scholarly journals Lymph Node Macrophages Restrict Murine Cytomegalovirus Dissemination

2015 ◽  
Vol 89 (14) ◽  
pp. 7147-7158 ◽  
Author(s):  
Helen E. Farrell ◽  
Nick Davis-Poynter ◽  
Kimberley Bruce ◽  
Clara Lawler ◽  
Lars Dolken ◽  
...  
Keyword(s):  
Lymph Nodes ◽  
Vascular Endothelial Cells ◽  
Virus Production ◽  
Systemic Infection ◽  
Lytic Replication ◽  
Murine Cytomegalovirus ◽  
Chronic Infections ◽  
Entry Site ◽  
Mcmv Infection ◽  
Human Cmv

ABSTRACTCytomegaloviruses (CMVs) establish chronic infections that spread from a primary entry site to secondary vascular sites, such as the spleen, and then to tertiary shedding sites, such as the salivary glands. Human CMV (HCMV) is difficult to analyze, because its spread precedes clinical presentation. Murine CMV (MCMV) offers a tractable model. It is hypothesized to spread from peripheral sites via vascular endothelial cells and associated monocytes. However, viral luciferase imaging showed footpad-inoculated MCMV first reaching the popliteal lymph nodes (PLN). PLN colonization was rapid and further spread was slow, implying that LN infection can be a significant bottleneck. Most acutely infected PLN cells were CD169+subcapsular sinus macrophages (SSM). Replication-deficient MCMV also reached them, indicating direct infection. Many SSM expressed viral reporter genes, but few expressed lytic genes. SSM expressed CD11c, and MCMV with a cre-sensitive fluorochrome switch showed switched infected cells in PLN of CD11c-cre mice but yielded little switched virus. SSM depletion with liposomal clodronate or via a CD169-diphtheria toxin receptor transgene shifted infection to ER-TR7+stromal cells, increased virus production, and accelerated its spread to the spleen. Therefore, MCMV disseminated via LN, and SSM slowed this spread by shielding permissive fibroblasts and poorly supporting viral lytic replication.IMPORTANCEHCMV chronically infects most people, and it can cause congenital disability and harm the immunocompromised. A major goal of vaccination is to prevent systemic infection. How this is established is unclear. Restriction to humans makes HCMV difficult to analyze. We show that peripheral MCMV infection spreads via lymph nodes. Here, MCMV infected filtering macrophages, which supported virus replication poorly. When these macrophages were depleted, MCMV infected susceptible fibroblasts and spread faster. The capacity of filtering macrophages to limit MCMV spread argued that their infection is an important bottleneck in host colonization and might be a good vaccine target.

scholarly journals Elimination of ie1 Significantly Attenuates Murine Cytomegalovirus Virulence but Does Not Alter Replicative Capacity in Cell Culture

2005 ◽  
Vol 79 (11) ◽  
pp. 7182-7194 ◽  
Author(s):  
Peter Ghazal ◽  
Astrid E. Visser ◽  
Montse Gustems ◽  
Rosalía García ◽  
Eva Maria Borst ◽  
...  
Keyword(s):  
Cell Types ◽  
Lytic Replication ◽  
Scid Mice ◽  
Early Gene ◽  
Murine Cytomegalovirus ◽  
Wild Type Virus ◽  
Mcmv Infection ◽  
Similar Dose ◽  
Nih 3T3

ABSTRACT The major immediate-early (MIE) genes of cytomegaloviruses (CMV) are broadly thought to be decisive regulators of lytic replication and reactivation from latency. To directly assess the role of the MIE protein IE1 during the infection of murine CMV (MCMV), we constructed an MCMV with exon 4 of the ie1 gene deleted. We found that, independent of the multiplicity of infection, the resulting recombinant virus, MCMVdie1, which fails to express the IE1 protein, was fully competent for early gene expression and replicated in different cultured cell types with identical kinetics to those of parental or revertant virus. Immunofluorescence microscopy studies revealed that MCMVdie1 was greatly impaired in its capacity to disrupt promyelocytic leukemia bodies in NIH 3T3 cells early after infection, a process that has been proposed to increase viral transcription efficiency. We examined MCMVdie1 in the murine model using both immunocompetent BALB/c and severe combined immunodeficient (SCID) mice. When MCMVdie1 was inoculated into these two types of mice, significantly lower viral titers were detected in infected organs than in those of the wild-type virus-infected animals. Moreover, the ie1-deficient MCMV exhibited a markedly reduced virulence. While all animals infected with 5 × 104 PFU of parental virus died by 30 days postinfection, SCID mice infected with a similar dose of MCMVdie1 did not succumb before 60 days postinfection. The in vivo defective growth phenotype of MCMVdie1 was abrogated upon rescue of ie1. These results demonstrate the significance of the ie1 gene for promoting an acute MCMV infection and virulence yet indicate that MCMV is able to grow in vivo, although impaired, in the absence of the ie1 gene.

