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2.
Arch Virol ; 168(2): 55, 2023 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-36609605

RESUMO

Porcine cytomegalovirus (PCMV), a porcine roseolovirus (PRV) that is closely related to human herpesviruses 6 and 7, is commonly found in commercial pigs. PCMV/PRV is important in xenotransplantation, because in preclinical trials in which pig organs were transplanted into non-human primates, transmission of PCMV/PRV was shown to be associated with significantly reduced survival of the xenotransplants. PCMV/PRV was also transmitted in the first transplantation of a pig heart into a human patient worldwide and apparently contributed to the death of the patient. The prevalence of PCMV/PRV in wild boars is largely unknown. In this study, we screened wild boars from several areas of northern Italy and Germany to test for the presence of PCMV/PRV using PCR-based and Western blot assays. By Western blot analysis, 54% and 82% of Italian and German wild boars, respectively, were found to be PCMV/PRV positive, while 36% and 60%, respectively, tested positive by real-time polymerase chain reaction (PCR). These data indicate that the virus is common in German and Italian wild boars and that the Western blot assay detected a PCMV/PRV infection more often than did real-time PCR. The data also indicate that pigs raised for xenotransplantation should be protected from contact with materials from wild boars and commercial pigs.


Assuntos
Infecções por Citomegalovirus , Roseolovirus , Doenças dos Suínos , Suínos , Animais , Humanos , Citomegalovirus/genética , Primatas , Reação em Cadeia da Polimerase em Tempo Real , Sus scrofa , Doenças dos Suínos/epidemiologia
3.
Virol J ; 20(1): 15, 2023 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-36707837

RESUMO

BACKGROUND: Porcine cytomegalovirus (PCMV) is a porcine roseolovirus (PCMV/PRV) which is widely distributed in pigs. Transmission of PCMV/PRV in preclinical xenotransplantations was shown to significantly reduce the survival time of the pig transplants in non-human primates. PCMV/PRV was also transmitted in the first transplantation of a pig heart into a human patient. To analyze how PCMV/PRV could be introduced into pig breeds, especially considering cloned transgenic pigs, and subsequently spread in breeding facilities, we screened ovaries and derived materials which are used to perform somatic cell nuclear transfer (SCNT). METHODS: DNA was isolated from ovarian tissues, follicular fluids, oocytes with cumulus cells, denuded oocytes and parthenotes. A real-time PCR with PCMV/PRV-specific primers and a probe was performed to detect PCMV/PRV. Furthermore, a Western blot assay using a recombinant fragment of the gB protein of PCMV/PRV was performed to screen for virus-specific antibodies in the follicular fluids. RESULTS: PCMV/PRV was found by real-time PCR in ovarian tissues, in the follicular fluid and in oocytes. In parthenotes the virus could not be detected, most-likely due to the low amount of DNA used. By Western blot assay specific antibodies against PCMV/PRV were found in 19 of 20 analyzed follicular fluids. CONCLUSION: PCMV/PRV was found in ovarian tissues, in the follicular fluids and also in denuded oocytes, indicating that the virus is present in the animals of which the oocytes were taken from. Despite several washing steps of the denuded oocytes, which are subsequently used for microinjection or SCNT, the virus could still be detected. Therefore, the virus could infect oocytes during genetic modifications or stay attached to the surface of the oocytes, potentially infecting SCNT recipient animals.


Assuntos
Citomegalovirus , Roseolovirus , Feminino , Animais , Suínos , Humanos , Transplante Heterólogo , Líquido Folicular , Roseolovirus/genética , Ovário , Primatas , Clonagem Molecular
4.
Xenotransplantation ; 29(5): e12775, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36082418

RESUMO

The potential for a donor-derived transmission of porcine cytomegalovirus/porcine roseolovirus (PCMV/PRV) to the recipient has been recognized since pigs were considered candidate donors for xenotransplantation. This review gives a short description of the viral properties and summarizes the current evidence of the effects of PCMV/PRV transmission in preclinical xenotransplantation. Despite evidence that PCMV/PRV does not infect human and non-human primate cells, activation in the transplanted organ and detrimental systemic complications have been described. As PCMV/PRV is a herpesvirus able to establish latency, the importance of adequate screening of donor pigs is emphasized, as no efficient treatment is available. Furthermore, easy and successful ways of elimination of PCMV/PRV from pig herds are indicated.


