bluuebunny/crossref_metadata_2025_split huggingface dataset:
Newly isolated porcine epidemic diarrhea virus resistance to interferon and neutralizing antibody
Authors: Shin Hyun-Jin , Park Jung-Eun 
Published: January 2023

Abstract
Porcine epidemic diarrhea virus (PEDV) infects pigs and causes enteric disease characterized by watery diarrhea and dehydration. Variant PEDV belonging to genogroup G2 has higher pathogenicity and morbidity than conventional PEDV belonging to genogroup G1. To understand the pathogenesis of the variant PEDV, we examined the susceptibility of the variant PEDV to interferon and PEDV specific neutralizing antibodies, which are known to important for the control of PEDV infection. We found that variant PEDV (WG strain) showed higher resistance to interferon than conventional PEDV (KPEDV-9 strain). Similarly, KPEDV-9 strain grew well in interferon-deficient Vero cells but did not grow in interferon-releasing porcine alveolar macrophages, whereas WG strain showed similar infectivity in both cells. We also found that WG strain is not blocked by the neutralizing antibodies against KPEDV-9, suggesting the differences in the antigenicity of two strains. To elucidate the possible mechanism of resistance to interferon and neutralizing antibody in variant PEDV, sequencing analysis was performed. We found huge variations in spike and ORF3 proteins. To test the impacts of these mutations on the acquisition of interferon and neutralizing antibody resistance, we are currently generating pseudotyped PEDV and recombinant PEDVs with mutations. Our results indicate that the recently introduced variant PEDV exhibits higher resistance to the interferon than the existing PEDV and avoids the neutralizing antibody against the existing PEDV. These results also provide understanding of the occurrence of variant PEDV and its pathogenesis.
Non-therapeutic administration of antimicrobial growth promoters to interrogate suppression mechanisms of innate and adaptive immune responses using an ovine model of stress
Authors: Clarke Sandra T , Inglis G. Douglas 
Published: January 2023

Abstract
Antimicrobial growth promoters (AGPs) have been administered in non-therapeutic concentrations in livestock feed to increase weight gain per unit of feed consumed. Daily low-dose antibiotic administration is capable of modulating immunity by suppressing inflammation, potentially increasing metabolic resources that can be allocated to muscle development. It is unknown how the AGPs tylosin (TYL) and chlortetracycline (CTC) influence acquired immunity. The objective of this study was to measure acquired immune responses, assess impacts on innate immunity and to elucidate mechanisms of immunosuppression by immunizing 10-week old lambs (male Suffolk cross) with keyhole limpet hemocyanin (KLH) during AGP administration (TYL, CTC or Control diets) while enduring intermittent physical stress. Over a 4-week period, 18 lambs (n=3 per diet/stress group) were monitored. Between the third-fourth experimental week, stressed lambs gained less weight (1.50 ± 0.49 kg) than non-stressed lambs (3.06 ± 0.37 kg, P &lt; 0.03). The weight of lambs fed AGPs did not surpass those on the control diet. Diet and stress did not impact serum concentrations of total IgG and IgM, or anti-KLH IgG and IgM specific titres. Endpoint hematological analysis revealed that stressed lambs had decreased red cell distribution width (RDW%, 29% vs. 31%, P&lt;0.01) and peripheral lymphocyte populations (5.72 × 103/μL vs. 4.69 × 103/μL, P&lt;0.02). A diet × stress interaction was observed for peripheral granulocyte population (P=0.02). The impending restriction of AGP usage in North America has generated interest in identifying AGP alternatives, and elucidation of the mechanisms of AGP function is needed to develop effective non-antibiotic alternatives that mimic their action.
T cells responses during resolving Hepacivirus A infection, a surrogate animal model for human Hepatitis C
Authors: Gimenez Fernada , Mealey Robert H. , Ramsay Joshua D. 
Published: January 2023

