scholarly journals Kinetic Analysis of the Specific Host Response to a Murine Gammaherpesvirus

1998 ◽  
Vol 72 (2) ◽  
pp. 943-949 ◽  
Author(s):  
Philip G. Stevenson ◽  
Peter C. Doherty
Keyword(s):  
Lymph Nodes ◽  
Cell Activation ◽  
Cytotoxic T Lymphocyte ◽  
Low Frequency ◽  
Neutralizing Antibody ◽  
Total Serum ◽  
Enzyme Linked Immunosorbent Assay ◽  
B Cell Activation ◽  
Murine Gammaherpesvirus ◽  
Gammaherpesvirus 68

ABSTRACT Respiratory infection of BALB/c mice with the murine gammaherpesvirus 68 (MHV-68) induces the clonal expansion of virus-specific cytotoxic T-lymphocyte (CTL) precursors (CTLp) in the regional, mediastinal lymph nodes (MLN). Some of these CTLps differentiate to become fully functional CTL effectors, which can be detected in both the lymphoid tissue and in the site of pathology in the lung. Though the lymph nodes and spleen harbor substantial populations of latently infected B cells for life, the level of virus-specific CTL activity decreases rapidly in all sites. The CD8+ CTLp numbers fall to background levels in the MLN within several months of the termination of the productive phase of MHV-68 infection in the respiratory epithelium but are maintained at relatively low frequency in the spleen. The continued presence of a gamma interferon-producing, MHV-68-specific CD4+ set can also be demonstrated in cultured spleen cells. The virus-specific immunoglobulin G (IgG) response is slow to develop, with serum neutralizing antibody and enzyme-linked immunosorbent assay titers continuing to rise for several months. The level of total serum IgG increases dramatically within 2 weeks of infection, probably as a consequence of polyclonal B-cell activation, and remains high. The immune response profile is clearly influenced by the persistence of this DNA virus.

scholarly journals Signaling through Toll-Like Receptors Induces Murine Gammaherpesvirus 68 Reactivation In Vivo

2008 ◽  
Vol 83 (3) ◽  
pp. 1474-1482 ◽  
Author(s):  
Lisa M. Gargano ◽  
J. Craig Forrest ◽  
Samuel H. Speck
Keyword(s):  
B Cell ◽  
Cell Activation ◽  
B Cell Activation ◽  
Toll Like Receptors ◽  
Murine Gammaherpesvirus ◽  
Latently Infected ◽  
Gammaherpesvirus 68 ◽  
Murine Gammaherpesvirus 68 ◽  
Stimulation Of

ABSTRACT Murine gammaherpesvirus 68 (MHV68) establishes a lifelong infection in mice and is used as a model pathogen to study the role of viral and host factors in chronic infection. The maintenance of chronic MHV68 infection, at least in some latency reservoirs, appears to be dependent on the capacity of the virus to reactivate from latency in vivo. However, the signals that lead to MHV68 reactivation in vivo are not well characterized. Toll-like receptors (TLRs), by recognizing the specific patterns of microbial components, play an essential role in the activation of innate immunity. In the present study, we investigated the capacity of TLR ligands to induce MHV68 reactivation, both in vitro and in vivo. The stimulation of latently infected B cell lines with ligands for TLRs 3, 4, 5, and 9 enhanced MHV68 reactivation; the ex vivo stimulation of latently infected primary splenocytes, recovered from infected mice, with poly(I:C), lipopolysaccharide, flagellin, or CpG DNA led to early B-cell activation, B-cell proliferation, and a significant increase in the frequency of latently infected cells reactivating the virus. In vivo TLR stimulation also induced B-cell activation and MHV68 reactivation, resulting in heightened levels of virus replication in the lungs which correlated with an increase in MHV68-specific CD8+ T-cell responses. Importantly, TLR stimulation also led to an increase in MHV68 latency, as evidenced by an increase in viral genome-positive cells 2 weeks post-in vivo stimulation by specific TLR ligands. Thus, these data demonstrate that TLR stimulation can drive MHV68 reactivation from latency and suggests that periodic pathogen exposure may contribute to the homeostatic maintenance of chronic gammaherpesvirus infection through stimulating virus reactivation and reseeding latency reservoirs.