Assuntos
Infecções por Citomegalovirus , Roseolovirus , Animais , Citomegalovirus/fisiologia , Infecções por Citomegalovirus/veterinária , Humanos , Primatas , Suínos , Doadores de Tecidos , Transplante Heterólogo
5.
J Virol ; 96(17): e0083122, 2022 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-36000848

RESUMO

The guinea pig is the only small animal model for congenital cytomegalovirus (CMV) but requires species-specific guinea pig cytomegalovirus (GPCMV). Infection of epithelial cells and trophoblasts by GPCMV requires the viral glycoprotein pentamer complex (PC) and endocytic entry because of the absence of platelet-derived growth factor receptor alpha (PDGFRA). Endothelial cells represent an important cell type for infection, dissemination in the host, and disease but have been poorly evaluated for GPCMV. Novel endothelial cell lines were established from animal vascular systems, including aorta (EndoC) and placental umbilical cord vein (GPUVEC). Cell lines were characterized for endothelial cell protein markers (PECAM1, vWF, and FLI1) and evaluated for GPCMV infection. Only PC-positive virus was capable of infecting endothelial cells. Individual knockout mutants for unique PC components (GP129, GP131, and GP133) were unable to infect endothelial cells without impacting fibroblast infection. Ectopic expression of PDGFRA in EndoC cells enabled GPCMV(PC-) infection via direct cell entry independent of the PC. Neutralizing antibodies to the essential viral gB glycoprotein were insufficient to prevent endothelial cell infection, which also required antibodies to gH/gL and the PC. Endothelial cell infection was also dependent upon viral tegument pp65 protein (GP83) to counteract the IFI16/cGAS-STING innate immune pathway, similar to epithelial cell infection. GPCMV endothelial cells were lytically (EndoC) or persistently (GPUVEC) infected dependent on tissue origin. The ability to establish a persistent infection in the umbilical cord could potentially enable sustained and more significant infection of the fetus in utero. Overall, results demonstrate the importance of this translationally relevant model for CMV research. IMPORTANCE Congenital CMV is a leading cause of cognitive impairment and deafness in newborns, and a vaccine is a high priority. The only small animal model for congenital CMV is the guinea pig and guinea pig cytomegalovirus (GPCMV) encoding functional HCMV homolog viral glycoprotein complexes necessary for cell entry that are neutralizing-antibody vaccine targets. Endothelial cells are important in HCMV for human disease and viral dissemination. GPCMV endothelial cell infection requires the viral pentamer complex (PC), which further increases the importance of this complex as a vaccine target, as antibodies to the immunodominant and essential viral glycoprotein gB fail to prevent endothelial cell infection. GPCMV endothelial cell infection established either a fully lytic or a persistent infection, depending on tissue origin. The potential for persistent infection in the umbilical cord potentially enables sustained infection of the fetus in utero, likely increasing the severity of congenital disease.


Assuntos
Infecções por Citomegalovirus/virologia , Células Endoteliais/virologia , Roseolovirus , Animais , Anticorpos Neutralizantes , Linhagem Celular , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Feminino , Cobaias , Humanos , Recém-Nascido , Infecção Persistente , Placenta , Gravidez , Proteínas do Envelope Viral/metabolismo
6.
Viruses ; 14(4)2022 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-35458490