scholarly journals CD4 T Cell-Mediated Immune Control of Cytomegalovirus Infection in Murine Salivary Glands

Pathogens ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 1531
Author(s):  
Nathan Zangger ◽  
Josua Oderbolz ◽  
Annette Oxenius
Keyword(s):  
T Cells ◽  
T Cell ◽  
Salivary Glands ◽  
Cd4 T Cells ◽  
Current Knowledge ◽  
Lytic Replication ◽  
Cd4 T Cell ◽  
Murine Cytomegalovirus ◽  
Mcmv Infection ◽  
Protective Function

CD4 T cells are well known for their supportive role in CD8 T cell and B cell responses during viral infection. However, during murine cytomegalovirus (MCMV) infection in the salivary glands (SGs), CD4 T cells exhibit direct antiviral effector functions to control the infection. In this mucosal organ, opposed to other infected tissues, MCMV establishes a sustained lytic replication that lasts for several weeks. While the protective function of CD4 T cells is exerted through the production of the pro-inflammatory cytokines interferon gamma (IFNγ) and tumor necrosis factor alpha (TNF), the reasons for their markedly delayed control of lytic MCMV infection remain elusive. Here, we review the current knowledge on the dynamics and mechanisms of the CD4 T cell-mediated control of MCMV-infected SGs, including their localization in the SG in relation to MCMV infected cells and other immune cells, their mode of action, and their regulation.

scholarly journals Mucosal and Parenteral Vaccination against Acute and Latent Murine Cytomegalovirus (MCMV) Infection by Using an Attenuated MCMV Mutant

1998 ◽  
Vol 72 (1) ◽  
pp. 442-451 ◽  
Author(s):  
Margaret R. MacDonald ◽  
Xi-Yang Li ◽  
Richard M. Stenberg ◽  
Ann E. Campbell ◽  
Herbert W. Virgin
Keyword(s):  
Tissue Culture ◽  
T Cells ◽  
Cd8 T Cells ◽  
Gamma Interferon ◽  
Murine Cytomegalovirus ◽  
Effective Vaccine ◽  
Mcmv Infection ◽  
Virus Challenge ◽  
Human Cmv ◽  
Deficient Mice

ABSTRACT We used a live attenuated murine cytomegalovirus (MCMV) mutant to analyze mechanisms of vaccination against acute and latent CMV infection. We selected MCMV mutant RV7 as a vaccine candidate since this virus grows well in tissue culture but is profoundly attenuated for growth in normal and severe combined immunodeficient (SCID) mice (V. J. Cavanaugh et al., J. Virol. 70:1365–1374, 1996). BALB/c mice were immunized twice (0 and 14 days) subcutaneously (s.c.) with tissue culture-passaged RV7 and then challenged with salivary gland-passaged wild-type MCMV (sgMCMV) intraperitoneally (i.p.) on day 28. RV7 vaccination protected mice against challenge with 105 PFU of sgMCMV, a dose that killed 100% of mock-vaccinated mice. RV7 vaccination reduced MCMV replication 100- to 500-fold in the spleen between 1 and 8 days after challenge. We used the capacity to control replication of MCMV in the spleen 4 days after challenge as a surrogate for protection. Protection was antigen specific and required both live RV7 and antigen-specific lymphocytes. Interestingly, RV7 was effective when administered s.c., i.p., perorally, intranasally, and intragastrically, demonstrating that attenuated CMV applied to mucosal surfaces can elicit protection against parenteral virus challenge. B cells and immunoglobulin G were not essential for RV7-induced immunity since B-cell-deficient mice were effectively vaccinated by RV7. CD8 T cells, but not CD4 T cells, were critical for RV7-induced protection. Depletion of CD8 T cells by passive transfer of monoclonal anti-CD8 (but not anti-CD4) antibody abrogated RV7-mediated protection, and RV7 vaccination was less efficient in CD8 T-cell-deficient mice with a targeted mutation in the β2-microglobulin gene. Although gamma interferon is important for innate resistance to MCMV, it was not essential for RV7 vaccination since gamma interferon receptor-deficient mice were protected by RV7 vaccination. Establishment of and/or reactivation from latency by sgMCMV was decreased by RV7 vaccination, as measured by diminished reactivation of MCMV from splenic explants. We found no evidence for establishment of splenic latency by RV7 after s.c. vaccination. We conclude that RV7 administered through both systemic and mucosal routes is an effective vaccine against MCMV infection. It may be possible to design human CMV vaccines with similar properties.

