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Malignant pleural mesothelioma (MPM) is a highly aggressive cancer with a long latency period and dismal prognosis. Recently, tazemetostat (EPZ-6438), an inhibitor of the histone methyltransferase EZH2, has entered clinical trials due to... more
Malignant pleural mesothelioma (MPM) is a highly aggressive cancer with a long latency period and dismal prognosis. Recently, tazemetostat (EPZ-6438), an inhibitor of the histone methyltransferase EZH2, has entered clinical trials due to the antiproliferative effects reported on MPM cells. However, the direct and indirect effects of epigenetic reprogramming on the tumor microenvironment are hitherto unexplored. To investigate the impact of tumor-associated macrophages (TAMs) on MPM cell responsiveness to tazemetostat, we developed a three-dimensional MPM spheroid model that recapitulates in vitro, both monocytes’ recruitment in tumors and their functional differentiation toward a TAM-like phenotype (Mo-TAMs). Along with an increased expression of genes for monocyte chemoattractants, inhibitory immune checkpoints, immunosuppressive and M2-like molecules, Mo-TAMs promote tumor cell proliferation and spreading. Prolonged treatment of MPM spheroids with tazemetostat enhances both the re...
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Citrullination is the conversion of arginine-to-citrulline by protein arginine deiminases (PADs), whose dysregulation is implicated in the pathogenesis of various types of cancers and autoimmune diseases. Consistent with the ability of... more
Citrullination is the conversion of arginine-to-citrulline by protein arginine deiminases (PADs), whose dysregulation is implicated in the pathogenesis of various types of cancers and autoimmune diseases. Consistent with the ability of human cytomegalovirus (HCMV) to induce post-translational modifications of cellular proteins to gain a survival advantage, we show that HCMV infection of primary human fibroblasts triggers PAD-mediated citrullination of several host proteins, and that this activity promotes viral fitness. Citrullinome analysis reveals significant changes in deimination levels of both cellular and viral proteins, with interferon (IFN)-inducible protein IFIT1 being among the most heavily deiminated one. As genetic depletion of IFIT1 strongly enhances HCMV growth, and in vitro IFIT1 citrullination impairs its ability to bind to 5’-ppp-RNA, we propose that viral-induced IFIT1 citrullination is a mechanism of HCMV evasion from host antiviral resistance. Overall, our findin...
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Longitudinal mapping of antibody-based SARS-CoV-2 immunity is critical for public health control of the pandemic and vaccine development. We performed a longitudinal analysis of the antibody-based immune response in a cohort of 100... more
Longitudinal mapping of antibody-based SARS-CoV-2 immunity is critical for public health control of the pandemic and vaccine development. We performed a longitudinal analysis of the antibody-based immune response in a cohort of 100 COVID-19 individuals who were infected during the first wave of infection in northern Italy. The SARS-CoV-2 humoral response was tested using the COVID-SeroIndex, Kantaro Quantitative SARS-CoV-2 IgG Antibody RUO Kit (R&D Systems, Bio-Techne, Minneapolis, USA) and pseudotype-based neutralizing antibody assay. Using sequential serum samples collected from 100 COVID-19 recovered individuals from northern Italy—mostly with mild disease—at 2 and 10 months after their first positive PCR test, we show that 93% of them seroconverted at 2 months, with a geometric mean (GeoMean) half-maximal neutralization titer (NT50) of 387.9. Among the 35 unvaccinated subjects retested at 10 months, 7 resulted seronegative, with an 80% drop in seropositivity, while 28 showed dec...
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HSP90 is secreted by cancer cells into the extracellular milieu, where it exerts protumoral activities by activating extracellular substrate proteins and triggering autocrine signals through cancer cell surface receptors. Emerging... more
HSP90 is secreted by cancer cells into the extracellular milieu, where it exerts protumoral activities by activating extracellular substrate proteins and triggering autocrine signals through cancer cell surface receptors. Emerging evidence indicates that HSP90 co-chaperones are also secreted and may direct HSP90 extracellular activities. In this study, we found that the HSP90 co-chaperone Morgana is released by cancer cells and, in association with HSP90, induces cancer cell migration through TLR2, TLR4, and LRP1. In syngeneic cancer mouse models, a mAb targeting Morgana extracellular activity reduced primary tumor growth via macrophage-dependent recruitment of CD8+ T lymphocytes, blocked cancer cell migration, and inhibited metastatic spreading. Overall, these data define Morgana as a new player in the HSP90 extracellular interactome and suggest that Morgana may regulate HSP90 activity to promote cancer cell migration and suppress antitumor immunity. Significance: This work suggest...