Abstract
Hepacivirus A (HcV A) is a hepatotropic equine virus and the closest known relative of hepatitis C virus (HCV). HcV A is also highly similar to HCV in its replication kinetics and severity of associated acute hepatitis, but, unlike HCV, HcV A is typically cleared by the host before causing significant disease. As such, HcV A is considered a tenable model for defining the correlates of resolving hepaciviral infection and vaccine development. The pathogenesis of acute HcV A-hepatitis and the mechanism(s) that lead to viral clearance are unknown. In this study we aimed to characterize T cell responses in horses (n=2) following inoculation with plasma containing HcV A. Viremia and hepatic injury were monitored by RT-PCR and plasma liver enzyme activity [gamma glutamyl transferase (GGT) and sorbitol dehydrogenase (SDH)], respectively. HcV A-specific T-cell responses were evaluated every two weeks by interferon gamma Elispot following ex-vivo PBMC stimulation with peptides pools spanning the HcV A polyprotein. Liver biopsies were collected prior to infection, at the peak of liver enzyme activity, and following viral clearance to quantify CD4, CD8 and proinflammatory cytokine mRNA levels, and characterize CD3+ T cell infiltration by immunohistochemistry (IHC). No distinct HcV A specific peripheral T cell response was detected during infection, but when liver enzymes peaked, IHC revealed a mean 15 fold increase in CD3+ T cell infiltration. CD4, CD8 and proinflammatory cytokine mRNA levels were also significantly increased at the same time point. In conclusion, our findings suggest that acute HcV A-hepatitis is mediated by CD3+ T cells and that HcV A-specific T cell response are likely sequestered in the liver.
Functional comparison of human and non-human primate neutrophil responses
Authors: Brinkworth Jessica F , Van Etten Kathrine , Bhatt Priya , McClure Keaton , Valizadegan Negin , Woo Minkyu , Gunasekera Suvanthee , Suarez Yaravi , Aldridge Brian 
Published: January 2023

Abstract
Humans and apes are neutrophilic, maintaining high levels (50–70% of circulating leukocytes) of this short-lived, highly reactive cell type (neutrophils), while most primates maintain significantly lower proportions(20–40% circulating leukocytes). Neutrophils are key limiters of bacterial and parasitic infection, amplifying inflammation, phagocytosing and presenting, and trapping invading foreign material, as well as committing bystander tissue damage in these efforts. The comparative neutrophilia of humans, therefore, suggests alterations in neutrophil activities such that higher proportions are both required and tolerated in this species. To address this possibility, we analyzed transcriptomic, and cell physiological responses of neutrophils from humans, and two biomedically important primates, rhesus macaque and common marmoset. Cells were isolated via a density gradient and stimulated with 1ng-1ug of lipopolysaccarhide (LPS) from Escherichia coli K12 or the bacteria itself (MOI 10:1) for 1–3 hours. Transcriptomic responses were captured by RNAseq, and physiological responses [phagocytosis, apoptosis, extracellular trapping (NETing)] by fluorescent microscopy. The species differed strongly the expression of genes in innate immune and cell trafficking pathways. Overall, primates exhibited NETing and apoptosis sensitivity to even the lowest dose of LPS. Humans, however, displayed a unique complement of neutrophil antimicrobial responses - phagocytosing and apoptosising more, while NETing less than the other species. These results suggest inter-species differences in important neutrophil antimicrobial strategies that may impact interpretation of primate biomedical models.
IFN-lambda modulates dendritic cells to facilitate protective T cell immunity during influenza A virus infection
Authors: Hemann Emily A , Green Richard , Turnbull Bryan , Langlois Ryan A , Savan Ram , Gale Michael 
Published: January 2023

Abstract
Influenza A virus (IAV) remains a global health burden for which therapeutic and vaccination strategies to limit infection and drive robust, protective immune responses are still needed. Type III interferon (IFN), IFN-lambda (IFNλ), restricts IAV in vivo compared to type I IFN. IFNλ signaling in both epithelial cells and neutrophils contribute to this innate antiviral control of IAV. However, the contribution of IFNλ to program protective adaptive immune reposes against IAV has not been defined. To investigate the role of IFNλ in programming effective immunity against IAV, we evaluated responses in lungs and lymph nodes (LN) of WT and IFNλ receptor knock out (Ifnlr−/−) mice following IAV infection. Ifnlr−/− mice had significantly reduced pulmonary IAV-specific CD8 T cell responses during primary infection compared to WT that resulted in loss of protection against subsequent heterosubtypic IAV re-challenge. We found that this defect in the T cell response was not an intrinsic T cell defect, but instead was due to disruption of IFNλ-dependent dendritic cell (DC) function, as confirmed by infection of conditional Ifnlr−/− mice. Analysis of cell function revealed BMDCs respond to IFNλ, and that Ifnlr−/− DCs are defective in antigen uptake, processing, cell maturation, and cell migration. Transcriptomic analysis of DCs sorted from LN show that IFNλ (but not type I IFN) signaling is essential to modulate an IL-10 immunoregulatory program during IAV infection that links with the reduced function observed in Ifnlr−/− DCs. Our studies reveal a novel role for IFNλ in programming DCs for effective T cell actions to control IAV infection that may be broadly applicable to development of therapeutics against respiratory and other viral infections.
Regulation of IL-37 and its signaling co-receptor IL-1R8 in HIV infection
Authors: Ahmad Ali , Samarani Suzanne , Abulkhir Ayoub , Amre Devendra 
Published: January 2023