RESUMO

Congenital cytomegalovirus (CMV) is a leading cause of disease in newborns and a vaccine is a high priority. The guinea pig is the only small animal model for congenital CMV but requires guinea pig cytomegalovirus (GPCMV). Previously, a disabled infectious single cycle (DISC) vaccine strategy demonstrated complete protection against congenital GPCMV (22122 strain) and required neutralizing antibodies to various viral glycoprotein complexes. This included gB, essential for all cell types, and the pentamer complex (PC) for infection of non-fibroblast cells. All GPCMV research has utilized prototype strain 22122 limiting the translational impact, as numerous human CMV strains exist allowing re-infection and congenital CMV despite convalescent immunity. A novel GPCMV strain isolate (designated TAMYC) enabled vaccine cross strain protection studies. A GPCMV DISC (PC+) vaccine (22122 strain) induced a comprehensive immune response in animals, but vaccinated animals challenged with the TAMYC strain virus resulted in sustained viremia and the virus spread to target organs (liver, lung and spleen) with a significant viral load in the salivary glands. Protection was better than natural convalescent immunity, but the results fell short of previous DISC vaccine sterilizing immunity against the homologous 22122 virus challenge, despite a similarity in viral glycoprotein sequences between strains. The outcome suggests a limitation of the current DISC vaccine design against heterologous infection.


Assuntos
Infecções por Citomegalovirus , Vacinas contra Citomegalovirus , Roseolovirus , Animais , Anticorpos Antivirais , Citomegalovirus/fisiologia , Cobaias , Eficácia de Vacinas , Proteínas do Envelope Viral/metabolismo
7.
J Exp Med ; 219(3)2022 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-35226043

RESUMO

Infections with herpesviruses, including human roseoloviruses, have been proposed to cause autoimmune disease, but defining a causal relationship and mechanism has been difficult due to the ubiquitous nature of infection and development of autoimmunity long after acute infection. Murine roseolovirus (MRV) is highly related to human roseoloviruses. Herein we show that neonatal MRV infection induced autoimmune gastritis (AIG) in adult mice in the absence of ongoing infection. MRV-induced AIG was dependent on replication during the neonatal period and was CD4+ T cell and IL-17 dependent. Moreover, neonatal MRV infection was associated with development of a wide array of autoantibodies in adult mice. Finally, neonatal MRV infection reduced medullary thymic epithelial cell numbers, thymic dendritic cell numbers, and thymic expression of AIRE and tissue-restricted antigens, in addition to increasing thymocyte apoptosis at the stage of negative selection. These findings strongly suggest that infection with a roseolovirus early in life results in disruption of central tolerance and development of autoimmune disease.


Assuntos
Doenças Autoimunes , Gastrite , Roseolovirus , Animais , Linfócitos T CD4-Positivos , Tolerância Central , Camundongos , Timo
8.
Mol Neurodegener ; 17(1): 10, 2022 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-35033173

RESUMO

BACKGROUND: The role of viral infection in Alzheimer Disease (AD) pathogenesis is an area of great interest in recent years. Several studies have suggested an association between the human roseoloviruses, HHV-6 and HHV-7, and AD. Amyloid-ß (Aß) plaques are a hallmark neuropathological finding of AD and were recently proposed to have an antimicrobial function in response to infection. Identifying a causative and mechanistic role of human roseoloviruses in AD has been confounded by limitations in performing in vivo studies. Recent -omics based approaches have demonstrated conflicting associations between human roseoloviruses and AD. Murine roseolovirus (MRV) is a natural murine pathogen that is highly-related to the human roseoloviruses, providing an opportunity to perform well-controlled studies of the impact of roseolovirus on Aß deposition. METHODS: We utilized the 5XFAD mouse model to test whether MRV induces Aß deposition in vivo. We also evaluated viral load and neuropathogenesis of MRV infection. To evaluate Aß interaction with MRV, we performed electron microscopy. RNA-sequencing of a cohort of AD brains compared to control was used to investigate the association between human roseolovirus and AD. RESULTS: We found that 5XFAD mice were susceptible to MRV infection and developed neuroinflammation. Moreover, we demonstrated that Aß interacts with viral particles in vitro and, subsequent to this interaction, can disrupt infection. Despite this, neither peripheral nor brain infection with MRV increased or accelerated Aß plaque formation. Moreover, -omics based approaches have demonstrated conflicting associations between human roseoloviruses and AD. Our RNA-sequencing analysis of a cohort of AD brains compared to controls did not show an association between roseolovirus infection and AD. CONCLUSION: Although MRV does infect the brain and cause transient neuroinflammation, our data do not support a role for murine or human roseoloviruses in the development of Aß plaque formation and AD.