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A causal link between viral infections and autoimmunity has been studied for a long time and the role of some viruses in the induction or exacerbation of systemic lupus erythematosus (SLE) in genetically predisposed patients has been... more
A causal link between viral infections and autoimmunity has been studied for a long time and the role of some viruses in the induction or exacerbation of systemic lupus erythematosus (SLE) in genetically predisposed patients has been proved. The strength of the association between different viral agents and SLE is variable. Epstein–Barr virus (EBV), parvovirus B19 (B19V), and human endogenous retroviruses (HERVs) are involved in SLE pathogenesis, whereas other viruses such as Cytomegalovirus (CMV) probably play a less prominent role. However, the mechanisms of viral–host interactions and the impact of viruses on disease course have yet to be elucidated. In addition to classical mechanisms of viral-triggered autoimmunity, such as molecular mimicry and epitope spreading, there has been a growing appreciation of the role of direct activation of innate response by viral nucleic acids and epigenetic modulation of interferon-related immune response. The latter is especially important for ...
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Interleukin-1β (IL-1β) is a key effector of the inflammasome complex in response to pathogens and danger signals. Although it is well known that assembly of the inflammasome triggers proteolytic cleavage of the biologically inactive... more
Interleukin-1β (IL-1β) is a key effector of the inflammasome complex in response to pathogens and danger signals. Although it is well known that assembly of the inflammasome triggers proteolytic cleavage of the biologically inactive precursor pro-IL-1β into its mature secreted form, the mechanism by which human cytomegalovirus (HCMV) regulates IL-1β production via the inflammasome is still poorly understood. Here, we show that the infection of human foreskin fibroblasts (HFFs) with a mutant HCMV lacking the tegument protein pp65 (v65Stop) results in higher expression levels of mature IL-1β compared to its wild-type counterpart, suggesting that pp65 mediates HCMV immune evasion through downmodulation of IL-1β. Furthermore, we show that enhanced IL-1β production by the v65Stop mutant is due in part to induction of DNA binding and the transcriptional activity of NF-κB. Lastly, we demonstrate that HCMV infection of HFFs triggers a non-canonical IL-1β activation pathway where caspase-8 p...
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The assembly of human cytomegalovirus (HCMV) virions is an orchestrated process that requires, as an essential prerequisite, the complex crosstalk between viral structural proteins. Currently, however, the mechanisms governing the... more
The assembly of human cytomegalovirus (HCMV) virions is an orchestrated process that requires, as an essential prerequisite, the complex crosstalk between viral structural proteins. Currently, however, the mechanisms governing the successive steps in the constitution of virion protein complexes remain elusive. Protein phosphorylation is a key regulator determining the sequential changes in the conformation, binding, dynamics, and stability of proteins in the course of multiprotein assembly. In this review, we present a comprehensive map of the HCMV virion proteome, including a refined view on the virion phosphoproteome, based on previous publications supplemented by new results. Thus, a novel dataset of viral and cellular proteins contained in HCMV virions is generated, providing a basis for future analyses of individual phosphorylation steps and sites involved in the orchestrated assembly of HCMV virion-specific multiprotein complexes. Finally, we present the current knowledge on t...
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The human cytomegalovirus (HCMV) is a widespread pathogen and is associated with severe diseases in immunocompromised individuals. Moreover, HCMV infection is the most frequent cause of congenital malformation in developed countries.... more
The human cytomegalovirus (HCMV) is a widespread pathogen and is associated with severe diseases in immunocompromised individuals. Moreover, HCMV infection is the most frequent cause of congenital malformation in developed countries. Although nucleoside analogs have been successfully employed against HCMV, their use is hampered by the occurrence of serious side effects. There is thus an urgent clinical need for less toxic, but highly effective, antiviral drugs. Strigolactones (SLs) are a novel class of plant hormones with a multifaceted activity. While their role in plant-related fields has been extensively explored, their effects on human cells and their potential applications in medicine are far from being fully exploited. In particular, their antiviral activity has never been investigated. In the present study, a panel of SL analogs has been assessed for antiviral activity against HCMV. We demonstrate that TH-EGO and EDOT-EGO significantly inhibit HCMV replication in vitro, impai...