scholarly journals Potential Application of TALENs against Murine Cytomegalovirus Latent Infections

Viruses ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 414 ◽  
Author(s):  
Shiu-Jau Chen ◽  
Yuan-Chuan Chen
Keyword(s):  
Cell Culture ◽  
Significant Inhibition ◽  
Lytic Replication ◽  
Early Gene ◽  
Murine Cytomegalovirus ◽  
Latent Infections ◽  
Transcription Activator ◽  
Plasmid Transfection ◽  
Human Cmv ◽  
Global Health Problem

Cytomegalovirus (CMV) infections are still a global health problem, because the latent viruses persist in humans and cause recurring diseases. Currently, there are no therapies for CMV latent infections and the therapies for active infections are limited by side effects and other problems. It is impossible to eradicate latent viruses in animals. HCMV (human CMV) is specific to human diseases; however, it is difficult to study HCMV due to its host specificity and long life cycle. Fortunately, MCMV (murine CMV) provides an excellent animal model. Here, three specific pairs of transcription activator-like effector nuclease (TALEN) plasmids (MCMV1–2, 3–4, and 5–6) were constructed to target the MCMV M80/80.5 sequence in order to test their efficacy in blocking MCMV lytic replication in NIH3T3 cell culture. The preliminary data showed that TALEN plasmids demonstrate specific targeting and cleavage in the MCMV M80/80.5 sequence and effectively inhibit MCMV growth in cell culture when the plasmid transfection is prior to the viral infection. The most specific pairs of TALEN plasmids (MCMV3–4) were further used to confirm the negative regulation of latent MCMV replication and gene expression in Balb/c mice. The injection of specific TALEN plasmids caused significant inhibition in the copy number level of immediately early gene (ie-1) DNA in five organs of mice, when compared with the controls. The result demonstrated that TALENs potentially provide an effective strategy to remove latent MCMV in animals.

scholarly journals Oral Treatment of Murine Cytomegalovirus Infections with Ether Lipid Esters of Cidofovir

2004 ◽  
Vol 48 (9) ◽  
pp. 3516-3522 ◽  
Author(s):  
Earl R. Kern ◽  
Deborah J. Collins ◽  
W. Brad Wan ◽  
James R. Beadle ◽  
Karl Y. Hostetler ◽  
...  
Keyword(s):  
Oral Treatment ◽  
Ether Lipid ◽  
Murine Cytomegalovirus ◽  
Significant Protection ◽  
Mcmv Infection ◽  
Lipid Ester ◽  
Human Cmv ◽  
Cytomegalovirus Infections ◽  
Ester Prodrugs

ABSTRACT To improve the oral bioavailability of cidofovir (CDV), a series of ether lipid ester prodrugs were synthesized and evaluated for activity against murine cytomegalovirus (MCMV) infection. Four of these analogs, hexadecyloxypropyl (HDP)-CDV, octadecyloxyethyl (ODE)-CDV, oleyloxyethyl (OLE)-CDV, and oleyloxypropyl (OLP)-CDV, were found to have greater activity than CDV against human CMV and MCMV in vitro. The efficacy of oral treatment with these compounds against MCMV infections in BALB/c mice was then determined. Treatment with HDP-CDV, ODE-CDV, OLE-CDV, or OLP-CDV at 2.0 to 6.7 mg/kg of body weight provided significant protection when daily treatments were initiated 24 to 48 h after viral inoculation. Additionally, HDP-CDV or ODE-CDV administered twice weekly or as a single dose of 1.25 to 10 mg/kg was effective in reducing mortality when treatment was initiated at 24 h, 48 h, or, in some cases, 72 h after viral inoculation. In animals treated daily with HDP-CDV or ODE-CDV, virus titers in lung, liver, spleen, kidney, pancreas, salivary gland, and blood were reduced 3 to 5 log10-fold, which was comparable to CDV given intraperitoneally. These results indicated that HDP-CDV or ODE-CDV given orally was as effective as parenteral CDV for the treatment of experimental MCMV infection and suggest that further evaluation for use in CMV infections in humans is warranted.