Assuntos
Doença de Alzheimer , Roseolovirus , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Transgênicos , Placa Amiloide/patologia , Roseolovirus/metabolismo
9.
Viruses ; 13(12)2021 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-34960639

RESUMO

The development of a vaccine against congenital human cytomegalovirus (HCMV) infection is a major priority. The pentameric complex (PC) of virion envelope proteins gH, gL, UL128, UL130, and UL131A is a key vaccine target. To determine the importance of immunity to the homologous PC encoded by guinea pig cytomegalovirus (GPCMV) in preventing congenital CMV, PC-intact and PC-deficient live-attenuated vaccines were generated and directly compared for immunogenicity and efficacy against vertical transmission in a vertical transmission model. A virulent PC-intact GPCMV (PC/intact) was modified by galK mutagenesis either to abrogate PC expression (PC/null; containing a frame-shift mutation in GP129, homolog of UL128) or to delete genes encoding three MHC Class I homologs and a protein kinase R (PKR) evasin while retaining the PC (3DX/Δ145). Attenuated vaccines were compared to sham immunization in a two-dose preconception subcutaneous inoculation regimen in GPCMV seronegative Hartley guinea pigs. Vaccines induced transient, low-grade viremia in 5/12 PC/intact-, 2/12 PC/null-, and 1/11 3DX/Δ145-vaccinated animals. Upon completion of the two-dose vaccine series, ELISA titers for the PC/intact group (geometic mean titer (GMT) 13,669) were not significantly different from PC/null (GMT 8127) but were significantly higher than for the 3DX/Δ145 group (GMT 6185; p < 0.01). Dams were challenged with salivary gland-adapted GPCMV in the second trimester. All vaccines conferred protection against maternal viremia. Newborn weights were significantly lower in sham-immunized controls (84.5 ± 2.4 g) compared to PC/intact (96 ± 2.3 g), PC/null (97.6 ± 1.9 g), or 3DX/Δ145 (93 ± 1.7) pups (p < 0.01). Pup mortality in sham-immunized controls was 29/40 (73%) and decreased to 1/44 (2.3%), 2/46 (4.3%), or 4/40 (10%) in PC/intact, PC/null, or 3DX/Δ145 groups, respectively (all p < 0.001 compared to control). Congenital GPCMV transmission occurred in 5/44 (11%), 16/46 (35%), or 29/38 (76%) of pups in PC/intact, PC/null, or 3DX/Δ145 groups, versus 36/40 (90%) in controls. For infected pups, viral loads were lower in pups born to vaccinated dams compared to controls. Sequence analysis demonstrated that infected pups in the vaccine groups had salivary gland-adapted GPCMV and not vaccine strain-specific sequences, indicating that congenital transmission was due to the challenge virus and not vaccine virus. We conclude that inclusion of the PC in a live, attenuated preconception vaccine improves immunogenicity and reduces vertical transmission, but PC-null vaccines are equal to PC-intact vaccines in reducing maternal viremia and protecting against GPCMV-related pup mortality.