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Sjoegren’s syndrome (SS) is a chronic autoimmune disease characterized. [...]
Research Interests: Proceedings and MDPI
To examine the expression of Ifi 200 genes in vivo and add new information about their function, polyclonal monospecific rabbit antibodies, designated N-term or C-term, were raised against both the N-terminus and C-terminus of the 204... more
To examine the expression of Ifi 200 genes in vivo and add new information about their function, polyclonal monospecific rabbit antibodies, designated N-term or C-term, were raised against both the N-terminus and C-terminus of the 204 protein (p204) respectively. Western blotting analysis demonstrated that p204 and D3, another member of the Ifi 200 gene family, are constitutively expressed, though at different degrees, in bone marrow, thymus and lymph nodes, and barely detectable in the spleen. Poly rI:rC treatment did not modulate their expression. Peritoneal resident macrophages (Mphi) from untreated mice were negative, but displayed high levels of both p204 and D3 on poly rI:rC treatment. A significant increase of these proteins is also observed when Mphi are cultured overnight in vitro with IFNs or LPS. Lung, kidney and brain were negative for p204 and D3 expression. These results, together with immunohistochemical analysis, demonstrate that the 204 gene has an expression pattern restricted to cells of the myelomonocytic lineage similar to that observed for the human homolog, the myeloid nuclear differentiation antigen (MNDA) suggesting its potential involvement in the differentiation and maturation of this cell lineage.
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The germline encoded proteins serving as "pattern recognition receptors" (PRRs) constitute the earliest step in the innate immune response by recognizing the "pathogen-associated molecular patterns" (PAMPs) that... more
The germline encoded proteins serving as "pattern recognition receptors" (PRRs) constitute the earliest step in the innate immune response by recognizing the "pathogen-associated molecular patterns" (PAMPs) that comprise microbe nucleic acids and proteins usually absent from healthy hosts. Upon detection of exogenous nucleic acid two different innate immunity signaling cascades are activated. The first culminates in the production of chemokines, cytokines, and type I interferons (IFN-I), while the second leads to inflammasome complex formation. Human cytomegalovirus (HCMV), a member of the -herpesvirus subfamily, is a wide spread pathogen that infects a vast majority of the world's population. The virion has an icosahedral capsid that contains a linear dsDNA genome of approximately 240 kb, surrounded by an outer lipid envelope and a proteinaceous tegument containing several viral proteins. Despite the numerous and multifaceted antiviral effects of IFNs and c...
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Many malignancies that occur in high excess in kidney transplant recipients (KTRs) are due to viruses that thrive in the setting of immunosuppression. Keratinocyte carcinoma (KC), the most frequently occurring cancer type in KTR, has been... more
Many malignancies that occur in high excess in kidney transplant recipients (KTRs) are due to viruses that thrive in the setting of immunosuppression. Keratinocyte carcinoma (KC), the most frequently occurring cancer type in KTR, has been associated with skin infection by human papillomavirus (HPV) from the beta genus. In this report, we extend our previous investigation aimed at identifying the presence of active β-HPV infection in skin tumors from KTRs through detection of viral protein expression. Using a combination of antibodies raised against the E4 and L1 proteins of the β-genotypes, we were able to visualize infection in five tumors [one keratoacanthoma (KA), three actinic keratoses (AKs), and one seborrheic keratoses (SKs)] that were all removed from two patients who had been both transplanted twice, had developed multiple KCs, and presented with a long history of immunosuppression (>30 years). These infected tissues displayed intraepidermal hyperplasia and increased exp...
