Liver Sinusoidal Endothelial Cells Are a Site of Murine Cytomegalovirus Latency and Reactivation

Seckert, Christof K.; Renzaho, Angélique; Tervo, Hanna-Mari; Krause, C.; Deegen, Petra; Kühnapfel, Birgit; Reddehase, Matthias J.; Grzimek, Natascha K. A.

doi:10.1128/jvi.00870-09

Cited by 96 publications

(115 citation statements)

References 108 publications

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“…In addition, EC have recently been identified as sites of virus latency (65), and at least liver EC are able to directly stimulate a cytotoxic T-cell response (36). Using MCMV-⌬M94 constructs for conditional gene expression, we noticed substantial differences in the abilities of EC and Hc to activate a CD8 ϩ T-cell response.…”

Section: Discussionmentioning

confidence: 93%

A Spread-Deficient Cytomegalovirus for Assessment of First-Target Cells in Vaccination

Mohr

Arapović

Mühlbach

et al. 2010

J Virol

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Human cytomegalovirus (HCMV) is a human pathogen that causes severe disease primarily in the immunocompromised or immunologically immature individual. To date, no vaccine is available. We describe use of a spread-deficient murine CMV (MCMV) as a novel approach for betaherpesvirus vaccination. To generate a spread-deficient MCMV, the conserved, essential gene M94 was deleted. Immunization with MCMV-⌬M94 is apathogenic and protective against wild-type challenge even in highly susceptible IFN␣␤R ؊/؊ mice. MCMV-⌬M94 was able to induce a robust CD4؉ and CD8 ؉ T-cell response as well as a neutralizing antibody response comparable to that induced by wild-type infection. Endothelial cells were identified as activators of CD8 ؉ T cells in vivo. Thus, the vaccination with a spread-deficient betaherpesvirus is a safe and protective strategy and allows the linkage between cell tropism and immunogenicity. Furthermore, genomes of MCMV-⌬M94 were present in lungs 12 months after infection, revealing first-target cells as sites of genome maintenance.

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Section: Discussionmentioning

confidence: 93%

A Spread-Deficient Cytomegalovirus for Assessment of First-Target Cells in Vaccination

Mohr

Arapović

Mühlbach

et al. 2010

J Virol

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“…It has been proposed that intermittent low-level antigen expression during latent MCMV infection induces inflationary CD8 T-cell responses (Seckert et al, 2012), and it has been reported recently that inflationary responses occur due to the proliferation of T-cells in contact with the blood circulation, rather than in organ parenchyma (Smith et al, 2014), probably because endothelial cells lining blood vessels are a major site of MCMV latency (Seckert et al, 2009). If this model is accurate, and considering that mice infected by the i.n.…”

Section: Discussionmentioning

confidence: 99%

Murine cytomegalovirus (CMV) infection via the intranasal route offers a robust model of immunity upon mucosal CMV infection

Oduro

Redeker

Lemmermann

et al. 2016

Journal of General Virology

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Cytomegalovirus (CMV) is a ubiquitous virus, causing the most common congenital infection in humans, yet a vaccine against this virus is not available. Experimental studies of immunity against CMV in animal models of infection, such as the infection of mice with mouse CMV (MCMV), have relied mainly on parenteral infection protocols, although the virus naturally transmits by mucosal routes via body fluids. To characterize the biology of infections by mucosal routes, we compared the kinetics of virus replication, latent viral load and CD8 T-cell responses in lymphoid organs upon experimental intranasal (targeting the respiratory tract) and intragastric (targeting the digestive tract) infection with systemic intraperitoneal infection of two unrelated mouse strains. We observed that intranasal infection induced robust and long-term virus replication in the lungs and salivary glands but limited replication in the spleen. CD8 T-cell responses were somewhat weaker than upon intraperitoneal infection but showed similar kinetic profiles and phenotypes of antigen-specific cells. In contrast, intragastric infection resulted in abortive or poor virus replication in all tested organs and poor T-cell responses to the virus, especially at late times after infection. Consistent with the T-cell kinetics, the MCMV latent load was high in the lungs but low in the spleen of intranasally infected mice and lowest in all tested organs upon intragastric infection. In conclusion, we showed that intranasal but not intragastric infection of mice with MCMV represents a robust model to study the short-and long-term biology of CMV infection by a mucosal route.