Assuntos
Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Infecções por Roseolovirus/transmissão , Roseolovirus/imunologia , Vacinas Atenuadas/imunologia , Animais , Feminino , Cobaias , Humanos , Gravidez , Roseolovirus/fisiologia , Infecções por Roseolovirus/congênito , Infecções por Roseolovirus/virologia , Vacinação , Carga Viral , Viremia
10.
Viruses ; 13(8)2021 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-34452332

RESUMO

A vaccine against congenital cytomegalovirus infection is a high priority. Guinea pig cytomegalovirus (GPCMV) is the only congenital CMV small animal model. GPCMV encodes essential glycoprotein complexes for virus entry (gB, gH/gL/gO, gM/gN) including a pentamer complex (gH/gL/GP129/GP131/GP133 or PC) for endocytic cell entry. The cohorts for protection against congenital CMV are poorly defined. Neutralizing antibodies to the viral glycoprotein complexes are potentially more important than an immunodominant T-cell response to the pp65 protein. In GPCMV, GP83 (pp65 homolog) is an evasion factor, and the GP83 mutant GPCMV has increased sensitivity to type I interferon. Although GP83 induces a cell-mediated response, a GP83-only-based vaccine strategy has limited efficacy. GPCMV attenuation via GP83 null deletion mutant in glycoprotein PC positive or negative virus was evaluated as live-attenuated vaccine strains (GP83dPC+/PC-). Vaccinated animals induced antibodies to viral glycoprotein complexes, and PC+ vaccinated animals had sterilizing immunity against wtGPCMV challenge. In a pre-conception vaccine (GP83dPC+) study, dams challenged mid-2nd trimester with wtGPCMV had complete protection against congenital CMV infection without detectable virus in pups. An unvaccinated control group had 80% pup transmission rate. Overall, gB and PC antibodies are key for protection against congenital CMV infection, but a response to pp65 is not strictly necessary.


Assuntos
Anticorpos Neutralizantes/imunologia , Infecções por Citomegalovirus/prevenção & controle , Citomegalovirus/imunologia , Roseolovirus/imunologia , Linfócitos T/imunologia , Proteínas do Envelope Viral/imunologia , Proteínas da Matriz Viral/imunologia , Vacinas Virais/administração & dosagem , Animais , Anticorpos Antivirais/imunologia , Citomegalovirus/genética , Infecções por Citomegalovirus/congênito , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/virologia , Feminino , Cobaias , Humanos , Masculino , Roseolovirus/genética , Infecções por Roseolovirus/congênito , Infecções por Roseolovirus/imunologia , Infecções por Roseolovirus/prevenção & controle , Infecções por Roseolovirus/virologia , Vacinação , Proteínas do Envelope Viral/administração & dosagem , Proteínas do Envelope Viral/genética , Proteínas da Matriz Viral/administração & dosagem , Proteínas da Matriz Viral/genética , Vacinas Virais/genética , Vacinas Virais/imunologia
11.
J Gen Virol ; 102(3)2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33729125

RESUMO

Multiple strains of human cytomegalovirus (HCMV) can cause congenital cytomegalovirus (cCMV) by primary or secondary infection. The viral gB glycoprotein is a leading vaccine candidate, essential for infection of all cell-types, and immunodominant antibody target. Guinea pig cytomegalovirus (GPCMV) is the only small animal model for cCMV. Various gB vaccines have shown efficacy but studies have utilized truncated gB and protection against prototype strain 22122 with preferential tropism to fibroblasts despite encoding a gH-based pentamer complex for non-fibroblast infection. A highly cell-associated novel strain of GPCMV (TAMYC) with 99 % identity in gB sequence to 22122 exhibited preferred tropism to epithelial cells. An adenovirus vaccine encoding full-length gB (AdgB) was highly immunogenic and partially protected against 22122 strain challenge in vaccinated animals but not when challenged with TAMYC strain. GPCMV studies with AdgB vaccine sera on numerous cell-types demonstrated impaired neutralization (NA50) compared to fibroblasts. GPCMV-convalescent sera including pentamer complex antibodies increased virus neutralization on non-fibroblasts and anti-gB depletion from GPCMV-convalescent sera had minimal impact on epithelial cell neutralization. GPCMV(PC+) 22122-convalescent animals challenged with TAMYC exhibited higher protection compared to AdgB vaccine. Overall, results suggest that antibody response to both gB and PC are important components of a GPCMV vaccine.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Infecções por Citomegalovirus/imunologia , Vacinas contra Citomegalovirus/imunologia , Roseolovirus/patogenicidade , Animais , Infecções por Citomegalovirus/prevenção & controle , Cobaias , Testes de Neutralização , Reação em Cadeia da Polimerase em Tempo Real , Roseolovirus/fisiologia , Proteínas do Envelope Viral/imunologia , Carga Viral
12.
Microbiol Immunol ; 65(1): 28-39, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33616978