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β-HPV cause near ubiquitous latent skin infection within long-lived hair follicle keratinocyte stem cells (HF KSC). In patients with epidermodysplasia verruciformis (EV), β-HPV viral replication is associated with skin keratosis and... more
β-HPV cause near ubiquitous latent skin infection within long-lived hair follicle keratinocyte stem cells (HF KSC). In patients with epidermodysplasia verruciformis (EV), β-HPV viral replication is associated with skin keratosis and cutaneous squamous cell carcinoma (SCC). To determine the role of HF KSC in β-HPV induced skin carcinogenesis, we utilized a transgenic mouse model in which the keratin 14 promoter drives expression of the entire HPV8 early region (HPV8tg). HPV8tg mice developed thicker skin in comparison to wild type littermates consistent with a hyperproliferative epidermis. HF keratinocyte proliferation was evident within the Lrig1+ KSC population (69 vs 55%, p<0.001, n=6), and not in the CD34+, LGR5+ and LGR6+ KSC populations. This was associated with a 2.8-fold expansion in Lrig1+ keratinocytes and 3.8 fold increased colony forming efficiency. Consistent with this, we observed nuclear p63 expression throughout this population and the HF infundibulum and adjoining...
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Inflammatory bowel disease (IBD) is characterized by a chronic inflammation of the gut, partly driven by defects in the expression and function of pattern recognition receptors, including the IFI16 protein. Because this protein is a... more
Inflammatory bowel disease (IBD) is characterized by a chronic inflammation of the gut, partly driven by defects in the expression and function of pattern recognition receptors, including the IFI16 protein. Because this protein is a target for autoantibodies and its aberrant expression was reported in colonic mucosa from active patients with ulcerative colitis, we studied its expression and specific seroresponse in patients with IBD before and after infliximab (IFX) therapy. Anti-IFI16 antibodies (IgG and IgA subtypes) were measured in the sera of 74 patients with IBD: 48 patients with Crohn's disease (CD) and 26 patients with ulcerative colitis, prospectively harvested before and after IFX therapy. Anti-GP2 antibodies (both IgG and IgA subtypes) were also tested for comparison. The patient antibody statuses were qualitatively and quantitatively associated with disease phenotype and response to IFX therapy. Significantly higher titers of anti-IFI16 IgG were found in both CD and ...
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A key player in the intrinsic resistance against human cytomegalovirus (HCMV) is the interferon-γ-inducible protein 16 (IFI16), which behaves as a viral DNA sensor in the first hours post infection and as a repressor of viral gene... more
A key player in the intrinsic resistance against human cytomegalovirus (HCMV) is the interferon-γ-inducible protein 16 (IFI16), which behaves as a viral DNA sensor in the first hours post infection and as a repressor of viral gene transcription in the later stages. Previous studies on HCMV replication demonstrated that IFI16 binds to the viral protein kinase pUL97, undergoes phosphorylation and relocalizes to the cytoplasm of infected cells. In this study, we demonstrate that the tegument protein pp65 (pUL83) recruits IFI16 to the promoter of the UL54 gene and downregulates viral replication as shown by use of the HCMV mutant v65Stop, which lacks pp65 expression. Interestingly, at late time-points of HCMV infection, IFI16 is stabilized by its interaction with pp65, which stood in contrast to IFI16 degradation, observed in herpes simplex virus (HSV-1)-infected cells. Moreover, we found that its translocation to the cytoplasm, in addition to pUL97, strictly depends on pp65, as demonst...
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The nuclear pathogenic DNA sensor IFI16, induced by several pro-inflammatory cytokines, is a multifaceted protein with various functions. As recently demonstrated by our group, it acts as a viral restriction factor against HCMV... more
The nuclear pathogenic DNA sensor IFI16, induced by several pro-inflammatory cytokines, is a multifaceted protein with various functions. As recently demonstrated by our group, it acts as a viral restriction factor against HCMV replication by down-regulating viral early and late but not immediate-early mRNAs as well as their protein expression. Following transfection of virus-derived DNA, or treatment with UVB, IFI16 delocalizes from the nucleus to the cytoplasm and is then eventually released into the extracellular milieu. Our recent results indicate a unique feature displayed by HCMV to overcome the restriction of IFI16, by its upregulation and further mislocalization into egressing virions during the early stages of HCMV infection. IFI16 is also a target for autoantibodies as specific antibodies have been demonstrated in the sera of patients affected by systemic autoimmune diseases. With our latest experiments using an in-house capture ELISA, we demonstrate that significant levels of IFI16 protein can also exist as circulating form in the sera of autoimmune patients. We also show that free rIFI16 protein severely limits tubulogenesis and transwell migration activities of endothelial cells, while these inhibitory effects are fully reversed in the presence of anti-IFI16 N-terminal antibodies, indicating that its extracellular activity resides within the N-terminus. Furthermore, our in vivo results show that endogenous IFI16 released by apoptotic cells bind neighboring cells in a co-culture. Immunofluorescence assays revealed existence of high-affinity binding sites on the plasma membrane of endothelial cells, whose characterization is currently in progress. Altogether, our data demonstrate that IFI16 inside a cell can act as viral restriction factor, which can be evaded by herpes viruses, while outside the cell IFI16 can exist as circulating protein in the sera of autoimmune patients which bind endothelial cells causing damage, suggesting a new inflammatory and alarmin function. Proteomic analysis is being performed to characterize the intracellular signaling triggered by extracellular IFI16 and dissect the molecular mechanisms behind its inflammatory role.