Abstract
IL-37 is a member of the IL-1 family with potent anti-inflammatory and immune deviating effects. The cytokine exerts its biological effects via IL-1R8 (also formerly known as TIR-8 and SIGIRR), the signaling component of its receptor. Little is known about the regulation of the cytokine and of its receptor in HIV infection. The objective of this study was to investigate how the production of the cytokine and the expression of the signalling component of its receptor on immune cells was regulated in HIV infection. The study was conducted using biological samples from a cross section of HIV-infected individuals. Concentrations of the cytokine and soluble (shed) IL-1R8 in serum samples were determined by ELISA. The expression of IL-1R8 on immune cells was determined by flow cytometry. The effects of exogenous IL-37 on HIV replication in human PHA blasts were determined in in vitro assays. We found that the cytokine concentrations tended to decrease in treatment-naïve HIV-infected individuals compared with the ART-treated patients. Higher concentrations of the cytokine were observed in sera from LTNP. The transcripts for the most complete isoform of the cytokine, b, disappeared from the patients’ PBMC. The expression of IL-1R8 on immune cells was decreased in HIV-infected individuals. On the other hand, concentrations of its soluble form increased in the sera from the virus-infected individuals. The trend was reversed in the patients undergoing anti-retroviral treatment. Soluble IL-1R8 attenuated anti-inflammatory effects of the cytokine. Collectively, these results suggest that the IL-37/IL-1R8 axis is functionally compromised in HIV-infected individuals.
Regulation and perturbation of Myocyte enhancer factor-2 (MEF-2) activity in Adult T-cell leukemia/lymphoma
Authors: Madugula Kiran Kumar , DeMarino Catherine , Panfil Amanda , Dobzanki Alex , Ginwala Rashida , Khan Zafar , Kashanchi Fatah , Lemasson Isabelle , Green Patrick , Harhaj Ed , Jain Pooja 
Published: January 2023

Abstract
HTLV-1 is a complex human retrovirus, an etiologic agent in causing malignant and intractable T-cell neoplasia. About 5% of the infected population would progress to acquiring a more aggressive form of non-Hodgkin’s lymphoma (NHL), termed as Adult T-cell leukemia/Lymphoma (ATLL). MEF-2 transcription factors are a family of genes that are involved in distinct functions in various tissues and isoforms of MEF-2 are 2A, 2B, 2C, 2D in mammals whose mutations are implicated in various cancers. Earlier studies from our lab delineated the role of MEF-2A in increased viral gene expression and inhibition of MEF-2A lead to the reduction in HTLV-1 viral replication and associated T-cell transformation. Presently, we have adopted to novel cyto-analytical techniques to quantitate gene transcripts and protein expression patterns at a single cell level for all the MEF-2 isoforms in different cell systems representing productive viral infection and/or ATLL. These studies revealed post-translationally modified, overexpression of MEF-2C and downregulated expression of MEF-2B which are known to be oncogene and tumor suppressor respectively. Similar results were obtained with a unique and specific HDAC-IIa inhibitor namely MC1568, which led to a dose-dependent cancer cell (but not normal) death in vitro while inhibiting viral proteins (Tax and HBZ) expression in vivo. In addition, exposure of HTLV-1-infected cells to MC1568 resulted in the activation of autophagy marker, LC3-II that is currently under investigation to a more in-depth mechanistic analysis.
HIV infection induces CD44+PD-L1+ tumor initiating cells in AIDS associated non-AIDS defining cancers
Authors: Gupta Harshita B. , Zhang Xinyue , Curiel Tyler J , Kulkarni Smita 
Published: January 2023