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“…MCMV latency in the mouse model of infection is clearly documented in LSEC (20), and IFN-␤ contains lytic MCMV gene expression in this cell type (21). In contrast, latent HCMV has been described in precursor cells of the myeloid lineage (14), and their ex vivo differentiation into mature mDC results in chromatin remodeling and initiation of lytic gene expression (55).…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, the establishment of latency appears to be restricted to certain cell types. Latent HCMV was found in blood monocytes and in progenitor cells of the myeloid lineage (14)(15)(16)(17)(18)(19), whereas liver sinusoidal endothelial cells (LSEC) were shown to be a site of MCMV latency and reactivation (20,21), although myeloid cells might also present a latent reservoir in the mouse (22,23).…”

mentioning

confidence: 99%

Type I Interferon Released by Myeloid Dendritic Cells Reversibly Impairs Cytomegalovirus Replication by Inhibiting Immediate Early Gene Expression

Holzki

Dağ

Dekhtiarenko

et al. 2015

J Virol

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Cytomegalovirus (CMV) is a ubiquitous beta-herpesvirus whose reactivation from latency is a major cause of morbidity and mortality in immunocompromised hosts. Mouse CMV (MCMV) is a well-established model virus to study virus-host interactions. We showed in this study that the CD8-independent antiviral function of myeloid dendritic cells (mDC) is biologically relevant for the inhibition of MCMV replication in vivo and in vitro. In vivo ablation of CD11c ؉ DC resulted in higher viral titers and increased susceptibility to MCMV infection in the first 3 days postinfection. We developed in vitro coculture systems in which we cocultivated MCMV-infected endothelial cells or fibroblasts with T cell subsets and/or dendritic cells. H uman cytomegalovirus (HCMV) is a betaherpesvirus which establishes a lifelong latent infection in immunocompetenthosts. Latent HCMV is present in the majority of people worldwide, but the primary infection is usually asymptomatic. The primary infection is well contained by the immune cells, such as natural killer (NK) cells and T cells, which also prevent viral reactivation from latency (1, 2).Their activation depends on cross talk with dendritic cells (DC) (3, 4), and this interaction plays an important role in CMV control (5-7). The direct effect of DC on viral replication remains, however, unclear.In immunocompromised hosts, like AIDS patients or people undergoing transplantation, the virus cannot be contained, and its reactivation from latency has been associated with severe disease (8). Therefore, to develop new therapeutic approaches against CMV disease, it is exceedingly important to understand the immune mechanisms that drive the virus into latency.Murine cytomegalovirus (MCMV) is a natural pathogen of the mouse. It shows numerous analogies in latency and reactivation to the human virus, and its genome displays substantial similarity to the HCMV one (9). Therefore, MCMV is a widely used model for CMV infection and immunity (10)(11)(12).During primary infection, MCMV infects various different cell types, such as macrophages and DC but also nonhematopoietic cells, including endothelial and epithelial cells (13). On the other hand, the establishment of latency appears to be restricted to certain cell types. Latent HCMV was found in blood monocytes and in progenitor cells of the myeloid lineage (14-19), whereas liver sinusoidal endothelial cells (LSEC) were shown to be a site of MCMV latency and reactivation (20, 21), although myeloid cells might also present a latent reservoir in the mouse (22, 23).

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Liver Sinusoidal Endothelial Cells Are a Site of Murine Cytomegalovirus Latency and Reactivation

Cited by 96 publications

References 108 publications

A Spread-Deficient Cytomegalovirus for Assessment of First-Target Cells in Vaccination

A Spread-Deficient Cytomegalovirus for Assessment of First-Target Cells in Vaccination

Murine cytomegalovirus (CMV) infection via the intranasal route offers a robust model of immunity upon mucosal CMV infection

Type I Interferon Released by Myeloid Dendritic Cells Reversibly Impairs Cytomegalovirus Replication by Inhibiting Immediate Early Gene Expression

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