scholarly journals Murine gammaherpesvirus 68 bcl-2 homologue contributes to latency establishment in vivo

2005 ◽  
Vol 86 (1) ◽  
pp. 31-40 ◽  
Author(s):  
Brigitte D. de Lima ◽  
Janet S. May ◽  
Sofia Marques ◽  
J. Pedro Simas ◽  
Philip G. Stevenson
Keyword(s):  
Cell Activation ◽  
Ex Vivo ◽  
Lytic Replication ◽  
B Cell Activation ◽  
Murine Gammaherpesvirus ◽  
Gammaherpesvirus 68 ◽  
Murine Gammaherpesvirus 68

The gammaherpesviruses are characteristically latent in lymphocytes and exploit lymphocyte proliferation to establish a large, persistent pool of latent genomes. Murine gammaherpesvirus 68 (MHV-68) allows the in vivo analysis of viral genes that contribute to this and other aspects of host colonization. In this study, the MHV-68 bcl-2 homologue, M11, was disrupted either in its BH1 homology domain or upstream of its membrane-localizing C-terminal domain. Each M11 mutant showed normal lytic replication in vitro and in vivo, but had a reduction in peak splenic latency. Lower infectious-centre titres correlated with lower in vivo B-cell activation, lower viral genome loads and reduced viral tRNA expression. This was therefore a true latency deficit, rather than a deficit in ex vivo reactivation. Stable, long-term levels of splenic latency were normal. M11 function therefore contributed specifically to viral latency amplification in infected lymphoid tissue.

scholarly journals Non-Antigen-Specific B-Cell Activation following Murine Gammaherpesvirus Infection Is CD4 Independent In Vitro but CD4 Dependent In Vivo

1999 ◽  
Vol 73 (2) ◽  
pp. 1075-1079 ◽  
Author(s):  
Philip G. Stevenson ◽  
Peter C. Doherty
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Total Serum ◽  
B Cell Activation ◽  
Murine Gammaherpesvirus ◽  
Vitro Effect

ABSTRACT The murine gammaherpesvirus MHV-68 multiplies in the respiratory epithelium after intranasal inoculation, then spreads to infect B cells in lymphoid germinal centers. Exposing B cells to MHV-68 in vitro caused an increase in cell size, up-regulation of the CD69 activation marker, and immunoglobulin M (IgM) production. The infectious process in vivo was also associated with increased CD69 expression on B cells in the draining lymph nodes and spleen, together with a rise in total serum Ig. However, whereas the in vitro effect on B cells was entirely T-cell independent, evidence of in vivo B-cell activation was minimal in CD4+ T-cell-deficient (I-Ab−/−) or CD4+ T-cell-depleted mice. Furthermore, the Ig present at high levels in serum was predominantly of the IgG class. Surprisingly, the titer of influenza virus-specific serum IgG in previously immunized mice fell following MHV-68 infection, suggesting that there was relatively little activation of memory B cells. Thus, CD4+T cells seemed both to amplify a direct viral activation of B cells in lymphoid tissue and to promote new Ig class switching despite a lack of obvious cognate antigen.

scholarly journals Protective Role of Cytotoxic T Lymphocytes in Filovirus Hemorrhagic Fever

2011 ◽  
Vol 2011 ◽  
pp. 1-13 ◽  
Author(s):  
Kelly Lyn Warfield ◽  
Gene Garrard Olinger
Keyword(s):  
Animal Models ◽  
Ebola Virus ◽  
Cytotoxic T Lymphocyte ◽  
Low Frequency ◽  
Neutralizing Antibody ◽  
Hemorrhagic Fever ◽  
Protective Role ◽  
Emerging Viruses ◽  
Lethal Challenge ◽  
Ctl Responses

