The expression of p16INK4a tumor suppressor is upregulated by human cytomegalovirus infection and required for optimal viral replication

Zannetti, Claudia; Mondini, Michele; Andrea, Marco De; Caposio, Patrizia; Hara, Eiji; Peters, Gordon; Gribaudo, Giorgio; Gariglio, Marisa; Landolfo, Santo

doi:10.1016/j.virol.2006.01.042

Cited by 15 publications

(16 citation statements)

References 21 publications

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“…We were particularly interested in events occurring at times prior to the failure of the pUL117-deficient virus to block host DNA synthesis (i.e., 0–36 hpi) as misregulation of these events was the most likely cause of the defect. HCMV up-regulates p16 at late times [13],[30], inhibits cyclin A accumulation [8],[31],[32], and prevents MCM complex loading onto chromatin [17],[18]. When infecting G0-synchronized HFFs in the presence of serum, HCMV induced p16 accumulation and expressed another viral inhibitory protein IE2 independent of pUL117 (Fig.…”

Section: Resultsmentioning

confidence: 99%

Human Cytomegalovirus Protein pUL117 Targets the Mini-Chromosome Maintenance Complex and Suppresses Cellular DNA Synthesis

et al. 2010

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Modulation of host DNA synthesis is essential for many viruses to establish productive infections and contributes to viral diseases. Human cytomegalovirus (HCMV), a large DNA virus, blocks host DNA synthesis and deregulates cell cycle progression. We report that pUL117, a viral protein that we recently identified, is required for HCMV to block host DNA synthesis. Mutant viruses in which pUL117 was disrupted, either by frame-shift mutation or by a protein destabilization-based approach, failed to block host DNA synthesis at times after 24 hours post infection in human foreskin fibroblasts. Furthermore, pUL117-deficient virus stimulated quiescent fibroblasts to enter S-phase, demonstrating the intrinsic ability of HCMV to promote host DNA synthesis, which was suppressed by pUL117. We examined key proteins known to be involved in inhibition of host DNA synthesis in HCMV infection, and found that many were unlikely involved in the inhibitory activity of pUL117, including geminin, cyclin A, and viral protein IE2, based on their expression patterns. However, the ability of HCMV to delay the accumulation of the mini-chromosome maintenance (MCM) complex proteins, represented by MCM2 and MCM4, and prevent their loading onto chromatin, was compromised in the absence of pUL117. When expressed alone, pUL117 slowed cell proliferation, delayed DNA synthesis, and inhibited MCM accumulation. Knockdown of MCM proteins by siRNA restored the ability of pUL117-deficient virus to block cellular DNA synthesis. Thus, targeting MCM complex is one mechanism pUL117 employs to help block cellular DNA synthesis during HCMV infection. Our finding substantiates an emerging picture that deregulation of MCM is a conserved strategy for many viruses to prevent host DNA synthesis and helps to elucidate the complex strategy used by a large DNA virus to modulate cellular processes to promote infection and pathogenesis.

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Section: Resultsmentioning

confidence: 99%

Human Cytomegalovirus Protein pUL117 Targets the Mini-Chromosome Maintenance Complex and Suppresses Cellular DNA Synthesis

et al. 2010

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“…Although telomere shortening has been shown in acute infections in experimental animal models (Asghar, Hasselquist, et al., 2015; Asghar et al., 2016; Ilmonen et al., 2008), such effect has not been reported in humans. Previous studies have shown that chronic viral infections (i.e., HCV, CMV, and HIV) accelerate cellular aging in humans, as reflected by shorter telomere length and elevated CDKN2A expression (van de Berg et al., 2010; Gianesin et al., 2016; Leung et al., 2017; Pathai et al., 2013; Robinson et al., 2013; Zannetti et al., 2006). Furthermore, genome‐wide association studies (GWAS) have linked CDKN2A to many age‐related pathologies, including susceptibility to frailty and increased risk of coronary artery disease, myocardial infarction, type 2 diabetes, and Alzheimer's disease (Jeck et al., 2012).…”

Section: Discussionmentioning

confidence: 99%

“…In this study of acute malaria infection, we find distinct dynamics of cellular aging not observed during chronic infection (van de Berg et al., 2010; Gianesin et al., 2016; Leung et al., 2017; Pathai et al., 2013; Robinson et al., 2013; Zannetti et al., 2006). After successful treatment and in the absence of new infections, the effect on cellular aging markers was largely reversed as reflected by lower CDKN2A expression, higher telomerase activity, and gradual restoration of telomere length in peripheral blood of travelers from three months postinfection up to one year.…”

Section: Discussionmentioning

confidence: 99%

Cellular aging dynamics after acute malaria infection: A 12‐month longitudinal study

et al. 2017

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SummaryAccelerated cellular aging and reduced lifespan have recently been shown in birds chronically infected with malaria parasites. Whether malaria infection also affects cellular aging in humans has not been reported. Here, we assessed the effect of a single acute Plasmodium falciparum malaria infection on cellular aging dynamics in travelers prospectively followed over one year in Sweden. DNA and RNA were extracted from venous blood collected at the time of admission and repeatedly up to one year. Telomere length was measured using real‐time quantitative PCR, while telomerase activity and CDKN2A expression were measured by reverse transcriptase (RT)–qPCR. Our results show that acute malaria infection affects cellular aging as reflected by elevated levels of CDKN2A expression, lower telomerase activity, and substantial telomere shortening during the first three months postinfection. After that CDKN2A expression declined, telomerase activity increased and telomere length was gradually restored over one year, reflecting that cellular aging was reversed. These findings demonstrate that malaria infection affects cellular aging and the underlying cellular mechanism by which pathogens can affect host cellular aging and longevity need to be elucidated. Our results urge the need to investigate whether repeated malaria infections have more pronounced and long‐lasting effects on cellular aging and lifespan (similarly to what was observed in birds) in populations living in malaria endemic areas.

