflammatory response in macrophages lacking DAP12. Surprisingly, DAP12-deficient macrophages produced increased amounts of inflammatory cytokines in response to Toll-like receptor and Fc receptor stimulation, demonstrating that DAP12 inhibits inflammatory responses in wild-type macrophages. This inhibition was dependent upon the DAP12 ITAM. In vivo, DAP12-deficient mice were more susceptible to LPS/D-galactosamine-induced shock and more resistant to Listeria monocytogenes infection. TREM-2, a DAP12-associated Ig superfamily receptor, was responsible for the DAP12-mediated inhibition of TLR and FcR responses in macrophages. Additionally, a fusion protein containing the extracellular domain of TREM-2 bound to macrophages. These results suggest that the interaction of TREM-2 and its ligand on macrophages results in an inhibitory signal that can reduce the macrophage inflammatory response.
αB-crystallin protects the retina during S. aureus induced endophthalmitis (45.2)
Authors: Gregory Meredith , Whiston Emily , Sugi Norito , Sack Coralynn , Kamradt Merideth C , Heimer Susan , Gilmore Michael S , Ksander Bruce R 
Published: January 2023

Abstract
Purpose: Bacterial infections in the posterior of the eye (endophthalmitis) result in toxin-related retinal destruction. However, it is not known whether apoptosis contributes to infection pathology. We are investigating whether αB-crystallin protects retinal tissue during S. aureus endophthalmitis. αB-crystallin is an anti-apoptotic small heat shock protein constitutively expressed in the retina. We hypothesize that αB-crystallin protects the retina from apoptosis.
Methods: 129S6/SvEv αB-crystallin KO and wild-type mice received intravitreal injections of 500 CFU S. aureus. Clinical examinations and ERGs (electroretinalgram) were performed at 24, 48, 72 and 96 hours. Eyes were analyzed histologically for apoptosis via TUNEL staining.
Results: Infected WT mice had only low levels of apoptosis in the inner nuclear layer of the retina. By contrast, infected KO mice displayed:
decreased ERG retinal function,increased retinal destruction via histopathology, andhigher levels of apoptosis in the ganglion cell, inner nuclear and outer nuclear retinal layers at 48 hours.
Further experiments demonstrated that
S. aureus triggers up-regulation of αB-crystallin in the retina andS. aureus produces a protease that cleaves and inactivates αB-crystallin in vitro and in vivo.
Conclusions: Bacterial-induced apoptosis of the retina occurs during endophthalmitis. αB-crystallin is increased to prevent retinal apoptosis, while bacterial proteases are released in an attempt to invade the retina. NIH-EY-016145 (M Gregory)