Infection with many emerging viruses, such as the hemorrhagic fever disease caused by the filoviruses, Marburg (MARV), and Ebola virus (EBOV), leaves the host with a short timeframe in which to mouse a protective immune response. In lethal cases, uncontrolled viral replication and virus-induced immune dysregulation are too severe to overcome, and mortality is generally associated with a lack of notable immune responses. Vaccination studies in animals have demonstrated an association of IgG and neutralizing antibody responses against the protective glycoprotein antigen with survival from lethal challenge. More recently, studies in animal models of filovirus hemorrhagic fever have established that induction of a strong filovirus-specific cytotoxic T lymphocyte (CTL) response can facilitate complete viral clearance. In this review, we describe assays used to discover CTL responses after vaccination or live filovirus infection in both animal models and human clinical trials. Unfortunately, little data regarding CTL responses have been collected from infected human survivors, primarily due to the low frequency of disease and the inability to perform these studies in the field. Advancements in assays and technologies may allow these studies to occur during future outbreaks.

Antigen stored in dendritic cells after macropinocytosis is released unprocessed from late endosomes to target B cells

Blood ◽  
2012 ◽  
Vol 119 (1) ◽  
pp. 95-105 ◽  
Author(s):  
Delphine Le Roux ◽  
Agnès Le Bon ◽  
Audrey Dumas ◽  
Kahina Taleb ◽  
Martin Sachse ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
B Cells ◽  
Lymph Nodes ◽  
B Lymphocytes ◽  
Cell Activation ◽  
B Cell Activation ◽  
Extracellular Medium ◽  
Native Form ◽  
Active Processes ◽  
Endocytic Compartments

Abstract B lymphocytes can be triggered in lymph nodes by nonopsonized antigens (Ag), potentially in their native form. However, the mechanisms that promote encounter of B lymphocytes with unprocessed antigens in lymph nodes are still elusive. We show here that antigens are detected in B cells in the draining lymph nodes of mice injected with live, but not fixed, dendritic cells (DCs) loaded with antigens. This highlights active processes in DCs to promote Ag transfer to B lymphocytes. In addition, antigen-loaded DCs found in the draining lymph node were CD103+. Using 3 different model Ag, we then show that immature DCs efficiently take up Ag by macropinocytosis and store the internalized material in late endocytic compartments. We find that DCs have a unique ability to release antigens from these compartments in the extracellular medium, which is controlled by Rab27. B cells take up the regurgitated Ag and the chemokine CXCL13, essential to attract B cells in lymph nodes, enhances this transfer. Our results reveal a unique property of DCs to regurgitate unprocessed Ag that could play an important role in B-cell activation.

scholarly journals Expansion of SARS-CoV-2-specific Antibody-secreting Cells and Generation of Neutralizing Antibodies in Hospitalized COVID-19 Patients

2020 ◽  
Author(s):  
Renata Varnaitė ◽  
Marina García ◽  
Hedvig Glans ◽  
Kimia T. Maleki ◽  
John Tyler Sandberg ◽  
...  
Keyword(s):  
B Cell ◽  
Specific Antibody ◽  
Neutralizing Antibodies ◽  
Cell Activation ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
B Cell Activation ◽  
Immunological Parameters ◽  
Antibody Secreting Cell ◽  
Antibody Levels

AbstractCoronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in late 2019 and has since become a global pandemic. Pathogen-specific antibodies are typically a major predictor of protective immunity, yet B cell and antibody responses during COVID-19 are not fully understood. Here, we analyzed antibody-secreting cell (ASC) and antibody responses in twenty hospitalized COVID-19 patients. The patients exhibited typical symptoms of COVID-19, and presented with reduced lymphocyte numbers and increased T cell and B cell activation. Importantly, we detected an expansion of SARS-CoV-2 nucleocapsid protein-specific ASCs in all twenty COVID-19 patients using a multicolor FluoroSpot assay. Out of the 20 patients, 16 had developed SARS-CoV-2-neutralizing antibodies by the time of inclusion in the study. SARS-CoV-2-specific IgA, IgG and IgM antibody levels positively correlated with SARS-CoV-2-neutralizing antibody titers, suggesting that SARS-CoV-2-specific antibody levels may reflect the titers of neutralizing antibodies in COVID-19 patients during the acute phase of infection. Lastly, we showed that interleukin 6 (IL-6) and C-reactive protein (CRP) concentrations were higher in serum of patients who were hospitalized for longer, supporting the recent observations that IL-6 and CRP could be used to predict COVID-19 severity. Altogether, this study constitutes a detailed description of clinical and immunological parameters in twenty COVID-19 patients, with a focus on B cell and antibody responses, and provides tools to study immune responses to SARS-CoV-2 infection and vaccination.

scholarly journals Pathogenesis of a Model Gammaherpesvirus in a Natural Host

2010 ◽  
Vol 84 (8) ◽  
pp. 3949-3961 ◽  
Author(s):  
David J. Hughes ◽  
Anja Kipar ◽  
Jeffery T. Sample ◽  
James P. Stewart
Keyword(s):  
Neutralizing Antibody ◽  
Natural Host ◽  
Alveolar Epithelial Cells ◽  
Wood Mice ◽  
Murine Gammaherpesvirus ◽  
Alveolar Epithelial ◽  
Latently Infected ◽  
In The Wild ◽  
Gammaherpesvirus 68 ◽  
Murine Gammaherpesvirus 68

ABSTRACT Murine gammaherpesvirus 68 (MHV-68) infection of laboratory mice (Mus musculus) is an established model of gammaherpesvirus pathogenesis. The fact that M. musculus is not a host in the wild prompted us to reassess MHV-68 infection in wood mice (Apodemus sylvaticus), a natural host. Here, we report significant differences in MHV-68 infection in the two species: (i) following intranasal inoculation, MHV-68 replicated in the lungs of wood mice to levels approximately 3 log units lower than in BALB/c mice; (ii) in BALB/c mice, virus replication in alveolar epithelial cells was accompanied by a diffuse, T-cell-dominated interstitial pneumonitis, whereas in wood mice it was restricted to focal granulomatous infiltrations; (iii) within wood mice, latently infected lymphocytes were abundant in inducible bronchus-associated lymphoid tissue that was not apparent in BALB/c mice; (iv) splenic latency was established in both species, but well-delineated secondary follicles with germinal centers were present in wood mice, while only poorly delineated follicles were seen in BALB/c mice; and, perhaps as a consequence, (v) production of neutralizing antibody was significantly higher in wood mice. These differences highlight the value of this animal model in the study of MHV-68 pathogenesis.

scholarly journals B cells discriminate HIV-1 Envelope protein affinities by sensing antigen binding association rates

2022 ◽  
Author(s):  
Md. Alamgir Hossain ◽  
Kara Anasti ◽  
Brian Watts ◽  
Kenneth Cronin ◽  
Advaiti Pai Kane ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Neutralizing Antibody ◽  
Antigen Binding ◽  
B Cell Activation ◽  
Kinetic Rates ◽  
Env Protein ◽  
Hiv 1

HIV-1 Envelope (Env) proteins designed to induce neutralizing antibody responses allow study of the role of affinities (equilibrium dissociation constant, KD) and kinetic rates (association/dissociation rates) on B cell antigen recognition. It is unclear whether affinity discrimination during B cell activation is based solely on Env protein binding KD, and whether B cells discriminate between proteins of similar affinities but that bind with different kinetic rates. Here we used a panel of Env proteins and Ramos B cell lines expressing IgM BCRs with specificity for CD4 binding-site broadly neutralizing (bnAb) or a precursor antibody to study the role of antigen binding kinetic rates on both early (proximal/distal signaling) and late events (BCR/antigen internalization) in B cell activation. Our results support a kinetic model for B cell activation in which Env protein affinity discrimination is based not on overall KD, but on sensing of association rate and a threshold antigen-BCR half-life.

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