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Search Results: 1 - 10 of 89265 matches for " Herbert W Virgin IV ? "
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MDA-5 Recognition of a Murine Norovirus
Stephen A. McCartney,Larissa B. Thackray,Leonid Gitlin,Susan Gilfillan,Herbert W. Virgin IV,Marco Colonna
PLOS Pathogens , 2008, DOI: 10.1371/journal.ppat.1000108
Abstract: Noroviruses are important human pathogens responsible for most cases of viral epidemic gastroenteritis worldwide. Murine norovirus-1 (MNV-1) is one of several murine noroviruses isolated from research mouse facilities and has been used as a model of human norovirus infection. MNV-1 infection has been shown to require components of innate and adaptive immunity for clearance; however, the initial host protein that recognizes MNV-1 infection is unknown. Because noroviruses are RNA viruses, we investigated whether MDA5 and TLR3, cellular sensors that recognize dsRNA, are important for the host response to MNV-1. We demonstrate that MDA5?/? dendritic cells(DC) have a defect in cytokine response to MNV-1. In addition, MNV-1 replicates to higher levels in MDA5?/? DCs as well as in MDA5?/? mice in vivo. Interestingly, TLR3?/? DCs do not have a defect in vitro, but TLR3?/? mice have a slight increase in viral titers. This is the first demonstration of an innate immune sensor for norovirus and shows that MDA5 is required for the control of MNV-1 infection. Knowledge of the host response to MNV-1 may provide keys for prevention and treatment of the human disease.
Antibody-Independent Control of γ-Herpesvirus Latency via B Cell Induction of Anti-Viral T Cell Responses
Kelly B McClellan,Shivaprakash Gangappa,Samuel H Speck,Herbert W. Virgin IV
PLOS Pathogens , 2006, DOI: 10.1371/journal.ppat.0020058
Abstract: B cells can use antibody-dependent mechanisms to control latent viral infections. It is unknown whether this represents the sole function of B cells during chronic viral infection. We report here that hen egg lysozyme (HEL)-specific B cells can contribute to the control of murine γ-herpesvirus 68 (γHV68) latency without producing anti-viral antibody. HEL-specific B cells normalized defects in T cell numbers and proliferation observed in B cell?/? mice during the early phase of γHV68 latency. HEL-specific B cells also reversed defects in CD8 and CD4 T cell cytokine production observed in B cell?/? mice, generating CD8 and CD4 T cells necessary for control of latency. Furthermore, HEL-specific B cells were able to present virally encoded antigen to CD8 T cells. Therefore, B cells have antibody independent functions, including antigen presentation, that are important for control of γ-herpesvirus latency. Exploitation of this property of B cells may allow enhanced vaccine responses to chronic virus infection.
Guanylate-binding Protein 1 (Gbp1) Contributes to Cell-autonomous Immunity against Toxoplasma gondii
Elizabeth M. Selleck,Sarah J. Fentress,Wandy L. Beatty,Daniel Degrandi,Klaus Pfeffer,Herbert W. Virgin IV,John D. MacMicking,L. David Sibley
PLOS Pathogens , 2013, DOI: 10.1371/journal.ppat.1003320
Abstract: IFN-γ activates cells to restrict intracellular pathogens by upregulating cellular effectors including the p65 family of guanylate-binding proteins (GBPs). Here we test the role of Gbp1 in the IFN-γ-dependent control of T. gondii in the mouse model. Virulent strains of T. gondii avoided recruitment of Gbp1 to the parasitophorous vacuole in a strain-dependent manner that was mediated by the parasite virulence factors ROP18, an active serine/threonine kinase, and the pseudokinase ROP5. Increased recruitment of Gbp1 to Δrop18 or Δrop5 parasites was associated with clearance in IFN-γ-activated macrophages in vitro, a process dependent on the autophagy protein Atg5. The increased susceptibility of Δrop18 mutants in IFN-γ-activated macrophages was reverted in Gbp1?/? cells, and decreased virulence of this mutant was compensated in Gbp1?/? mice, which were also more susceptible to challenge with type II strain parasites of intermediate virulence. These findings demonstrate that Gbp1 plays an important role in the IFN-γ-dependent, cell-autonomous control of toxoplasmosis and predict a broader role for this protein in host defense.
Replication of Norovirus in Cell Culture Reveals a Tropism for Dendritic Cells and Macrophages
Christiane E. Wobus,Stephanie M. Karst,Larissa B. Thackray,Kyeong-Ok Chang,Stanislav V. Sosnovtsev,Ga?l Belliot,Anne Krug,Jason M. Mackenzie,Kim Y. Green,Herbert W. Virgin IV
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.0020432
Abstract: Noroviruses are understudied because these important enteric pathogens have not been cultured to date. We found that the norovirus murine norovirus 1 (MNV-1) infects macrophage-like cells in vivo and replicates in cultured primary dendritic cells and macrophages. MNV-1 growth was inhibited by the interferon-αβ receptor and STAT-1, and was associated with extensive rearrangements of intracellular membranes. An amino acid substitution in the capsid protein of serially passaged MNV-1 was associated with virulence attenuation in vivo. This is the first report of replication of a norovirus in cell culture. The capacity of MNV-1 to replicate in a STAT-1-regulated fashion and the unexpected tropism of a norovirus for cells of the hematopoietic lineage provide important insights into norovirus biology.