Abstract
The antiretroviral therapy (ART) significantly increased the number of aging HIV patients and the non-AIDS defining cancers (NADC) have become the most frequent co-morbidity and causes of death among HIV patients. The role of HIV infection in cancer initiation and progression is unclear. Tumor initiating cells (TIC) are responsible for chemo-resistance, metastasis and mortality. Our previous work demonstrated that tumor-intrinsic PD-L1 correlate with proportion (%) of TIC and virulence. Supernatants from HIV infected peripheral blood lymphocyte (PBMC) cultures (HIV-sup) significantly increased % TIC (CD44+PD-L1+) in two human tumor cell lines-SCC4 (squamous carcinoma) and HeLa (cervical cancer). HIV single stranded RNA (ssRNA) binds TLR7/8, and leads to immune activation and inflammation. The Cancer Genome Atlas database analyses showed that squamous cancer and cervical adenocarcinoma patients with TLR7/8 amplification had significantly poor overall survival. TLR7 agonist R848 led to significant increase in % TIC, whereas treatment of the cancer cells with HIV-sup in presence of TLR7/8 inhibitor ODN2088 reversed this effect. Similarly, pharmacological inhibition (by ACHP) of TLR7/8 mediated NFkB signaling pathway decreased TIC % two-fold, confirming HIV mediated TLR7/8 signaling has pro-TIC effects. High levels of inflammatory cytokine IFNα correlates with HIV load and persistent infection. Treatment with IFNα led to a significant increase in TIC whereas blocking IFNα-induced JAK signaling by ruxolitinib, in presence of HIV-sup reduced TIC significantly. Thus, our novel data gives insight into HIV induced host-pathogen interactions that lead to TIC prevalence.
Microglia secrete exosomes during persistent virus infection of the central nervous system that promote demyelinating disease
Authors: Olson Julie K , Luong Nhungoc 
Published: January 2023

Abstract
Theiler’s murine encephalomyelitis virus (TMEV)-induced demyelinating disease is a mouse model for multiple sclerosis (MS). TMEV infection of susceptible mice leads to a persistent viral infection of microglia in the central nervous system (CNS) which contributes to the development of a chronic progressive demyelinating disease associated with an inflammatory immune response. We have previously shown that TMEV infection of microglia activates an innate immune response with expression of cytokines, chemokines, and effector molecules associated with development and progression of demyelinating disease. Recently, we have shown that TMEV-infected microglia secrete exosomes, which are membrane-bound nanovesicles (60–150 nm). Exosomes contain and facilitate intercellular transfer of a wide variety of materials, including miRNA, mRNA, and proteins. We wanted to determine whether the exosomes secreted by TMEV-infected microglia can be taken up by other CNS resident cells and contribute to the persistent virus infection and inflammatory response during demyelinating disease. Our studies showed that exosomes secreted from microglia during TMEV-induced demyelinating disease (63–98 dpi) contain viral RNA/genome and can be taken up by other CNS resident cells. These exosomes activated the CNS resident cells to express inflammatory cytokines and chemokines. More importantly, the exosomes secreted by microglia during TMEV-induced demyelinating disease could induce MS-like pathology including neuroinflammation and demyelination in naïve mice. These results suggest that exosomes secreted by infected microglia may directly contribute to the development and progression of demyelinating disease.
IL-33 promotes antiviral immunity and protects against congenital Zika disease in mice
Authors: Liang Yuejin , Escano Jerome , Sun Jiaren 
Published: January 2023

