Biphasic viremia and viral gene expression in leukocytes during acute cytomegalovirus infection of mice

Collins, Timothy M.; Quirk, Mary; Jordan, M. Colin

doi:10.1128/jvi.68.10.6305-6311.1994

Cited by 70 publications

(34 citation statements)

References 33 publications

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“…However filtering macrophages also restrict the macrophage-tropic murine pathogens lymphocytic choriomeningitis virus [43] and murine coronavirus [44] via IFN-I. As IFN-I contributes to myeloid cell homeostasis [45], incomplete evasion may be a viral compromise necessary to exploit myeloid cells for dissemination and persistence [4].…”

Section: Discussionmentioning

confidence: 99%

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Type 1 Interferons and NK Cells Limit Murine Cytomegalovirus Escape from the Lymph Node Subcapsular Sinus

et al. 2016

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Cytomegaloviruses (CMVs) establish chronic, systemic infections. Peripheral infection spreads via lymph nodes, which are also a focus of host defence. Thus, this is a point at which systemic infection spread might be restricted. Subcapsular sinus macrophages (SSM) captured murine CMV (MCMV) from the afferent lymph and poorly supported its replication. Blocking the type I interferon (IFN-I) receptor (IFNAR) increased MCMV infection of SSM and of the fibroblastic reticular cells (FRC) lining the subcapsular sinus, and accelerated viral spread to the spleen. Little splenic virus derived from SSM, arguing that they mainly induce an anti-viral state in the otherwise susceptible FRC. NK cells also limited infection, killing infected FRC and causing tissue damage. They acted independently of IFN-I, as IFNAR blockade increased NK cell recruitment, and NK cell depletion increased infection in IFNAR-blocked mice. Thus SSM restricted MCMV infection primarily though IFN-I, with NK cells providing a second line of defence. The capacity of innate immunity to restrict MCMV escape from the subcapsular sinus suggested that enhancing its recruitment might improve infection control.

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Section: Discussionmentioning

confidence: 99%

“…MCMV has particular value for understanding how CMVs work in vivo, as its host provides the standard model of mammalian cell biology. MCMV exploits myeloid cells to spread [4,5], and live imaging shows peripheral to systemic spread via lymph nodes (LN) [6], so LN myeloid cells are likely to be a key target for limiting systemic infection.…”

Section: Introductionmentioning

confidence: 99%

Type 1 Interferons and NK Cells Limit Murine Cytomegalovirus Escape from the Lymph Node Subcapsular Sinus

et al. 2016

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“…The failure of RV7 to replicate in target organs of the infected mouse and its greatly reduced ability to grow in a differentiated macrophage cell line strongly suggest that the nonessential regions of MCMV HindIII-J and -I deleted in this mutant play important roles in pathogenesis in vivo. Interactions between CMV and macrophages are viewed as critical to viral pathogenesis (3,6,12,14,26,33,53,54,60,61). Peripheral blood monocytes function to disseminate virus during acute infection (12,53,60,61), and monocytes and macrophages are the most likely cell types harboring latent CMV (6,33,60,61).…”

Section: Discussionmentioning

confidence: 99%

“…During a natural MCMV infection, monocytes and macrophages play critical roles in viral pathogenesis, particularly in dissemination and latency (12,33,60). The state of macrophage differentiation clearly influences permissiveness for MCMV replication (6,36,46).…”

Section: In Vitro Growth Of MCMV Mutants In Ic-21 Macrophagesmentioning

confidence: 99%

Murine cytomegalovirus with a deletion of genes spanning HindIII-J and -I displays altered cell and tissue tropism