Effective Control of Chronic γ-Herpesvirus Infection by Unconventional MHC Class Ia–Independent CD8 T Cells
Douglas C Braaten equal contributor,James Scott McClellan equal contributor,Ilhem Messaoudi equal contributor,Scott A Tibbetts,Kelly B McClellan,Janko Nikolich-Zugich equal contributor,Herbert W Virgin IV equal contributor
PLOS Pathogens , 2006, DOI: 10.1371/journal.ppat.0020037
Abstract: Control of virus infection is mediated in part by major histocompatibility complex (MHC) Class Ia presentation of viral peptides to conventional CD8 T cells. Although important, the absolute requirement for MHC Class Ia–dependent CD8 T cells for control of chronic virus infection has not been formally demonstrated. We show here that mice lacking MHC Class Ia molecules (Kb?/?xDb?/? mice) effectively control chronic γ-herpesvirus 68 (γHV68) infection via a robust expansion of β2-microglobulin (β2-m)-dependent, but CD1d-independent, unconventional CD8 T cells. These unconventional CD8 T cells expressed: (1) CD8αβ and CD3, (2) cell surface molecules associated with conventional effector/memory CD8 T cells, (3) TCRαβ with a significant Vβ4, Vβ3, and Vβ10 bias, and (4) the key effector cytokine interferon-γ (IFNγ). Unconventional CD8 T cells utilized a diverse TCR repertoire, and CDR3 analysis suggests that some of that repertoire may be utilized even in the presence of conventional CD8 T cells. This is the first demonstration to our knowledge that β2-m–dependent, but Class Ia–independent, unconventional CD8 T cells can efficiently control chronic virus infection, implicating a role for β2-n–dependent non-classical MHC molecules in control of chronic viral infection. We speculate that similar unconventional CD8 T cells may be able to control of other chronic viral infections, especially when viruses evade immunity by inhibiting generation of Class Ia–restricted T cells.
A Surface Groove Essential for Viral Bcl-2 Function During Chronic Infection In Vivo
Joy Loh equal contributor,Qiulong Huang equal contributor,Andrew M Petros,David Nettesheim,Linda F. van Dyk,Lucia Labrada,Samuel H Speck,Beth Levine,Edward T Olejniczak ?,Herbert W Virgin IV
PLOS Pathogens , 2005, DOI: 10.1371/journal.ppat.0010010
Abstract: Antiapoptotic Bcl-2 family proteins inhibit apoptosis in cultured cells by binding BH3 domains of proapoptotic Bcl-2 family members via a hydrophobic BH3 binding groove on the protein surface. We investigated the physiological importance of the BH3 binding groove of an antiapoptotic Bcl-2 protein in mammals in vivo by analyzing a viral Bcl-2 family protein. We show that the γ-herpesvirus 68 (γHV68) Bcl-2 family protein (γHV68 v-Bcl-2), which is known to inhibit apoptosis in cultured cells, inhibits both apoptosis in primary lymphocytes and Bax toxicity in yeast. Nuclear magnetic resonance determination of the γHV68 v-Bcl-2 structure revealed a BH3 binding groove that binds BH3 domain peptides from proapoptotic Bcl-2 family members Bax and Bak via a molecular mechanism shared with host Bcl-2 family proteins, involving a conserved arginine in the BH3 peptide binding groove. Mutations of this conserved arginine and two adjacent amino acids to alanine (SGR to AAA) within the BH3 binding groove resulted in a properly folded protein that lacked the capacity of the wild-type γHV68 v-Bcl-2 to bind Bax BH3 peptide and to block Bax toxicity in yeast. We tested the physiological importance of this v-Bcl-2 domain during viral infection by engineering viral mutants encoding a v-Bcl-2 containing the SGR to AAA mutation. This mutation resulted in a virus defective for both efficient reactivation of γHV68 from latency and efficient persistent γHV68 replication. These studies demonstrate an essential functional role for amino acids in the BH3 peptide binding groove of a viral Bcl-2 family member during chronic infection.
