scholarly journals Murine polyomavirus microRNAs promote viruria during the acute phase of infection

2017 ◽  
Author(s):  
James M. Burke ◽  
Clovis R. Bass ◽  
Emin T. Ulug ◽  
Christopher S. Sullivan
Keyword(s):  
Immune Response ◽  
Acute Phase ◽  
Adaptive Immune Response ◽  
Natural Host ◽  
Mutant Virus ◽  
Virus Shedding ◽  
Adaptive Immune ◽  
Murine Polyomavirus ◽  
Serious Disease

AbstractPolyomaviruses (PyVs) can cause serious disease in immunosuppressed hosts. Several pathogenic PyVs encode microRNAs (miRNAs), small RNAs that regulate gene expression via RNA silencing. Despite recent advances in understanding the activities of PyV miRNAs, the biological functions of PyV miRNAs duringin vivoinfections are mostly unknown. Studies presented here use murine polyomavirus (MuPyV) as a model to assess the roles of the PyV miRNAs in a natural host. This analysis reveals that a MuPyV mutant that is unable to express miRNAs has enhanced viral DNA loads in select tissues at late times after infection, indicating that during infection of a natural host, PyV miRNAs function to reduce viral replication during the persistent phase of infection. Additionally, MuPyV miRNAs promote viruria during the acute phase of infection as evidenced by a defect in shedding during infection with the miRNA mutant virus. The viruria defect of the miRNA mutant virus could be rescued by infecting Rag2-/-mice. These findings implicate miRNA activity in both the persistent and acute phases of infection and suggest a role for MuPyV miRNA in evading the adaptive immune response.ImportanceMicroRNAs are expressed by diverse viruses, but for only a few is there any understanding of theirin vivofunction. PyVs can cause serious disease in immunocompromised hosts. Therefore, increased knowledge of how these viruses interact with the immune response is of possible clinical relevance. Here we show a novel activity for a viral miRNA in promoting virus shedding. This work indicates that in addition to any role for the PyV miRNA in long-term persistence, that it also has biological activity during the acute phase. As this mutant phenotype is alleviated by infection of mice lacking an effective adaptive immune response, our work also connects thein vivoactivity of a PyV miRNA to the immune response. Given that PyV-associated disease is associated with alterations in the immune response, our findings may help to better understand how the balance between PyV and the immune response becomes altered in pathogenic states.

scholarly journals The Murine Polyomavirus MicroRNA Locus Is Required To Promote Viruria during the Acute Phase of Infection

2018 ◽  
Vol 92 (16) ◽  
Author(s):  
James M. Burke ◽  
Clovis R. Bass ◽  
Rodney P. Kincaid ◽  
Emin T. Ulug ◽  
Christopher S. Sullivan
Keyword(s):  
Immune Response ◽  
Acute Phase ◽  
Adaptive Immune Response ◽  
Natural Host ◽  
Mutant Virus ◽  
Adaptive Immune ◽  
Mirna Locus ◽  
Murine Polyomavirus ◽  
Serious Disease

