Viral targeting of hematopoietic progenitors and inhibition of DC maturation as a dual strategy for immune subversion

Sevilla, Noemı́; McGavern, Dorian B.; Teng, Chao; Kunz, Stefan; Oldstone, Michael B. A.

doi:10.1172/jci20243

Cited by 152 publications

(156 citation statements)

References 69 publications

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“…Further studies in adult mice demonstrated that enhanced viral infiltration into the white pulp of the spleen was associated with increased binding to α-DG (152) and that clone 13 also more effectively targeted fibroblastic reticular cells resulting in decreased conduit function of the spleen (160). The disruption in splenic function (158,160), physical destruction of dendritic cells (161), and inhibition of dendritic cell differentiation and maturation (162,163) are likely contributors to the immunosuppression observed during clone 13 infection. More recently, it has also been revealed that inhibitory molecule such as PD-1 (164) and IL-10 (165) are upregulated early following clone 13 infection and also contribute to the immunosuppressive milieu.…”

Section: Lcmv Clone 13 and Chronic Infectionmentioning

confidence: 99%

Lymphocytic choriomeningitis infection of the central nervous system

Kang

McGavern

2008

Front Biosci

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Viral infection of the central nervous system (CNS) can result in a multitude of responses including pathology, persistence or immune clearance. Lymphocytic choriomeningitis virus (LCMV) is a powerful model system to explore these potential outcomes of CNS infection due to the diversity of responses that can be achieved after viral inoculation. Several factors including tropism, timing, dose and variant of LCMV in combination with the development or suppression of the corresponding immune response dictates whether lethal meningitis, chronic infection or clearance of LCMV in the CNS will occur. Importantly, the functionality and positioning of the LCMV-specific CD8 + T cell response are critical in directing the subsequent outcome of CNS LCMV infection. Although a basic understanding of LCMV and immune interactions in the brain exists, the molecular machinery that shapes the balance between pathogenesis and clearance in the LCMV-infected CNS remains to be elucidated. This review covers the various outcomes of LCMV infection in the CNS and what is currently known about the impact of the virus itself versus the immune response in the development of disease or clearance. KeywordsLCMV; Clone 13; Virus; Meningitis; Immunotherapy; Brain; Neurons; Astrocytes; Immunodeficient; Neonates; Growth Hormone; T cell; behavior; Review INTRODUCTIONThe parameters that dictate pathology versus clearance after CNS viral infection are relatively undefined. The CNS contains highly integrated populations of neurons and glial cells responsible for our livelihood, and immune infiltration has the potential to severely disrupt the function of this sensitive compartment. Consequently, through evolutionary pressures the CNS has become immunologically specialized and now possesses the ability to HHS Public AccessAuthor manuscript Front Biosci. Author manuscript; available in PMC 2017 January 30.Published in final edited form as:Front Biosci. ; 13: 4529-4543. Author Manuscript Author ManuscriptAuthor Manuscript Author Manuscript modulate (or suppress) leukocyte behavior in a manner that fundamentally differs from that observed in most peripheral tissues. This evolutionary acquisition, which is advantageous from the standpoint of host survival, likely facilitates the entry and replication of viruses within the CNS. A multitude of viruses have the capacity to gain access to the CNS and upon doing so can establish a chronic infection, drive immunopathology, or alter the function of residents cells, making clearance of the invading pathogen essential. Therefore, a fundamental knowledge of viral-immune interactions in the CNS is essential if we ultimately intend to therapeutically modulate CNS immune responses in humans to achieve viral clearance in the absence of immunopathology. LCMV infection of mice provides an outstanding model system to explore such interactions and extend the lessons learned to virus infections of humans. GENERAL BACKGROUND ON LCMVLCMV is a natural pathogen of both human and murine populations (1). Human transmissio...

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Section: Lcmv Clone 13 and Chronic Infectionmentioning

confidence: 99%

Lymphocytic choriomeningitis infection of the central nervous system

Kang

McGavern

2008

Front Biosci

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“…In favour of this, blockade of IL-10 may cause strain dependent reversal of chronic to resolved infection (Richter et al, 2013). Th e virus prevents infected progenitor cells from maturing into DCs and migrating to the spleen thereby preventing the host from producing new DCs (Sevilla et al, 2004) (Fig. 6).…”

Section: Immune Response Controlmentioning

confidence: 99%

Lymphocytic choriomeningitis virus: ways to establish and maintain non-cytolytic persistent infection

Labudová¹,

Pastorek²,

Pastoreková³

2016

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Summary. -Lymphocytic choriomeningitis virus (LCMV) is a prototype virus of the Arenaviridae family that is attracting considerable attention both as an important experimental model system to study acute and persistent viral infections, and as a neglected human pathogen of clinical signifi cance. Notably, LCMV is capable of persisting in an infected host, and escaping the immune system. Here we describe the strategies used by the virus to establish and maintain long-term infection in vitro and/or persistent infection in vivo. We discuss how the viral components (RNA, nucleoprotein, glycoprotein, Z protein) manipulate the host cell machinery to facilitate survival and spread of the virus without disturbing the basal cellular processes. Deep understanding of these strategies is inevitable for the development of approaches towards restricting the virus spread and/or preventing its harmful reactivation. Th is review summarizes the current status in this area and presents ideas emerging from existing data.Keywords: lymphocytic choriomeningitis virus; arenaviruses; persistent infection E-mail: virulama@savba.sk; phone: +421-2-59302439. Abbreviations: ATF6 = activating transcription factor 6; DC = dendritic cells; DG = dystroglycan; ECM = extracellular matrix; eIF-4E/G = eukaryotic translation initiation factor 4E or 4G; eIF-4G = eukaryotic translation initiation factor 4G; GAPDH = glyceraldehyd-3-phosphate dehydrogenase; GP1,2 = glycoprotein 1, 2; GPC = glycoprotein precursor; IRE1 = inositol-requiring protein 1; IRF-3 = IFN regulatory factor 3; PERK = PKR-like ER kinase; PML = promyelocytic leukemia; UPR = unfolded protein response; ZP = Z protein

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“…Therefore, the enhanced infection of DCs, followed by reduced T cell stimulatory capacity, is probably one of the mechanisms by which chronic pathogens initiate immunosuppression within the host (79,80). More interestingly, independent of preferential DC infection by chronic pathogens, it has been reported that the functional impairment of DCs is associated with the exhaustion of T cell function and progression of disease during HIV, HBV, HCV, and LCMV infections (81)(82)(83)(84)(85)(86). However, the molecular mechanisms underlying impaired T cell function mediated by DCs during chronic pathogen infection have to be fully elucidated.…”

Section: Extrinsic Factors Regulating T Cell Immunity In a Chronic Anmentioning

confidence: 99%