bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cytokine-based cancer immunotherapy impairs primary T cell immunity (VAC3P.942)
Authors: Sckisel Gail , Bouchlaka Myriam , Mirsoian Annie , Sungur Can , Soulika Athena , Wiltrout Robert , Blazar Bruce , Murphy William 
Published: January 2023

Abstract
Cancer immunotherapy has made great strides towards becoming a viable alternative to traditional cancer treatment options. Under the premise of specificity and long lasting memory, immunotherapy is hypothesized to provide what traditional cancer therapies lack. However, despite success in tumor efficacy, the smoking gun of tumor-specific immunity has yet to be uncovered. Few studies to date have found correlations between tumor specific T cells and outcomes, particularly with stimulatory regimens. Here we show evidence that following cytokine based immunotherapy regimens, primary CD4 T cell responses towards mitogenic or cognate antigenic stimulation were greatly hampered. This lack of CD4 immunity was further exacerbated by acute thymic involution. Interestingly, the paralysis was confined to the CD4 T cell subset and was transient, resolving within 2 weeks of cessation of therapy. Paralyzed T cells significantly upregulated SOCS3 and failed to undergo proper STAT phosphorylation and CD25 upregulation following TCR engagement. The consequences of this paralysis were impaired vaccination and viral clearance, and also suggest impairment in the development of subsequent primary anti-tumor T cell responses. Taken together, these data suggest that cytokine-based immunotherapies may actually impair the development of immunity towards novel tumor antigens and may put patients at risk for opportunistic infections.
Denileukin diftitox depletes regulatory T cells without clinical benefit in advanced stage epithelial ovarian carcinoma (VAC3P.945)
Authors: Curiel Tyler , Thibodeaux Suzanne , Wall Shawna , Pandeswara Sri Lakshmi , Daniel Benjamin , Drerup Justin , Murthy Kruthi , Kryczek Ilona , Zou Weiping , Barnett Brian 
Published: January 2023

Abstract
Denileukin diftitox (DT) depletes regulatory T cells (Treg) that correlates with immune and clinical benefits in metastatic human melanoma and improved clinical outcomes in a renal cancer vaccine trial. We tested immune and clinical effects of Treg depletion using DT in a phase 0/I cancer trial and a phase II ovarian cancer trial. In our phase 0/I trial, we noted reductions in blood Treg prevalence and concentration (median ~18% and ~50%, respectively) 3-7 days after one intravenous DT infusion at 9 or 12 μg/kg, in 6 of 7 evaluable patients with breast, lung, and ovarian cancers, and melanoma, and increased blood IFN-γ+ and Ki-67+ T cells. Weekly DT significantly reduced metastatic tumors in one ovarian cancer patient prompting a small phase II trial in epithelial ovarian cancers. 28 patients received DT once every 3-4 weeks which significantly depleted functional Tregs from blood and the tumor microenvironment, but with variable immune outcomes and no significant clinical efficacy. Weekly DT eventually reduced effector T cells. In mouse ovarian cancer models we found that: i) DT efficacy depended on adaptive immunity, ii) its IL-2 moiety did not mediate clinical effects, and iii) its treatment mechanism appeared distinct from anti-CD25 antibody, which depleted Tregs in a human breast cancer trial. DT depletes Tregs in various carcinomas but requires more dosing and schedule studies. Treg-specific agents and combination treatments could also improve Treg depletion efficacy.
Mathematical modeling of the human immune response to vaccination (VIR1P.969)
Authors: Ganusov Vitaly , Le Dustin 
Published: January 2023

Abstract
With major advances in experimental techniques to track antigen-specific immune responses many basic questions on the kinetics of virus-specific immunity in humans remain unanswered. To gain insights into kinetics of T and B cell responses in human volunteers we combine mathematical models and experimental data from recent studies employing vaccines against yellow fever and smallpox. We found that the peak of the yellow fever-specific CD8 T cell response is determined by the rate of T cell proliferation and not by the precursor frequency of antigen-specific cells as has been suggested in several studies in mice. We also found that the rise in the virus-specific T cell numbers accurately explains clearance of yellow fever virus in the blood. Our additional mathematical model describes well the kinetics of virus-specific plasma cell and antibody response to vaccinia virus in vaccinated individuals. The model suggests that to explain the data either the rate of antibody production by plasma cells has to increase with time since immunization, or production of the majority of antibodies comes from cells located in tissues and not in the blood. Taken together, our analysis provides novel insights into mechanisms by which live vaccines induce highly efficient immunity to viral infections.
Critical roles for interferon-gamma producing immune cells during neonatal central nervous system infections (VIR1P.1005)
Authors: Ganesan Priya , O'Donnell Lauren 
Published: January 2023