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“…31 Highly purified HCMV stocks propagated in low-passage human embryonic lung (HEL) fibroblasts were used. 32 Lowpassage HEL cells and the laboratory type strain AD169 from American Type Culture Collection (VR-538; ATCC, Manassas, VA) were propagated at low virus-to-cell ratios (about 0.001 plaque-forming units [PFUs]/cells) to minimize generation of defective particles. Infections were initiated by intraperitoneal injection of 10 5 (BALB/c), 5 ϫ 10 5 (C57BL6, PTX3 ϩ/ϩ , and PTX3 Ϫ/Ϫ ) PFUs of MCMV.…”

Section: Pathogens Infections and Treatmentsmentioning

confidence: 99%

“…Cycling conditions were initial denaturation for 3 minutes at 95°C, followed by cycles of 1 minute at 95°C, 1 minute at 50°C, and 20 seconds at 72°C, and a final extension for 10 minutes at 72°C. To determine HCMV DNA copy number, total DNA was isolated as described 32 and viral DNA levels were measured by real-time RT-PCR using the Q-CMV Real Time Complete Kit (Nanogen Advanced Diagnostics, Turin, Italy), which amplifies the major immediate early antigen, HCMVUL123. The RT-PCR products were detected by measuring fluorescence with passive reference dye in Sequence Detection System ABI Prism 7300 (Applied Biosystems-Applera Italia-Monza, Milan, Italy).…”

Section: Quantification Of CMV Mrna and Dnamentioning

confidence: 99%

Pentraxin 3 protects from MCMV infection and reactivation through TLR sensing pathways leading to IRF3 activation

Bozza

Bistoni

Gaziano

et al. 2006

Blood

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Reactivation of latent human cytomegalovirus (HCMV) following allogeneic transplantation is a major cause of morbidity and mortality and predisposes to severe complications, including superinfection by Aspergillus species (spp). Antimicrobial polypeptides, including defensins and mannan-binding lectin, are known to block viral fusion by cross-linking sugars on cell surface. Pentraxin 3 (PTX3), a member of the long pentraxin family, successfully restored antifungal immunity in experimental hematopoietic transplantation. We assessed here whether PTX3 binds HCMV and murine virus (MCMV) and the impact on viral infectivity and superinfection in vivo. We found that PTX3 bound both viruses, reduced viral entry and infectivity in vitro, and protected from MCMV primary infection and reactivation as well IntroductionHuman cytomegalovirus (HCMV), a member of the Herpesviridae family, is a ubiquitous opportunistic pathogen that has an intimate lifelong relationship with its human host and establishes latency after clearance of primary infection. 1-3 Reactivation of latent virus following allogeneic transplantation immune responses results in progressive tissue damage manifesting as overt HCMV disease or complications of this infection, including acute and chronic graft rejection, graft-versus-host disease, and superinfection by other viruses, bacteria, and fungi, particularly Aspergillus species (spp). 3 Efforts have focused on the development of adoptive immunotherapeutic strategies to hasten host immune reconstruction, and cellular immunotherapy appears to be an attractive approach. 4,5 The immune control of murine CMV (MCMV) infection requires elements from both innate and adaptive immune systems. [6][7][8] Through the participation of members of the Toll-like receptors (TLRs) 9-11 and interferon (IFN) regulatory factor 3 (IRF) families, IRF3 in particular, 12,13 MCMV induces early dendritic cell (DC)-dependent type I IFN and interleukin-12 (IL-12) responses essential for mouse resistance to MCMV. 10,11,[14][15][16] The TLR9/ MyD88 signaling pathway mediates antiviral cytokine responses by plasmacytoid DCs (pDCs) that, through their unique capacity to secrete IFN-␣, and to a lesser extent IL-12 and other innate cytokines, are a cornerstone in the initiation of both innate and adaptive immune responses to MCMV. [15][16][17][18][19] However, conventional CD11b ϩ DCs also produce IFN-␣ independently of TLR9 and MyD88. 10,20 In addition to directly interfering with viral replication through ubiquitous cellular mechanisms, IFN-␣ controls natural killer (NK) cell cytotoxic activity 15 and regulates T-cell functions by activating classical DCs to more efficiently present antigens (Ags). 15 IL-12 and IL-18 secretion are instead required to prime a strong NK cell-dependent IFN-␥ response, 17,21,22 a process that is essential to counteract MCMV infection in the liver, in contrast to a perforin-dependent mechanism in the spleen. 23 Pentraxin 3 (PTX3) is a member of a superfamily of conserved proteins characterized by a cyclic mul...

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The expression of p16INK4a tumor suppressor is upregulated by human cytomegalovirus infection and required for optimal viral replication

Cited by 15 publications

References 21 publications

Human Cytomegalovirus Protein pUL117 Targets the Mini-Chromosome Maintenance Complex and Suppresses Cellular DNA Synthesis

Human Cytomegalovirus Protein pUL117 Targets the Mini-Chromosome Maintenance Complex and Suppresses Cellular DNA Synthesis

Cellular aging dynamics after acute malaria infection: A 12‐month longitudinal study

Pentraxin 3 protects from MCMV infection and reactivation through TLR sensing pathways leading to IRF3 activation

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