Research Interests: Immunology and Cytokine
The interferon-inducible DNA sensor IFI16 is involved in the modulation of cellular survival, proliferation, and differentiation. In the hematopoietic system, IFI16 is consistently expressed in the CD34+ stem cells and in peripheral blood... more
The interferon-inducible DNA sensor IFI16 is involved in the modulation of cellular survival, proliferation, and differentiation. In the hematopoietic system, IFI16 is consistently expressed in the CD34+ stem cells and in peripheral blood lymphocytes; however, little is known regarding its regulation during maturation of B- and T-cells. We explored the role of IFI16 in normal B-cell subsets by analysing its expression and relationship with the major transcription factors involved in germinal center (GC) development and plasma-cell (PC) maturation.IFI16mRNA was differentially expressed in B-cell subsets with significant decrease inIFI16mRNA in GC and PCs with respect to naïve and memory subsets.IFI16mRNA expression is inversely correlated with a few master regulators of B-cell differentiation such asBCL6, XBP1, POU2AF1, andBLIMP1. In contrast,IFI16expression positively correlated withSTAT3, REL, SPIB, RELA, RELB, IRF4, STAT5B, andSTAT5A. ARACNE algorithm indicated a direct regulation...
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ABSTRACTThe human interferon-inducible IFI16 protein, an innate immune sensor of intracellular DNA, was recently demonstrated to act as a restriction factor for human cytomegalovirus (HCMV) and herpes simplex virus 1 (HSV-1) infection by... more
ABSTRACTThe human interferon-inducible IFI16 protein, an innate immune sensor of intracellular DNA, was recently demonstrated to act as a restriction factor for human cytomegalovirus (HCMV) and herpes simplex virus 1 (HSV-1) infection by inhibiting both viral-DNA replication and transcription. Through the use of two distinct cellular models, this study provides strong evidence in support of the notion that IFI16 can also restrict human papillomavirus 18 (HPV18) replication. In the first model, an immortalized keratinocyte cell line (NIKS) was used, in which the IFI16 protein was knocked down through the use of small interfering RNA (siRNA) technology and overexpressed following transduction with the adenovirus IFI16 (AdVIFI16) vector. The second model consisted of U2OS cells transfected by electroporation with HPV18 minicircles. In differentiated IFI16-silenced NIKS-HPV18 cells, viral-load values were significantly increased compared with differentiated control cells. Consistent wit...
Research Interests: Biology, Virology, Epigenetics, Innate immunity, Medicine, and 15 moreBiological Sciences, HUMAN PAPILLOMAVIRUS, Humans, Keratinocytes, Histone Modifications, HPV, Cell nucleus, DNA sensors, IFI, Host Pathogen Interactions, Innate Host Restriction Factors, minicircle technology, hin, Papillomavirus Infections, and Medical and Health Sciences
The nuclear interferon-inducible-16 (IFI16) protein acts as DNA sensor in inflammasome signaling and as viral restriction factor. Following Herpesvirus infection or UV-B treatment, IFI16 delocalizes from the nucleus to the cytoplasm and... more
The nuclear interferon-inducible-16 (IFI16) protein acts as DNA sensor in inflammasome signaling and as viral restriction factor. Following Herpesvirus infection or UV-B treatment, IFI16 delocalizes from the nucleus to the cytoplasm and is eventually released into the extracellular milieu. Recently, our group has demonstrated the occurrence of IFI16 in sera of systemic-autoimmune patients that hampers biological activity of endothelia through high-affinity membrane binding. As a continuation, we studied the activity of endotoxin-free recombinant IFI16 (rIFI16) protein on primary endothelial cells. rIFI16 caused dose/time-dependent upregulation of IL-6, IL-8, CCL2, CCL5, CCL20, ICAM1, VCAM1, and TLR4, while secretion of IL-6 and IL-8 was amplified with lipopolysaccharide synergy. Overall, cytokine secretion was completely inhibited in MyD88-silenced cells and partially by TLR4-neutralizing antibodies. By screening downstream signaling pathways, we found that IFI16 activates p38, p44/...