scholarly journals Bystander Attenuation of Neuronal and Astrocyte Intercellular Communication by Murine Cytomegalovirus Infection of Glia

2007 ◽  
Vol 81 (13) ◽  
pp. 7286-7292 ◽  
Author(s):  
Winson S. C. Ho ◽  
Anthony N. van den Pol
Keyword(s):  
Intercellular Communication ◽  
Neuronal Development ◽  
Primary Cultures ◽  
Synaptic Activity ◽  
Murine Cytomegalovirus ◽  
Intercellular Signaling ◽  
Mcmv Infection ◽  
High Potassium ◽  
Infected Cells ◽  
The Brain

ABSTRACT Astrocytes are the first cells infected by murine cytomegalovirus (MCMV) in primary cultures of brain. These cells play key roles in intercellular signaling and neuronal development, and they modulate synaptic activity within the nervous system. Using ratiometric fura-2 digital calcium imaging of >8,000 neurons and glia, we found that MCMV-infected astrocytes showed an increase in intracellular basal calcium levels and an enhanced response to neuroactive substances, including glutamate and ATP, and to high potassium levels. Cultured neurons with no sign of MCMV infection showed attenuated synaptic signaling after infection of the underlying astrocyte substrate, and intercellular communication between astrocytes with no sign of infection was reduced by the presence of infected glia. These bystander effects would tend to cause further deterioration of cellular communication in the brain in addition to the problems caused by the loss of directly infected cells.

scholarly journals Enhancer Requirement for Murine Cytomegalovirus Growth and Genetic Complementation by the Human Cytomegalovirus Enhancer

1998 ◽  
Vol 72 (11) ◽  
pp. 8502-8509 ◽  
Author(s):  
Ana Angulo ◽  
Martin Messerle ◽  
Ulrich H. Koszinowski ◽  
Peter Ghazal
Keyword(s):  
Regulatory Region ◽  
Open Reading Frames ◽  
Productive Infection ◽  
Murine Cytomegalovirus ◽  
Growth Defect ◽  
Wild Type ◽  
Sequence Composition ◽  
Culture Cells ◽  
Sequence Elements ◽  
Human Cmv

ABSTRACT The cytomegalovirus (CMV) enhancer is a highly complex regulatory region containing multiple elements that interact with a variety of host-encoded transcription factors. Many of these sequence elements are conserved among the different species strains of CMV, although the arrangement of the various elements and overall sequence composition of the CMV enhancers differ remarkably. To delineate the importance of this region to a productive infection and to explore the possibility of generating a murine CMV (MCMV) under the control of human CMV (HCMV) genetic elements, the MCMV enhancer was resected and replaced either with nonregulatory sequences or with paralogous sequences from HCMV. The effects of these various deletions and substitutions on viral growth in transfected or infected tissue-culture cells were evaluated. We found that mutations in MCMV that eliminate or substitute for the enhancer with nonregulatory sequences showed a severe deficiency in virus synthesis. This growth defect is effectively complemented by the homologous MCMV enhancer as well as the HCMV enhancer. In the latter case, the chimeric viruses (hybrid MCMV strains) containing the molecularly shuffled human enhancer exhibit infectious kinetics similar to that of parental wild-type and wild-type revertant MCMV. These results also show that open reading frames m124, m124.1, and m125 located within the enhancer region are nonessential for growth of MCMV in cells. Most importantly, we conclude that the enhancer of MCMV is required for optimal infection and that its diverged human counterpart can advantageously replace its role in promoting viral infectivity.

A Sarcocystis-like Protozoon in a Sheep with Lymphadenopathy and Myocarditis

1978 ◽  
Vol 15 (2) ◽  
pp. 186-195 ◽  
Author(s):  
T. Landsverk ◽  
H. Gamlem ◽  
R. Svenkerud
Keyword(s):  
Electron Microscopy ◽  
Endothelial Cells ◽  
Lymph Node ◽  
Lymph Nodes ◽  
Light Microscopy ◽  
Vascular Endothelial Cells ◽  
Protozoan Parasite ◽  
Capillary Endothelium ◽  
Vascular Endothelial ◽  
Generalized Lymphadenopathy