Abstract
Viral infections in the central nervous system (CNS) are associated with devastating neurological consequences, particularly in newborns. Despite mounting innate and adaptive immune responses, neonates are often unable to control viruses in the brain and suffer extensive neuronal loss, potentially due to deficits in anti-viral cytokines. To study the response of the neonatal immune system to viral CNS infections, our laboratory uses a transgenic mouse model (NSE-CD46) of neuron-restricted measles virus (MV) infection. NSE-CD46 mice express the human isoform of CD46, a MV receptor, under the control of the neuron specific enolase (NSE) promoter, allowing for infection only in CNS neurons. Adult NSE-CD46 mice clear MV from the CNS in an interferon gamma (IFNγ) and T-cell dependent manner. In contrast, neonatal NSE-CD46 mice succumb, with 100% mortality at 15 days post infection (dpi). Neonatal mice lacking IFNγ (CD46+/IFNγ-KO) succumb more rapidly than NSE-CD46+ neonates (100% mortality, 10 dpi) despite higher T-cell infiltration in the CNS. CD46+/RAG-2-KO neonates, which lack T- and B-cells, show reduced mortality in comparison to other CD46+ genotypes and have lower MV RNA. We hypothesize that MV control in CD46+/RAG2-KO neonates could be provided by IFNγ-producing natural killer (NK) cells. Current experiments aim to define the mechanism of viral control in the CD46+/RAG2-KO neonates. This work will answer critical questions about viral control in the neonatal CNS.
Out-of-sequence signal 3 as a mechanism for virus-induced immune suppression of CD8 T cell proliferation (VIR1P.960)
Authors: Urban Stina , Welsh Raymond 
Published: January 2023

Abstract
Virus infections are known to induce a transient state of immune suppression often associated with an inhibition of T cell proliferation in response to mitogen or cognate-antigen stimulation. Recently, virus-induced immune suppression has been linked to responses to type 1 IFN, a signal 3 cytokine that normally can augment the proliferation and differentiation of T cells exposed to antigen (signal 1) and co-stimulation (signal 2). However, pre-exposure of CD8 T cells to IFN-inducers such as viruses or poly(I:C) prior to antigen signaling is inhibitory, indicating that the timing of IFN exposure is of essence. Studies with T cells lacking IFN receptors implicated a direct role for type 1 IFN in this process. CD8 T cells pretreated with poly(I:C) down-regulated the IFN receptor, up-regulated SOCS1, and were refractory to IFNβ-induced STAT phosphorylation. When exposed to a viral infection these CD8 T cells behaved more like 2-signal than 3-signal T cells, showing defects in short lived effector cell differentiation, reduced effector function, delayed cell division, and reduced levels of survival proteins. This suggests that IFN-pretreated CD8 T cells are unable to receive the positive effects that type 1 IFN provides as a signal 3 cytokine when delivered later in the signaling process. This desensitization mechanism may partially explain why vaccines function poorly in virus-infected individuals.
Anti-viral immune response in the central nervous system induces glial commitment in neural stem/progenitor cells (VIR1P.1010)
Authors: Kulkarni Apurva , O'Donnell Lauren 
Published: January 2023