Research Interests: Immunology, Biology, Cytokines, Inflammation, Autoimmunity, and 15 moreInnate immunity, Biological Sciences, Humans, Autoimmune diseases, Lipopolysaccharides, DNA sensors, IFI, Inflammasome, HCMV, Inflammasomes, Danger Signals, Innate Host Restriction Factors, Gene Expression Regulation, Medical and Health Sciences, and Human Umbilical Vein Endothelial Cells
IFI16, a member of the IFN-inducible PYHIN-200 gene family, displays multifaceted activity due to its ability to bind to various target proteins and, in turn, modulate a variety cell functions including proliferation, differentiation,... more
IFI16, a member of the IFN-inducible PYHIN-200 gene family, displays multifaceted activity due to its ability to bind to various target proteins and, in turn, modulate a variety cell functions including proliferation, differentiation, apoptosis/pyroptosis, senescence, and in?ammation. The last few year have seen major advances in our knowledge of IFI16 antiviral activity and its role in the immune response. Indeed, a wealth of evidence now supports a key role of IFI16 in the activation of innate immunity and viral restriction against Herpesviruses and Lentiviruses, such that the definition of IFI16 as a "restriction factor" is now widely accepted. However, most viruses have developed their own unique strategy to antagonize IFI16, leading to a modification or disruption of its function. This review summarizes our current understanding of how viral replication is sensed and then inhibited by IFI16 protein and the viral strategies employed to defeat this host defense mechanis...
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The association between human papillomavirus (HPV) DNA positivity, p53 codon 72 polymorphisms, and the type of leukocyte infiltration in head and neck squamous cell carcinomas (HNSCC) and their combined impact upon patient survival is... more
The association between human papillomavirus (HPV) DNA positivity, p53 codon 72 polymorphisms, and the type of leukocyte infiltration in head and neck squamous cell carcinomas (HNSCC) and their combined impact upon patient survival is poorly investigated. For this reason, leukocyte infiltration profile and p53 codon 72 polymorphisms were assessed in freshly removed HNSCC specimens (N=71 patients). HPV detection was performed by nested-PCR followed by DNA sequencing. Viral loads were determined by quantitative RT-PCR. The choice to investigate fresh instead of archive paraffin-embedded specimens was privileged to avoid possible artifacts due to sample processing. HPV DNA was detected in 14% of cases. Oropharyngeal carcinomas were the most frequently associated with the presence of HPV16 DNA (41%) and were associated with p53 Pro/Pro or Pro/Arg polymorphisms. In HPV16-positive oropharyngeal carcinomas increased infiltrations of CD3+ and FoxP3+ T-cells correlated with higher HPV16 copy...
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To evaluate the presence of autoantibodies to the high mobility group (HMG) structure specific recognition protein I (SSRP1) in sera from patients with systemic lupus erythematosus (SLE) or other rheumatic diseases. Antibodies to... more
To evaluate the presence of autoantibodies to the high mobility group (HMG) structure specific recognition protein I (SSRP1) in sera from patients with systemic lupus erythematosus (SLE) or other rheumatic diseases. Antibodies to SSRP1(anti-SSRP1) were measured in sera from patients with SLE, Sjogren's syndrome (SS), ulcerative colitis (UC), systemic sclerosis (SSc), rheumatoid arthritis (RA), and sera from healthy individuals by both an enzyme-linked immunoassay (ELISA) and Western blotting (WB) using the recombinant SSRP1 N-terminus as antigen. We found 28.8% of the sera from patients with SLE contained anti-SSRPI by both ELISA and WB assay, compared to 8.3% of the sera from healthy individuals. When the 40 sera from patients with other autoimmune diseases were tested, only 2 sera (5%) from individuals with SS showed a moderate reactivity to SSRPI in both ELISA and WB assays. The results show that anti-SSRPI can be identified in sera from patients with SLE, but not with other ...