RESUMO

Cytomegaloviruses (CMVs) encode various immunoevasins, including viral receptors for the Fc domain of host IgG (vFcγR), to evade host immune responses. Although guinea pig CMV (GPCMV) provides a useful animal model for congenital CMV infection, the GPCMV genes encoding such receptors have not yet been characterized. In this study, we analyzed a locus that may encode gene products for the GPCMV immune evasion mechanisms and identified the following. (a) RACE analyses identified four transcripts in the GP117 to GP122 locus. One of the transcripts contained the GP119.1 ORF, which has weak homologies with human CMV UL119/UL118 encoding a viral FcγR and with guinea pig FcγR. (b) A transient transfection assay with plasmids expressing EGFP-tagged GP119.1 or its mutated forms identified its true translational initiation site, localization mainly in the endoplasmic reticulum, and N-glycosylation. (c) Importantly, GP119.1 bound to guinea pig IgG or the IgG-Fc fragment. (d) GP119.1 is present in the virion with a molecular mass of 15 and 23~30 kDa, and a portion of the GP119.1 products are N-glycosylated. (e) GP119.1 was dispensable for viral growth on guinea pig fibroblasts and epithelial cells in vitro. Taken together, our findings indicate that GP119.1 is an IgG-Fc binding glycoprotein incorporated into the virion, and this finding warrants further studies on the functions of GP119.1 in animal models.


Assuntos
Glicoproteínas de Membrana , Roseolovirus , Proteínas do Envelope Viral , Animais , Cobaias , Imunoglobulina G , Vírion
13.
J Gen Virol ; 101(12): 1270-1279, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32915127

RESUMO

Cytomegaloviruses (CMVs) employ an array of strategies designed to interfere with host defence responses against pathogens. Studies on such evasion mechanisms are important for understanding the pathogenesis of CMV diseases. Although guinea pig CMV (GPCMV) provides a useful animal model for congenital CMV infection, its evasion strategies are not fully elucidated. Here, we analysed a genome locus that may encode gene products for the GPCMV evasion mechanisms and found the following. (1) RACE analyses identified five transcripts in the GP38-gp38.4 locus, one of which was a spliced product encoding gp38.1. Similarities in the splicing pattern and gene position of gp38.1 to human CMV UL37 and its exon 1 encoding vMIA (viral mitochondria-localized inhibitor of apoptosis) suggest that the gp38.1 gene encodes an apoptosis inhibitor. (2) In a transient transfection assay, gp38.1 localized in the mitochondria and relocated BAX from the cytoplasm to the mitochondria, although its co-localization with BAK was not evident. Further, the expression of gp38.1 partially reduced staurosporine-induced apoptosis. (3) GPCMV defective in the gp38.1 ORF (Δ38.1) and the virus that rescues the defect (r38.1) were generated. Guinea pig fibroblast cells infected with Δ38.1 died earlier than r38.1-infected cells, which resulted in the lower yields of Δ38.1. (4) In animals, viral loads in the spleens of r38.1-infected guinea pigs were higher than those in the spleens of Δ38.1-infected animals. In conclusion, although GPCMV gp38.1 exerts a vMIA-like function, its inhibitory effect was not robust, suggesting the presence of additional inhibitory molecule(s), such as a BAK-specific inhibitor.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Apoptose , Roseolovirus/genética , Roseolovirus/fisiologia , Proteínas Virais/metabolismo , Animais , Proteínas Reguladoras de Apoptose/genética , Sobrevivência Celular , Células Cultivadas , Genoma Viral , Glicosilação , Cobaias , Mitocôndrias/metabolismo , Fases de Leitura Aberta , Roseolovirus/crescimento & desenvolvimento , Infecções por Roseolovirus/virologia , Carga Viral , Proteínas Virais/genética , Proteína Killer-Antagonista Homóloga a bcl-2/metabolismo , Proteína X Associada a bcl-2/metabolismo
14.
J Alzheimers Dis ; 77(2): 543-545, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32804089