Abstract
Viral infections in the central nervous system (CNS) are characterized by infiltration of lymphocytes into the brain parenchyma and release of pro-inflammatory cytokines. The effects of cytokines on neural cell function and survival varies between cell types, and may depend upon the expression of endogenous signaling molecules. Both inflammatory and developmentally-regulated cytokines alter the activity of neural stem/ progenitor cells (NSPCs), which are critical for CNS development and repair. Moreover, the proliferation and fate of NSPCs are affected during viral CNS infections. Interferon-gamma (IFNγ) is a cytokine that is released in response to a viral infection in the brain and is required for clearance of certain viruses from the CNS. IFNγ signals via the Janus kinase/Signal transducer and activator of transcription (Jak/STAT) signaling pathway, which is also activated by developmental cytokines during cell fate decisions. The JAK/STAT pathway leads to transcription of genes (p21, p27) that affect proliferation. Therefore, we will test the hypothesis that the IFNγ influences NSPC proliferation and differentiation through Jak/STAT signaling. In preliminary studies, we found that IFNγ activates STAT1 and STAT3 proteins and decreases NCPS proliferation in vitro. Through these studies, we will define the role of the inflammatory response in modulating NSPC activity during viral infections.
Interleukin-1α released from HSV-1 infected skin keratinocytes initiates protective immunity against systemic infection (VIR1P.964)
Authors: Jensen Liselotte , Milora Katelynn , Miller Samantha , Sanmiguel Julio 
Published: January 2023

Abstract
Herpes simplex virus-1 (HSV-1) is a common human pathogen that typically causes self-limiting disease. However, neonates and patients with compromised immune systems are at risk of developing potentially fatal systemic disease. Previously we reported that IL-1α is released by keratinocytes treated with poly(I:C), a double stranded RNA analogue often utilized to simulate virus infections. The objective of this study was to examine whether IL-1 signaling plays a role in initiating protective immunity against HSV-1 infections. Extracellular release of IL-1α protein could be detected 6-24 hours after HSV-1 infection of primary human keratinocytes (4-5-fold increase, p&lt;0.01). This release was not associated with a correlating change in mRNA levels suggesting that the cells released a pre-formed pool of protein. HSV-1 triggered activation of inflammatory caspases-1/4 as determined using fluorescence labeled peptides (6-fold, p&lt;0.001); however, the cellular release of IL-1α was independent of caspases-1/4. IL-1R knockout (KO) mice exhibited an increased mortality following cutaneous HSV-1 infection (60 versus 25%, p&lt;0.01). Caspase-1/4 deficiency did not affect survival rates; hence, the protective function of IL-1R must be exclusively due to IL-1α signaling. Recruitment of leukocytes to the infected epidermis was delayed in IL-1R KO mice. Hence, HSV-1 triggered IL-1α release from infected cells appears important for initiating protective immunity against systemic HSV-1 infections.
Cell death in pandemic and seasonal influenza viruses (VIR2P.1027)
Authors: Hartmann Boris , Albrecht Randy , Marjanovic Nada , Patil Soanli , Fribourg Miguel , Sealfon Stuart 
Published: January 2023

Abstract
Pandemic influenza virus strains are exceptionally transmissible or virulent, leading to their potential for increased morbidity and mortality. Seasonal influenza strains are relatively predictable causing ~ 40,000 deaths, whereas the influenza pandemic of 1918 caused up to 100 million deaths. Little is known about the virus host interactions that contribute to pandemic and seasonal infections. To gain insight into these differences, we compared temporal gene programs and cell viability in human monocyte-derived dendritic cells (DCs) infected with pandemic (Cal/09, Brevig/1918) or seasonal (Tex/91, NC/99) strains. Influenza infection is associated with cell death at late timepoints related to virion release. Strikingly, as early as 4 hrs after infection, the seasonal strains caused a degree of widespread mRNA degradation and cell death not seen with the pandemic viruses. In contrast, in epithelial cells, only the late occurance (24 hrs) of cell death was observed. These studies identify a dramatic difference in the virus-host interaction between seasonal and pandemic influenza viruses in a crucial cell type of the innate and adaptive immune system.
TNF-α processing is required to limit the CD8+ T-cell response and the extent of lung injury during influenza infection (VIR2P.1015)
Authors: DeBerge Matthew , Ely Kenneth , Enelow Richard 
Published: January 2023