Cavanaugh

Stenberg

Staley

et al. 1996

J Virol

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Murine cytomegalovirus (MCMV) gene products dispensable for growth in cell culture are likely to have important functions within the infected host, influencing tissue tropism, dissemination, or immunological responses against the virus. To identify such genes, our strategy was to delete large regions of the MCMV genome likely to contain genes nonessential for virus replication in NIH 3T3 cells. Mutant virus RV7 contained a deletion of 7.7 kb spanning portions of MCMV HindIII-J and -I. This virus grew comparably to wild-type (WT) virus in NIH 3T3 fibroblasts, primary embryo fibroblasts, and bone marrow macrophages. However, RV7 failed to replicate in target organs of immunocompetent BALB/c mice and severe combined immunodeficient mice, which are exquisitely sensitive to MCMV infection. This defect in in vivo growth may be related to the observation that RV7 grew poorly in the peritoneal macrophage cell line IC-21, which is highly permissive for growth of WT MCMV. Two other mutant viruses with an insertion or smaller deletion in the region common to the RV7 deletion grew comparably to WT virus in the macrophage cell line and replicated in salivary gland tissue. The poor growth of RV7 in IC-21 cells was due to a block in immediate-early gene expression, as levels of RNA from immediate-early gene IE1 were reduced eightfold compared with levels for WT virus in macrophages infected with RV7. Consequently, levels of RNA from early and late genes were also reduced. The lower expression of IE1 in RV7-infected IC-21 macrophages was not due to defective entry of virus into the cells, as equal amounts of viral DNA were present in cells 3 h after infection with RV7 or WT MCMV. These studies demonstrate that deletion of sequences in HindIII-J and -I confer altered cell and tissue tropism.Cells. Murine NIH 3T3 fibroblasts (American Type Culture Collection [ATCC] CRL1658; ATCC, Rockville, Md.) were propagated in Dulbecco's modified essential medium (DMEM; Mediatech, Herndon, Va.) supplemented with 10% heat-inactivated bovine calf serum (HyClone Laboratories, Logan, Utah) and 1% L-glutamine (Gibco/BRL, Grand Island, N.Y.). IC-21 cells, a simian virus 40-transformed peritoneal macrophage cell line derived from C57BL/6 mice (41), were obtained from ATCC and were propagated in RPMI medium (Mediatech) supplemented with 10% heat-inactivated fetal calf serum (Gibco/BRL) and 1% L-glutamine. Primary fibroblasts, derived from the embryos of timedpregnant BALB/c.ByJ mice (Jackson Laboratory, Bar Harbor, Maine) on day 19 of gestation, were cultured in DMEM containing 20% heat-inactivated fetal calf serum, 1% L-glutamine, and 50 g of gentamicin sulfate (Sigma Chemical Co., St. Louis, Mo.) per ml.Virus. The parental WT MCMV used in this study was of the Smith strain (ATCC VR-194). Stocks of WT and mutant viruses were prepared in and titers were determined on NIH 3T3 cells as previously described (8). Mock preparations of virus consisted of culture supernatants from noninfected NIH 3T3 cells.Mice. BALB/c.ByJ mice, either 20-day-old weanlings (...

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“…Like UL128, M131-129 has homology to chemokines and thus may both recruit myeloid cells and promote their infection directly. In vivo, M131 Ϫ MCMV shows less monocyte recruitment and less salivary gland (SG) infection (15,16), consistent with MCMV spreading via myeloid cell recirculation (17,18). gO Ϫ MCMV propagates poorly in cultured fibroblasts (19).…”

mentioning

confidence: 73%

Murine Cytomegalovirus Glycoprotein O Promotes Epithelial Cell Infection In Vivo

Yunis

Farrell

Bruce

et al. 2019

J Virol

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Cytomegaloviruses (CMVs) establish systemic infections across diverse cell types. Glycoproteins that alter tropism can potentially guide their spread. Glycoprotein O (gO) is a nonessential fusion complex component of both human CMV (HCMV) and murine CMV (MCMV). We tested its contribution to MCMV spread from the respiratory tract. In vitro, MCMV lacking gO poorly infected fibroblasts and epithelial cells. Cell binding was intact, but penetration was delayed. In contrast, myeloid infection was preserved, and in the lungs, where myeloid and type 2 alveolar epithelial cells are the main viral targets, MCMV lacking gO showed a marked preference for myeloid infection. Its poor epithelial cell infection was associated with poor primary virus production and reduced virulence. Systemic spread, which proceeds via infected CD11c ϩ myeloid cells, was initially intact but then diminished, because less epithelial infection led ultimately to less myeloid infection. Thus, the tight linkage between peripheral and systemic MCMV infections gave gO-dependent infection a central role in host colonization. IMPORTANCE Human cytomegalovirus is a leading cause of congenital disease. This reflects its capacity for systemic spread. A vaccine is needed, but the best viral targets are unclear. Attention has focused on the virion membrane fusion complex. It has 2 forms, so we need to know what each contributes to host colonization. One includes the virion glycoprotein O. We used murine cytomegalovirus, which has equivalent fusion complexes, to determine the importance of glycoprotein O after mucosal infection. We show that it drives local virus replication in epithelial cells. It was not required to infect myeloid cells, which establish systemic infection, but poor local replication reduced systemic spread as a secondary effect. Therefore, targeting glycoprotein O of human cytomegalovirus has the potential to reduce both local and systemic infections.

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Biphasic viremia and viral gene expression in leukocytes during acute cytomegalovirus infection of mice

Cited by 70 publications

References 33 publications

Type 1 Interferons and NK Cells Limit Murine Cytomegalovirus Escape from the Lymph Node Subcapsular Sinus

Type 1 Interferons and NK Cells Limit Murine Cytomegalovirus Escape from the Lymph Node Subcapsular Sinus

Murine cytomegalovirus with a deletion of genes spanning HindIII-J and -I displays altered cell and tissue tropism

Murine Cytomegalovirus Glycoprotein O Promotes Epithelial Cell Infection In Vivo

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