A generalized enlargement of the lymph nodes was found in an emaciated adult ewe. Additional autopsy findings included tiny grey-white necrotic foci in the heart muscle, aspiration pneumonia and diffuse pleuritis. Light microscopy showed a generalized lymphadenopathy with Perilymphadenitis, depletion of lymphocytes and histiocytosis of the lymph node. In histiocytes and vascular endothelial cells of lymph nodes, septal capillary endothelium of lungs and capillary endothelium of myocardium, early stages of a protozoan parasite were found. In the myocardium, there were many foci of necrosis, some of which contained young cysts in the periphery. These cysts were morphologically similar to those of Sarcocystis. Electron microscopy of the early protozoan stages yielded evidence of schizogony and formation of merozoites.

Neck lumps

2018 ◽  
Author(s):  
Max Robinson ◽  
Keith Hunter ◽  
Michael Pemberton ◽  
Philip Sloan
Keyword(s):  
Lymph Nodes ◽  
Clinical Examination ◽  
Immune Surveillance ◽  
Systemic Infection ◽  
Neck Region ◽  
Anatomical Location ◽  
Regional Lymph Nodes ◽  
Size Consistency ◽  
Routine Clinical Examination ◽  
Anatomy Of The Neck

Whilst dental healthcare professionals naturally focus on assessment of the teeth and the supporting tissues, they also have an important role in assessing the whole oro-facial complex and the neck. Assessment of the neck is particularly important, not least, because it contains the regional lymph nodes that are involved in immune surveillance of the head and neck region. The neck also contains the major salivary glands: the sub­mandibular gland and the tail of the parotid gland. Mid-line structures include the hyoid bone, larynx, and trachea, along with the thyroid gland and parathyroid glands. The assessment of these anatomical structures should form part of the routine clinical examination. The dis­covery of an abnormality in the neck, which may not have been noticed by the patient, may expedite the diagnosis of significant disease and facilitate a timely intervention. A through understanding of the anatomy of the neck is essential and informs the clinical examination. It is also important to understand the concept of the anatomical levels that map out the lymph node groups of the neck (Chapter 1; Fig. 1.2). Accurate assessment of the neck is usually best achieved by a combination of visual inspection and palpation, with the patient in a slightly reclined position, the clinician standing behind the patient. Any lumps, e.g. enlarged lymph nodes, are described by anatomical site, size, consistency (cystic, soft, rubbery, hard), whether the lump is mobile or fixed to the underlying tissue, and if palpation elic­its pain or discomfort. The combination of these parameters will help to formulate the differential diagnosis; for example, an isolated hard lump that is fixed to underlying structures is likely to represent meta­static cancer, whereas, bilateral soft lumps that are mobile and painful to palpation are likely to represent lymphadenitis as a consequence of systemic infection. Ultrasound examination can be used to ascertain important informa­tion about a neck lump such as the site (precise anatomical location, superficial or deep), size, consistency (solid or cystic), and multi-focality. Doppler settings can help to establish the vascularity of a lesion and its proximity to major vessels.

scholarly journals Comparative histopathology of the lymph nodes, spleen, liver and kidney in experimental ovine trypanosomosis

2009 ◽  
Vol 76 (4) ◽  
Author(s):  
S.O. Omotainse ◽  
V.O. Anosa
Keyword(s):  
Lymph Nodes ◽  
Chronic Condition ◽  
Trypanosoma Congolense ◽  
Pathological Changes ◽  
Trypanosome Species ◽  
Chronic Infections ◽  
Phagocytic Cells ◽  
Liver And Kidney ◽  
Immunological Reactions ◽  
Spleen And Lymph Nodes

The infection of Yankassa rams with three important trypanosome species affecting livestock, namely, Trypanosoma congolense, T. vivax and T. brucei produced both acute and chronic fatal conditions. Chronic infections were induced in the three infections by the application of subcurative doses of diaminazene aceturate (Berenil®). Pathological changes in the infected animals included splenomegaly and hepatomegaly which were more pronounced in acute than in chronic T. congolense infection. However, these changes were more severe in chronic than in acute T. vivax infection. While splenomegaly was more pronounced in chronic T. brucei infection than in acute, hepatomegaly and lymphadenopathy were more severe in acute than in the chronic condition. The increases in size of the spleen, lymph nodes and liver were associated with congestion, increases in cell density related to increased immunological reactions in the spleen and lymph nodes as well as increase in numbers, size and activity of the phagocytic cells in these organs.

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