RESUMO

Animal models to study Alzheimer's disease (AD) pathogenesis are under development. Since herpesviruses have been postulated to be capable of triggering the pathogenic process, AD animal models (mouse, pig, and non-human primates) should be controlled for the presence of these viruses. Only virus-free models allow studying the genetic factors and the effect of adding viruses. Roseoloviruses such as human herpesvirus 6 and the related viruses in the animals are the main topic of this commentary.


Assuntos
Doença de Alzheimer/virologia , Modelos Animais de Doenças , Infecções por Roseolovirus/prevenção & controle , Roseolovirus , Doença de Alzheimer/patologia , Animais , Herpesvirus Humano 6/isolamento & purificação , Humanos , Camundongos , Primatas , Roseolovirus/isolamento & purificação , Infecções por Roseolovirus/patologia , Suínos
15.
Viruses ; 11(12)2019 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-31801268

RESUMO

Viruses of the genus Roseolovirus belong to the subfamily Betaherpesvirinae, family Herpesviridae. Roseoloviruses have been studied in humans, mice and pigs, but they are likely also present in other species. This is the first comparative analysis of roseoloviruses in humans and animals. The human roseoloviruses human herpesvirus 6A (HHV-6A), 6B (HHV-6B), and 7 (HHV-7) are relatively well characterized. In contrast, little is known about the murine roseolovirus (MRV), also known as murine thymic virus (MTV) or murine thymic lymphotrophic virus (MTLV), and the porcine roseolovirus (PRV), initially incorrectly named porcine cytomegalovirus (PCMV). Human roseoloviruses have gained attention because they can cause severe diseases including encephalitis in immunocompromised transplant and AIDS patients and febrile seizures in infants. They have been linked to a number of neurological diseases in the immunocompetent including multiple sclerosis (MS) and Alzheimer's. However, to prove the causality in the latter disease associations is challenging due to the high prevalence of these viruses in the human population. PCMV/PRV has attracted attention because it may be transmitted and pose a risk in xenotransplantation, e.g., the transplantation of pig organs into humans. Most importantly, all roseoloviruses are immunosuppressive, the humoral and cellular immune responses against these viruses are not well studied and vaccines as well as effective antivirals are not available.


Assuntos
Genoma Viral/genética , Infecções por Roseolovirus/virologia , Roseolovirus/fisiologia , Animais , Antivirais/uso terapêutico , Humanos , Camundongos , Roseolovirus/genética , Roseolovirus/imunologia , Roseolovirus/patogenicidade , Infecções por Roseolovirus/tratamento farmacológico , Infecções por Roseolovirus/epidemiologia , Infecções por Roseolovirus/transmissão , Suínos , Integração Viral , Latência Viral
16.
J Gen Virol ; 99(10): 1425-1431, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30113297

RESUMO

As congenital cytomegalovirus (CMV) infection is the major cause of developmental abnormalities in children, the development of effective vaccines is critical to public health. Recent studies have demonstrated that the pentameric complex (Pentamer) of glycoproteins, which is required for human CMV infection of endothelial and epithelial cells, could be a potent vaccine antigen. As guinea pig CMV (GPCMV) infects congenitally and encodes homologues of all Pentamer components, GPCMV models are considered to be useful for the development of vaccine strategies. Here, to clarify the precise requirement of GP131, one of the GPCMV Pentamer components, for the infection of epithelial cells and macrophages, we prepared several mutants with a charged amino acid-to-alanine alteration in GP131 and found some differences in the effects of the mutations on the infection of the two cell types, suggesting the existence of cell type-dependent recognition or function of Pentamer in GPCMV infection.