Abstract
Influenza infection in humans evokes a potent CD8+ T-cell response, which is important for clearance of virus but may also exacerbate lung injury. TNF-α is a pleotropic cytokine that is important in regulating T-cell responses to disease. We sought to characterize the role of TNF-α during influenza infection by utilizing genetically modified mice that lack TNF-α or only express transmembrane TNF-α. We found that while TNF-α was dispensable for influenza virus clearance, soluble (s) TNF-α expression was required to limit the extent of injury. In the absence of sTNF-α, there was a significant increase in the virus-specific CD8+ T-cell response, which was due in part to increased resistance to activation-induced cell death. We found that sTNF-α mediated T-cell responses primarily through TNFR1, since mice lacking TNFR1 exhibited dysregulated immune responses and exacerbated injury similar to that observed in mice lacking sTNF-α. Interestingly, mice lacking TNFR2 had an impaired CD8+ T-cell response with attenuated injury. We also found that antibody neutralization of TNF-α early during infection enhanced the magnitude of the CD8+ T-cell response indicating that TNF-α expression has a dominant effect during T-cell priming to limit the size of the effector response later during infection. Taken together, these findings suggest that proteolytic processing of TNF-α is a critical event regulating the CD8+ T-cell response and the extent of immunopathology during influenza infection.
MMP-7 promotes host recovery and lung function to influenza virus infection (VIR2P.1016)
Authors: Sanders Catherine , Thomas Paul 
Published: January 2023

Abstract
Wound healing is a critical aspect of recovery from influenza virus-induced lung damage. However, relatively little attention has been given to the role of host recovery mechanisms in influenza virus pneumonia. MMP-7, or matrilysin, is produced in the airways following damage and is known to promote airway homeostasis and respiratory cell migration and differentiation, possibly via immunomodulatory processes. We hypothesized that MMP-7 is a critical factor in recovery from influenza infection for both airway damage repair and respiratory function. MMP-7-/- mice are more susceptible to PR/8 influenza infection, and, while showing weight loss similar to WT controls, succumb on days 8-13 after infection. MMP-7-/- lungs scored higher than WT lungs in both acute and chronic tissue damage measures on day 7 after infection by histology, demonstrating MMP-7’s ability to reduce tissue damage and limit tissue remodeling at peak disease. Curiously, MMP-7-/- BAL taken day 3 after infection have lower levels of IL-6, KC, and MIG than WT BAL. Plethysmographic respiratory analyses on days 8-11 showed MMP-7-/- mice to have slower breathing rates and exaggerated expiratory functions, suggesting a role for MMP-7 in promoting proper lung function during attempted resolution. This study provides evidence of the impact of a specific tissue remodeling protein on lung function and influenza disease outcome.
Pathogen clearance by engineering of novel innate immune defense (INM3P.414)
Authors: Pardington Paige , Chaudhary Anu , Norvell Meghan , Gupta Goutam , Dandekar Abhaya , Gouran Hossein , Uratsu Sandra , Aguero Cecilia , Feldstein Paul , Bruening George , Civerolo Edwin , Hao Guixia , Duan YongPing , Stover Ed 
Published: January 2023

Abstract
Pathogens circumvent host immune defense to propagate their lifecycle. We have been studying the mechanisms of pathogen-induced host cell death to develop a robust strategy for pathogen clearance. The strategy involves designing and developing a protein chimera with one domain for recognizing conserved pathogen membrane elements and another for lysing the pathogen membrane. This dualistic synergy of recognition and lysis permits rapid pathogen clearance thereby preventing host cell death and disease development. This strategy has been successfully applied to counteract bacterial infections and diseases in grape, citrus, and tobacco. We have engineered a chimera consisting of protease (recognition domain) and cecropin (lysis domain) to prevent Pierce’s disease, a deadly disease in grape caused by Xylella fastidiosa. We have shown that transgenic plants expressing the chimera of protease and cecropin effectively clear Xylella fastidiosa from sites of colonization. We have also designed a protein chimera of thionin (with both recognition and lysis domains) and a synthetic lytic peptide. We have shown that this same chimera prevents citrus canker which is caused by Xanthamonas axonopodis citri and wildfire disease in tobacco which is caused by Pseudomonas syringe pv. tobaci. This protein engineering strategy appears to be an effective therapy against a broad spectrum of plant pathogens. A similar approach is now being evaluated against multiple human pathogens.
Sphingosine 1-phosphate receptor 2 signaling suppresses macrophage phagocytosis and impairs host defense against sepsis (INM3P.416)
Authors: Fang XiangMing , Hou JinChao 
Published: January 2023