Abstract
Zika virus (ZIKV) infection during pregnancy can cause congenital Zika syndrome and other birth defects. The alarmin IL-33 can evoke strong antiviral immune responses during viral infection. However, whether IL-33 is involved in immune responses during ZIKV infection is not clear. In this study, we infected three-week-old wildtype (WT) and IL-33 knockout (KO) mice with ZIKV and analyzed the ZIKV-specific cytotoxic T lymphocyte (CTL) responses at 6 days post infection. We found that IL-33 deficiency resulted in decreased ZIKV-specific CTL responses as evidenced by lower numbers of IFN-g+TNF-a+ CD8+ T effectors. To determine if IL-33 contributes to anti-ZIKV immunity during pregnancy, we infected WT pregnant mice with ZIKV and found increased IL-33 in the placenta at a mid-gestational period (embryo E13.5) compared with that of uninfected ones. Likewise, elevated IL-33 expression was also observed in human trophoblast cell lines JEG-3 and HTR-8 upon ZIKV infection. To determine if IL-33 plays a protective role in congenital Zika disease, we infected pregnant WT and IL-33 KO mice by i.p. injection of ZIKV at E6.5 and found higher percentages of fetal demise and absorption in IL-33 KO mice compared with that in WT mice (16.7 % vs. 3.3 %) from necropsy on E13.5. In addition, the fetuses from IL-33 KO mice displayed smaller sizes than those of WT fetuses (55 mm2 vs. 48 mm2). Moreover, IL-33 deficient mice had lower numbers of virus-specific CD8+ T cells in the placenta, uterine and decidua. Importantly, IL-33 deficiency resulted in higher viral loads in both the placenta and fetus. In summary, our study highlights IL-33 as a key immune regulator in inducing anti-ZIKV CTL responses and protecting against congenital Zika disease.
Determining the impact of HLA type and chronic viral infection on peripheral T-cell receptor sharing between unrelated individuals
Authors: Johnson Sarah , Gittelman Rachel M , Sanders Catherine , Robins Harlan 
Published: January 2023

Abstract
T cells generate highly diverse T-cell receptors (TCRs) to recognize antigens, most of which are private to each individual. TCRs with low junctional complexity have a higher likelihood of being generated and shared across individuals. Additional factors that may further limit diversity and increase the likelihood that particular TCRs are public include: (a) thymus selection for maturation of TCRs that bind antigens presented by an individual’s human leukocyte antigen (HLA) proteins, and (b) T-cell proliferation upon exposure to cognate antigens, which remain in the periphery as memory T cells. Numerous public TCRs have been associated with particular HLA restrictions and antigen specificities1. Chowell et al. also showed that HLA diversity is important for mounting an effective T-cell response against solid tumors2. However, little is known about the impact of these forces on the diversity of the TCR repertoire and expected TCR sharing across individuals. Here, we leverage the TCR repertoires of 666 healthy individuals sequenced with the immunoSEQ® Assay (Adaptive Biotechnologies, Seattle, WA) to address these questions. We investigate (a) how HLA restriction affects immune repertoires by examining the effect of HLA heterozygosity and divergence on the diversity of the TCR repertoire; (b) how the similarity of HLA alleles between individuals impacts the number of TCRs shared between individuals and (c) the impact of shared antigen exposure by determining how age and CMV status impacts clone sharing between individuals. These data show that HLA type, age, and CMV exposure shape the immune repertoire and influence the sharing of clones between individuals.
Targeting both IL-17 and CXCR2 in the gut leads to the suppression of arthritis and joint inflammation in the autoimmune arthritis mice driven by a mycoplasma superantigen
Authors: Mu Hong-Hua 
Published: January 2023

Abstract
Individuals with autoimmune susceptible genes infected with environmental microbial agents might amplify an autoimmune condition by either exacerbating an ongoing disorder, including a relapse, or by leading to chronic progressive disease. Previously we have established an autoimmune arthritis model by infecting mice with the Mycoplasma arthriditis. M. arthritidis produces a potent superantigen (SAg) MAM, which was found to be responsible for the arthritis resembling human RA. In the present study we found that MAM can also activate intestinal immune cells in mice. Because the mechanisms leading from systemic autoimmunity to joint-specific autoimmune disease are unknown, we questioned if the autoimmunity initiates at mucosal sites. To address this question, by injecting mice with collagen II (CII), or with CII+MAM. We found that IL-17 and chemokine receptor CXCR2 were highly expressed within the intestinal lamina propria (LP) in CII+MAM mice but not in traditional CIA mice. In CII+MAM mice, overexpression of IL-17 and CXCR2 in the gut was shown to be strongly related to the arthritis severity. Massive infiltration of inflammatory leukocytes and the upregulation of chemokines, CXCL1, CXCL2, CXCL12, CCL2 and CCL5 in the joint tissues were detected and associated with the increased IL-17 and CXCR2 in the intestinal LP following CII+MAM immunization. Suppression of both IL-17 and CXCR2 at same time by blocking antibodies greatly alleviated arthritis. We also found that neither IL-17 nor CXCR2 alone is sufficient to trigger arthritis. Thus the results suggest that the excessive IL-17 and CXCR2 in the gut are related to the exacerbation of arthritis in a manner by which the inflammatory signals can be connected between the gut and the joints.