ABSTRACTPolyomaviruses (PyVs) can cause serious disease in immunosuppressed hosts. Several pathogenic PyVs encode microRNAs (miRNAs), small RNAs that regulate gene expression via RNA silencing. Despite recent advances in understanding the activities of PyV miRNAs, the biological functions of PyV miRNAs duringin vivoinfections are mostly unknown. The studies presented here used murine polyomavirus (MuPyV) as a model to assess the roles of the PyV miRNAs in a natural host. This analysis revealed that a MuPyV mutant that is unable to express miRNAs has enhanced viral DNA loads in select tissues at late times after infection. This is consistent with the PyV miRNAs functioning to reduce viral replication during the persistent phase of infection in a natural host. Additionally, the MuPyV miRNA locus promotes viruria during the acute phase of infection as evidenced by a defect in shedding during infection with the miRNA mutant virus. The viruria defect of the miRNA mutant virus could be rescued by infectingRag2−/−mice. These findings implicate the miRNA locus as functioning in both the persistent and acute phases of infection and suggest a role for MuPyV miRNA in evading the adaptive immune response.IMPORTANCEMicroRNAs are expressed by diverse viruses, but for only a few is there any understanding of theirin vivofunction. PyVs can cause serious disease in immunocompromised hosts. Therefore, increased knowledge of how these viruses interact with the immune response is of clinical relevance. Here we show a novel activity for a viral miRNA locus in promoting virus shedding. This work indicates that in addition to any role for the PyV miRNA locus in long-term persistence, it also has biological activity during the acute phase. As this mutant phenotype is alleviated by infection of mice lacking an adaptive immune response, our work also connects thein vivoactivity of the PyV miRNA locus to the immune response. Given that PyV-associated disease is associated with alterations in the immune response, our findings help to better understand how the balance between PyVs and the immune response becomes altered in pathogenic states.

Late Breaking Abstract - Hypoxia dampens the allergen-dependent adaptive immune response and ameliorates allergic asthma in vivo

2021 ◽  
Author(s):  
Mathias Hochgerner ◽  
Eva M Sturm ◽  
Diana Schnoegl ◽  
Grazyna Kwapiszewska ◽  
Horst Olschewski ◽  
...  
Keyword(s):  
Immune Response ◽  
Allergic Asthma ◽  
Adaptive Immune Response ◽  
Adaptive Immune

scholarly journals Consensus guidelines for the definition, detection and interpretation of immunogenic cell death

2020 ◽  
Vol 8 (1) ◽  
pp. e000337 ◽  
Author(s):  
Lorenzo Galluzzi ◽  
Ilio Vitale ◽  
Sarah Warren ◽  
Sandy Adjemian ◽  
Patrizia Agostinis ◽  
...  
Keyword(s):  
Immune Response ◽  
Cell Death ◽  
Adaptive Immune Response ◽  
Operational Definition ◽  
Immunogenic Cell Death ◽  
Adaptive Immune ◽  
Regulated Cell Death ◽  
Definition Of

Cells succumbing to stress via regulated cell death (RCD) can initiate an adaptive immune response associated with immunological memory, provided they display sufficient antigenicity and adjuvanticity. Moreover, multiple intracellular and microenvironmental features determine the propensity of RCD to drive adaptive immunity. Here, we provide an updated operational definition of immunogenic cell death (ICD), discuss the key factors that dictate the ability of dying cells to drive an adaptive immune response, summarize experimental assays that are currently available for the assessment of ICD in vitro and in vivo, and formulate guidelines for their interpretation.

scholarly journals Reduced Immune Response to Borrelia burgdorferi in the Absence of γδ T Cells

2011 ◽  
Vol 79 (10) ◽  
pp. 3940-3946 ◽  
Author(s):  
Cuixia Shi ◽  
Bikash Sahay ◽  
Jennifer Q. Russell ◽  
Karen A. Fortner ◽  
Nicholas Hardin ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Borrelia Burgdorferi ◽  
Adaptive Immune Response ◽  
Γδ T Cells ◽  
Content Type ◽  
Adaptive Immune ◽  
Cytokines And Chemokines

ABSTRACTLittle is known regarding the function of γδ T cells, although they accumulate at sites of inflammation in infections and autoimmune disorders. We previously observed that γδ T cellsin vitroare activated byBorrelia burgdorferiin a TLR2-dependent manner. We now observe that the activated γδ T cells can in turn stimulate dendritic cellsin vitroto produce cytokines and chemokines that are important for the adaptive immune response. This suggested thatin vivoγδ T cells may assist in activating the adaptive immune response. We examined this possibilityin vivoand observed that γδ T cells are activated and expand in number duringBorreliainfection, and this was reduced in the absence of TLR2. Furthermore, in the absence of γδ T cells, there was a significantly blunted response of adaptive immunity, as reflected in reduced expansion of T and B cells and reduced serum levels of anti-Borreliaantibodies, cytokines, and chemokines. This paralleled a greaterBorreliaburden in γδ-deficient mice as well as more cardiac inflammation. These findings are consistent with a model of γδ T cells functioning to promote the adaptive immune response during infection.