Abstract
Background: Sepsis is characterized by an inappropriate systemic inflammatory response and bacteremia that promote multiorgan failure and mortality. Sphingosine 1-phosphate receptor 2 (S1PR2) modulates endotoxin induced inflammation in endothelium. However, as a highly expressed S1P receptor in macrophage, its role in regulating macrophage response to bacterial infection remains unclear. Methods: Sepsis was induced in wild-type mice treated with S1PR2 antagonist or S1PR2-deficient mice. The antibacterial ability of cell specific S1PR2 was tested in bone marrow reconstitution or macrophage deletion mice. Signaling molecules responsible for S1PR2 mediated phagocytosis were also measured in bone marrow-derived macrophages. Results: Both genetic deletion and pharmaceutical inhibition of S1PR2 significantly limited bacterial burden, reduced lung damage, and improved survival in experimental sepsis. This protection was attributed to the enhanced phagocytic function of S1PR2-deficient macrophages. Absence of S1PR2 in macrophage inhibits RhoA-dependent cell contraction and promotes IQGAP1-Rac1-dependent lamellipodial protrusion, the different signalings of which depends on the extracellular stimulators. Conclusions: This study implies that S1PR2 as a critical receptor in macrophage, impairs phagocytosis and antimicrobial defense in the pathogenesis of sepsis. Interventions targeting S1PR2 signaling may serve as a promising therapeutic approach for sepsis.
Early type I interferon response correlates with Borrelia burgdorferi dissemination in a mouse model of Lyme disease (INM3P.417)
Authors: Petzke Mary , Brooks Andrew , Iyer Radha , Love Andrea , Spieler Zoe , Wormser Gary , Schwartz Ira 
Published: January 2023

Abstract
Borrelia burgdorferi genotypes differ in their capacity to cause disseminated Lyme disease. Gene array analysis was employed to profile the host transcriptome induced by Borrelia genotypes in the blood of C3H mice during early dissemination following intradermal inoculation. The greatest responses were elicited by Borrelia turicatae, a relapsing fever spirochete that reaches high densities in the blood (313 entities; 170 induced, 143 repressed) and by B515, a B. burgdorferi clinical isolate that causes disseminated infection (129 entities; 52 induced, 77 repressed). Induced transcripts included IFN-responsive genes and genes involved in immunity and inflammation. B331, a B. burgdorferi clinical isolate that did not disseminate, stimulated changes in the fewest number of entities (1 induced, 4 repressed). Transcriptional regulation of type I IFN and IFN-related genes was measured by RT-PCR in mouse skin biopsies collected from the site of infection 24 hours after inoculation. The mean fold change values for Ifnb, Cxcl10, Gbp1, Ifit1, Ifit3, Irf7, Mx1, and Stat2, were found to be significantly elevated in B515-infected mice relative to the control group. In contrast, transcription of these genes was not significantly changed in response to B331 or B31-4, a non-infectious B. burgdorferi mutant, although live B331 spirochetes could be recovered from skin. These results establish an association between B. burgdorferi genotype, dissemination, and early type I IFN induction.
Mycobacterium leprae infection disrupts the vitamin D-mediated antibacterial response (INM3P.362)
Authors: Zavala Kathryn , Amin Sima , Chun Rene , Modlin Robert , Hewison Martin , Adams John , Liu Philip 
Published: January 2023

Abstract
Leprosy is a debilitating disease caused by infection with Mycobacterium leprae (mLEP). Patients diagnosed with leprosy present on a spectrum of disease characterized by disseminated lepromatous leprosy (L-lep) at one end and self-limiting tuberculoid leprosy (T-lep) at the other end. Previous studies have demonstrated the role of the vitamin D (vit D) system in mediating the antibacterial response to mycobacterial infection; however, it is not understood how dysregulation of the vit D system contributes to disease outcomes. The present study investigates the factors that regulate vit D metabolism and activation in leprosy. Monocytes were infected with mLEP and analyzed for vit D system gene expression and metabolism. In contrast to stimulation with synthetic toll-like receptor 2 (TLR2) ligand, mLEP infection did not induce production of the biologically active form of vit D. Furthermore, gene expression of activating enzyme 1α-hydroxylase (CYP27B1) and vit D receptor (VDR) were not induced by infection. Conversely, treatment with irradiated mLEP induced expression of CYP27B1 and VDR. This suggests that infection does not stimulate the vit D intracrine system in the same manner described for TLR2-sensing of mycobacterial peptides. Instead, infection triggers mechanisms that repress vit D metabolism. Moreover, mLEP-infected T-lep-associated macrophages are resistant to this repression. This study highlights the role of the vit D system in the host response to mLEP infection.