Replication of Norovirus in Cell Culture Reveals a Tropism for Dendritic Cells and Macrophages
Christiane E Wobus,Stephanie M Karst,Larissa B Thackray,Kyeong-Ok Chang,Stanislav V Sosnovtsev,Ga?l Belliot,Anne Krug,Jason M Mackenzie,Kim Y Green,Herbert W. Virgin IV
PLOS Biology , 2004, DOI: 10.1371/journal.pbio.0020432
Abstract: Noroviruses are understudied because these important enteric pathogens have not been cultured to date. We found that the norovirus murine norovirus 1 (MNV-1) infects macrophage-like cells in vivo and replicates in cultured primary dendritic cells and macrophages. MNV-1 growth was inhibited by the interferon-αβ receptor and STAT-1, and was associated with extensive rearrangements of intracellular membranes. An amino acid substitution in the capsid protein of serially passaged MNV-1 was associated with virulence attenuation in vivo. This is the first report of replication of a norovirus in cell culture. The capacity of MNV-1 to replicate in a STAT-1-regulated fashion and the unexpected tropism of a norovirus for cells of the hematopoietic lineage provide important insights into norovirus biology.
Immune Mechanisms Responsible for Vaccination against and Clearance of Mucosal and Lymphatic Norovirus Infection
Karen A. Chachu,Anna D. LoBue,David W. Strong,Ralph S. Baric,Herbert W. Virgin
PLOS Pathogens , 2008, DOI: 10.1371/journal.ppat.1000236
Abstract: Two cardinal manifestations of viral immunity are efficient clearance of acute infection and the capacity to vaccinate against secondary viral exposure. For noroviruses, the contributions of T cells to viral clearance and vaccination have not been elucidated. We report here that both CD4 and CD8 T cells are required for efficient clearance of primary murine norovirus (MNV) infection from the intestine and intestinal lymph nodes. Further, long-lasting protective immunity was generated by oral live virus vaccination. Systemic vaccination with the MNV capsid protein also effectively protected against mucosal challenge, while vaccination with the capsid protein of the distantly related human Lordsdale virus provided partial protection. Fully effective vaccination required a broad immune response including CD4 T cells, CD8 T cells, and B cells, but the importance of specific immune cell types varied between the intestine and intestinal lymph nodes. Perforin, but not interferon gamma, was required for clearance of MNV infection by adoptively transferred T lymphocytes from vaccinated hosts. These studies prove the feasibility of both mucosal and systemic vaccination against mucosal norovirus infection, demonstrate tissue specificity of norovirus immune cells, and indicate that efficient vaccination strategies should induce potent CD4 and CD8 T cell responses.
Listeriolysin O Is Necessary and Sufficient to Induce Autophagy during Listeria monocytogenes Infection
Nicole Meyer-Morse,Jennifer R. Robbins,Chris S. Rae,Sofia N. Mochegova,Michele S. Swanson,Zijiang Zhao,Herbert W. Virgin,Daniel Portnoy
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0008610
Abstract: Recent studies have suggested that autophagy is utilized by cells as a protective mechanism against Listeria monocytogenes infection.
Interferon-Induced Ifit2/ISG54 Protects Mice from Lethal VSV Neuropathogenesis
Volker Fensterl,Jaime L. Wetzel,Srividya Ramachandran,Tomoaki Ogino,Stephen A. Stohlman,Cornelia C. Bergmann,Michael S. Diamond,Herbert W. Virgin,Ganes C. Sen
PLOS Pathogens , 2012, DOI: 10.1371/journal.ppat.1002712
Abstract: Interferon protects mice from vesicular stomatitis virus (VSV) infection and pathogenesis; however, it is not known which of the numerous interferon-stimulated genes (ISG) mediate the antiviral effect. A prominent family of ISGs is the interferon-induced with tetratricopeptide repeats (Ifit) genes comprising three members in mice, Ifit1/ISG56, Ifit2/ISG54 and Ifit3/ISG49. Intranasal infection with a low dose of VSV is not lethal to wild-type mice and all three Ifit genes are induced in the central nervous system of the infected mice. We tested their potential contributions to the observed protection of wild-type mice from VSV pathogenesis, by taking advantage of the newly generated knockout mice lacking either Ifit2 or Ifit1. We observed that in Ifit2 knockout (Ifit2?/?) mice, intranasal VSV infection was uniformly lethal and death was preceded by neurological signs, such as ataxia and hind limb paralysis. In contrast, wild-type and Ifit1?/? mice were highly protected and survived without developing such disease. However, when VSV was injected intracranially, virus replication and survival were not significantly different between wild-type and Ifit2?/? mice. When administered intranasally, VSV entered the central nervous system through the olfactory bulbs, where it replicated equivalently in wild-type and Ifit2?/? mice and induced interferon-β. However, as the infection spread to other regions of the brain, VSV titers rose several hundred folds higher in Ifit2?/? mice as compared to wild-type mice. This was not caused by a broadened cell tropism in the brains of Ifit2?/? mice, where VSV still replicated selectively in neurons. Surprisingly, this advantage for VSV replication in the brains of Ifit2?/? mice was not observed in other organs, such as lung and liver. Pathogenesis by another neurotropic RNA virus, encephalomyocarditis virus, was not enhanced in the brains of Ifit2?/? mice. Our study provides a clear demonstration of tissue-, virus- and ISG-specific antiviral action of interferon.
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