scholarly journals A Nonfunctional Opsonic Antibody Response Frequently Occurs after Pneumococcal Pneumonia and Is Associated with Invasive Disease

mSphere ◽  
2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Fabian Uddén ◽  
Jonas Ahl ◽  
Nils Littorin ◽  
Kristoffer Strålin ◽  
Simon Athlin ◽  
...  
Keyword(s):  
Immune Response ◽  
Antibody Response ◽  
Acute Phase ◽  
Pneumococcal Infection ◽  
Adaptive Immune Response ◽  
Invasive Disease ◽  
Community Acquired Pneumonia ◽  
Antibody Activity ◽  
Adaptive Immune ◽  
Convalescent Phase

ABSTRACT Naturally acquired opsonic antipneumococcal antibodies are commonly found in nonvaccinated adults and confer protection against infection and colonization. Despite this, only limited data exist regarding the adaptive immune response after pneumococcal exposure. To investigate the dynamics of naturally acquired antipneumococcal immunity in relation to an episode of infection, opsonic antibody activity was studied with paired acute-phase and convalescent-phase sera obtained from 54 patients with pneumococcal community-acquired pneumonia (CAP) using an opsonophagocytic assay (OPA). Results were compared with clinical characteristics and anticapsular immunoglobulin (Ig) concentrations. Interestingly, a nonfunctional opsonic antibody response (characterized by a decreased convalescent-phase serum OPA titer compared to that of the acute-phase serum or undetectable titers in both sera) was observed in 19 (35%) patients. A nonfunctional convalescent-phase response was significantly more common among patients with invasive pneumococcal disease (i.e., bacteremia) than in patients without invasive disease (53%; P = 0.019). Remaining individuals exhibited either an increased convalescent-phase OPA titer (n = 24 [44%]) or a detectable, but unchanged, titer at both time points (n = 11 [20%]). No correlation was found between anticapsular Ig concentrations and OPA titers. Our findings indicate that an episode of pneumococcal infection may act as an immunizing event, leading to an improved antipneumococcal adaptive immune status. However, in some cases, when patients with CAP also suffer from bacteremia, a nonfunctional opsonic antibody response may occur. Furthermore, the results suggest that factors other than anticapsular Ig concentrations are important for opsonic antibody activity in serum. IMPORTANCE Numerous reports on the dynamics of antipneumococcal immunity in relation to immunization with pneumococcal vaccines and on the prevalence of naturally acquired immunity in various populations have been published. In contrast, studies on the dynamics of the humoral immune response triggered by pneumococcal infection are scarce. This study provides valuable information that will contribute to fill this knowledge gap. Our main results indicate that a functional immune response frequently fails to occur after CAP, predominantly among patients with simultaneous bacteremia.

scholarly journals A minimum of two distinct heritable factors are required to explain correlation structures in proliferating lymphocytes

2010 ◽  
Vol 7 (48) ◽  
pp. 1049-1059 ◽  
Author(s):  
John F. Markham ◽  
Cameron J. Wellard ◽  
Edwin D. Hawkins ◽  
Ken R. Duffy ◽  
Philip D. Hodgkin
Keyword(s):  
Flow Cytometry ◽  
Immune Response ◽  
Adaptive Immune Response ◽  
Time Lapse ◽  
Experimental Information ◽  
Flow Cytometry Data ◽  
Adaptive Immune ◽  
Three Phase