Assuntos
Células Epiteliais/virologia , Macrófagos/virologia , Roseolovirus/crescimento & desenvolvimento , Roseolovirus/genética , Proteínas Estruturais Virais/genética , Proteínas Estruturais Virais/metabolismo , Substituição de Aminoácidos , Animais , Células Cultivadas , Cobaias , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Mutação de Sentido Incorreto
17.
J Immunol ; 199(9): 3212-3221, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-28972091

RESUMO

A recently described mouse homolog of the human roseoloviruses, murine roseolovirus (MRV), causes loss of peripheral and thymic CD4+ cells during neonatal infection of BALB/c mice. Despite significant disruptions to the normal adaptive immune response, infected BALB/c mice reproducibly recover from infection, consistent with prior studies on a related virus, mouse thymic virus. In this article, we show that, in contrast to published studies on mouse thymic virus, MRV appears to robustly infect neonatal C57BL/6 (B6) mice, causing severe depletion of thymocytes and peripheral T cells. Moreover, B6 mice recovered from infection. We investigated the mechanism of thymocyte and T cell loss, determining that the major thymocyte subsets were infected with MRV; however, CD4+ and CD4+CD8- T cells showed increased apoptosis during infection. We found that CD8+ T cells populated MRV-infected thymi. These CD8+ T cells expressed markers of activation, had restricted TCR repertoire, and accumulated intracellular effector proteins, consistent with a cytotoxic lymphocyte phenotype and suggesting their involvement in viral clearance. Indeed, absence of CD8+ T cells prevented recovery from MRV infection and led to lethality in infected animals, whereas B cell-deficient mice showed CD4+ T cell loss but recovered from infection without lethality. Thus, these results demonstrate that CD8+ T cells are required for protective immunity against a naturally occurring murine pathogen that infects the thymus and establish a novel infection model for MRV in B6 mice, providing the foundation for detailed future studies on MRV with the availability of innumerable mutant mice on the B6 background.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Infecções por Roseolovirus/imunologia , Roseolovirus/imunologia , Timo/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/patologia , Camundongos , Camundongos Knockout , Infecções por Roseolovirus/genética , Infecções por Roseolovirus/patologia , Timo/patologia
20.
Virology ; 509: 205-221, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28651121

RESUMO

Guinea pig cytomegalovirus (GPCMV) encodes a homolog pentameric complex (PC) for specific cell tropism and congenital infection. In human cytomegalovirus, the PC is an important antibody neutralizing target and GPCMV studies will aid in the development of intervention strategies. Deletion mutants of the C-terminal domains of unique PC proteins (UL128, UL130 and UL131 homologs) were unable to form a PC in separate transient expression assays. Minor modifications to the UL128 homolog (GP129) C-terminal domain enabled PC formation but viruses encoding these mutants had altered tropism to renal and placental trophoblast cells. Mutation of the presumptive CC chemokine motif encoded by GP129 was investigated by alanine substitution of the CC motif (codons 26-27) and cysteines (codons 47 and 62). GP129 chemokine mutants formed PC but GP129 chemokine mutant viruses had reduced epitropism. A GP129 chemokine mutant virus pathogenicity study demonstrated reduced viral load to target organs but highly extended viremia.


Assuntos
Células Epiteliais/virologia , Proteínas Mutantes/metabolismo , Multimerização Proteica , Roseolovirus/fisiologia , Trofoblastos/virologia , Proteínas do Envelope Viral/metabolismo , Tropismo Viral , Substituição de Aminoácidos , Animais , Análise Mutacional de DNA , Cobaias , Mutagênese Sítio-Dirigida , Proteínas Mutantes/genética , Roseolovirus/genética , Infecções por Roseolovirus/patologia , Infecções por Roseolovirus/veterinária , Infecções por Roseolovirus/virologia , Proteínas do Envelope Viral/genética , Viremia/patologia , Viremia/veterinária , Viremia/virologia , Virulência
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