During the adaptive immune response, lymphocyte populations undergo a characteristic three-phase process: expansion through a series of cell divisions; cessation of expansion; and, finally, most of the accumulated lymphocytes die by apoptosis. The data used, thus far, to inform understanding of these processes, both in vitro and in vivo , are taken from flow cytometry experiments. One significant drawback of flow cytometry is that individual cells cannot be tracked, so that it is not possible to investigate interdependencies in the fate of cells within a family tree. This deficit in experimental information has recently been overcome by Hawkins et al . (Hawkins et al . 2009 Proc. Natl Acad. Sci. USA 106 , 13 457–13 462 ( doi:10.1073/pnas.0905629106 )), who reported on time-lapse microscopy experiments in which B-cells were stimulated through the TLR-9 receptor. Cells stimulated in this way do not aggregate, so that data regarding family trees can be recorded. In this article, we further investigate the Hawkins et al . data. Our conclusions are striking: in order to explain the familial correlation structure in division times, death times and propensity to divide, a minimum of two distinct heritable factors are necessary. As the data show that two distinct factors are necessary, we develop a stochastic model that has two heritable factors and demonstrate that it can reproduce the key features of the data. This model shows that two heritable factors are sufficient. These deductions have a clear impact upon biological understanding of the adaptive immune response. They also necessitate changes to the fundamental premises behind the tools developed by statisticians to draw deductions from flow cytometry data. Finally, they affect the mathematical modelling paradigms that are used to study these systems, as these are widely developed based on assumptions of cellular independence that are not accurate.

scholarly journals Mi-2β-targeted inhibition induces immunotherapy response in melanoma

2020 ◽  
Author(s):  
Bo Zhu ◽  
Zhengyu Wang ◽  
Licheng Yao ◽  
Xingyu Lin ◽  
Jie Zhang ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Adaptive Immune Response ◽  
Underlying Mechanism ◽  
Adaptive Immune ◽  
Melanoma Patients ◽  
Ifn Γ ◽  
Targeted Inhibition

Abstract Recent development of some new immune checkpoint inhibitors has been particularly successfully in melanoma, but the majority of melanoma patients exhibit resistance. Understanding and targeting the potential underlying mechanism/targets, especially the tumor-intrinsic modulators to convert resistant melanomas to immunotherapy sensitivity will potentially provide a significant improvement in patient outcome. Here, Mi-2β, a chromatin remodeling enzyme was identified as a key melanoma-intrinsic effector regulating the adaptive anti-tumor immune response. Loss of Mi-2β rescued the immune response to immunotherapy in vivo. Mechanistically, targeting Mi-2β induced the adaptive immune response by transcriptionally enhancing expression of a set of IFN-γ-responsive genes including CXCL9, CXCL10 and IRF1. Finally, we developed a Mi-2β-targeted inhibitor Z36-MP5, which specifically and effectively induced a response to immune checkpoint blockades in otherwise resistant melanomas. Our work provides a new insight into the epigenetic regulation in adaptive immune response, and highlights a viable strategy to improve immunotherapies in melanoma.

scholarly journals Swine Dendritic Cell Response to Porcine Reproductive and Respiratory Syndrome Virus: An Update

2021 ◽  
Vol 12 ◽  
Author(s):  
Jesús Hernández ◽  
Yanli Li ◽  
Enric Mateu
Keyword(s):  
Immune Response ◽  
Adaptive Immune Response ◽  
Respiratory Pathogen ◽  
Respiratory Syndrome Virus ◽  
Adaptive Immune ◽  
Unexplored Area ◽  
Plasmacytoid Dcs ◽  
Antigen Presenting

Dendritic cells (DCs) are the most potent antigen-presenting cells, unique to initiate and coordinate the adaptive immune response. In pigs, conventional DCs (cDCs), plasmacytoid DCs (pDCs), and monocyte-derived DCs (moDCs) have been described in blood and tissues. Different pathogens, such as viruses, could infect these cells, and in some cases, compromise their response. The understanding of the interaction between DCs and viruses is critical to comprehend viral immunopathological responses. Porcine reproductive and respiratory syndrome virus (PRRSV) is the most important respiratory pathogen in the global pig population. Different reports support the notion that PRRSV modulates pig immune response in addition to their genetic and antigenic variability. The interaction of PRRSV with DCs is a mostly unexplored area with conflicting results and lots of uncertainties. Among the scarce certainties, cDCs and pDCs are refractory to PRRSV infection in contrast to moDCs. Additionally, response of DCs to PRRSV can be different depending on the type of DCs and maybe is related to the virulence of the viral isolate. The precise impact of this virus-DC interaction upon the development of the specific immune response is not fully elucidated. The present review briefly summarizes and discusses the previous studies on the interaction of in vitro derived bone marrow (bm)- and moDCs, and in vivo isolated cDCs, pDCs, and moDCs with PRRSV1 and 2.

scholarly journals Adequate immune response ensured by binary IL-2 and graded CD25 expression in a murine transfer model

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Franziska Fuhrmann ◽  
Timo Lischke ◽  
Fridolin Gross ◽  
Tobias Scheel ◽  
Laura Bauer ◽  
...  
Keyword(s):  
Immune Response ◽  
Adaptive Immune Response ◽  
Population Level ◽  
Treg Cells ◽  
Transfer Model ◽  
Antigen Specificity ◽  
Central Importance ◽  
Adaptive Immune ◽  
Response Range

The IL-2/IL-2Ralpha (CD25) axis is of central importance for the interplay of effector and regulatory T cells. Nevertheless, the question how different antigen loads are translated into appropriate IL-2 production to ensure adequate responses against pathogens remains largely unexplored. Here we find that at single cell level, IL-2 is binary (digital) and CD25 is graded expressed whereas at population level both parameters show graded expression correlating with the antigen amount. Combining in vivo data with a mathematical model we demonstrate that only this binary IL-2 expression ensures a wide linear antigen response range for Teff and Treg cells under real spatiotemporal conditions. Furthermore, at low antigen concentrations binary IL-2 expression safeguards by its spatial distribution selective STAT5 activation only of closely adjacent Treg cells regardless of their antigen specificity. These data show that the mode of IL-2 secretion is critical to tailor the adaptive immune response to the antigen amount.

scholarly journals Activating an adaptive immune response from a hydrogel scaffold imparts regenerative wound healing

2020 ◽  
Author(s):  
Donald R. Griffin ◽  
Maani M. Archang ◽  
Chen H. Kuan ◽  
Westbrook M. Weaver ◽  
Jason S. Weinstein ◽  
...  
Keyword(s):  
Immune Response ◽  
Wound Healing ◽  
Tissue Regeneration ◽  
Porous Scaffold ◽  
Adaptive Immune Response ◽  
Hydrogel Scaffold ◽  
Adaptive Immune ◽  
Scaffold Degradation

AbstractBiomaterial scaffolds represent a promising approach for material-based tissue regeneration. We previously developed microporous annealed particle (MAP) hydrogels - a flowable, microparticle-based hydrogel in which neighboring hydrogel particles are linked in situ to form a porous scaffold that accelerates wound healing. To promote more extensive tissue ingrowth before scaffold degradation, we aimed to slow scaffold degradation by switching the chirality of the crosslinking peptides from L-peptides to D-peptides. Unexpectedly, despite showing the predicted slower enzymatic degradation in vitro, D-peptide crosslinked MAP hydrogel (D-MAP) hastened material degradation in vivo and imparted significant tissue regeneration to healed cutaneous wounds, including increased tensile strength and hair neogenesis. By themselves, D-chiral peptides were poor activators of macrophage innate immune signaling in vivo, but MAP particles elicit IL-33 type 2 myeloid cell recruitment which is amplified in vivo in the presence of D-peptides. Remarkably, D-MAP elicited significant antigen-specific immunity against the D-chiral peptides, and an intact adaptive immune system was required for the hydrogel-induced skin regeneration. These findings demonstrate that the generation of an adaptive immune response from a biomaterial is sufficient to induce cutaneous regenerative healing despite faster scaffold degradation.

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