Research Interests: Rheumatology, Immunology, Molecular Biology, Autoimmunity, Rheumatoid Arthritis, and 15 moreMedicine, Western blotting, Humans, Systemic Lupus Erythematosus, Autoimmune diseases, Ulcerative colitis, The, Clinical Sciences, Antibody, Public health systems and services research, Sjogren´s Syndrome, DNA binding proteins, Enzyme Linked Immunosorbent Assay, Autoantibodies, and High mobility group proteins
The nuclear DNA sensor IFI16, a member of PYHIN family of proteins, was previously studied for its role in cell cycle regulation, tumor suppression, apoptosis and DNA damage signaling. Autoantibodies against IFI16 are prevalent in the... more
The nuclear DNA sensor IFI16, a member of PYHIN family of proteins, was previously studied for its role in cell cycle regulation, tumor suppression, apoptosis and DNA damage signaling. Autoantibodies against IFI16 are prevalent in the sera of patients with systemic autoimmunity, thus depicting physiological significance as an autoantigen. At present, the nuclear IFI16 protein has been thoroughly investigated for its role as an innate immune sensor involved in inflammasome signaling and viral restriction. While the sub-cellular localization of IFI16 during such events has been known, very little knowledge about its presence and significance in the extracellular space is available. Recently our group has discovered the presence of circulating IFI16 in the sera from systemic autoimmune patients indicating that in this setting it may be mislocalized form its nuclear site and secreted in the extracellular milieu. In this review, we will discuss the leakage of endogenous IFI16 that has be...
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Human papillomavirus (HPV) infections are normally controlled by an intact cell-mediated and humoral immune system. Patients with cell-mediated immunodeficiencies, whether primary, secondary or iatrogenic are all, therefore, at increased... more
Human papillomavirus (HPV) infections are normally controlled by an intact cell-mediated and humoral immune system. Patients with cell-mediated immunodeficiencies, whether primary, secondary or iatrogenic are all, therefore, at increased risk of developing extensive, persistent and recurrent warts.(1) The sequestration of HPV in epithelial cells can however provide protection for the virus, resulting in inefficient activation of innate immunity, poor priming of the adaptive response and permits infections to persist, even in immunocompetent individuals.(2) In addition, genome variations, especially those enhancing viral promoter activities, have been associated with enhanced viral replication and unusual clinical manifestations.(3-5) This article is protected by copyright. All rights reserved.
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Cellular proteins called 'restriction factors' (RFs) form an important component of the innate immune response to viral replication. However, viruses have learned how to antagonize RFs through mechanisms that are specific for each... more
Cellular proteins called 'restriction factors' (RFs) form an important component of the innate immune response to viral replication. However, viruses have learned how to antagonize RFs through mechanisms that are specific for each virus. Here, we summarize the general hallmarks of RFs before going on to discuss the specific strategies recruited by some key RFs that strive to hold human CMV (HCMV) infection back, as well as the counter-restriction mechanisms employed by the virus to overcome this innate defense. Such RFs include the cellular constituents of nuclear domain 10 (ND10), and IFI16, a nuclear member of the PYHIN protein family. Viral regulatory proteins, such as IE1 or pp71, try to oppose the ND10-induced blockade of virus replication by either modifying or disrupting this RF. IFI16, on the other hand, inhibits virus DNA synthesis by downregulating the transcription of viral gene UL54; the intruding virus attempts to antagonize IFI16 by mislocalizing it from the nu...
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Research Interests: Immunology, Biology, Innate immunity, Cercopithecus aethiops, Humans, and 15 moreAnimals, Cytomegalovirus, Interferon, IFI, Chromatin Immunoprecipitation, Cytomegalovirus Infections, HCMV, DNA Copy Number, Embryos, Innate Host Restriction Factors, DNA Polymerase, Dna Synthesis, fibroblasts, hin, and Human Cytomegalovirus
Research Interests: Biochemistry, Genetics, Immunology, Genomics, Kinetics, and 15 moreCancer, Biology, Autoimmunity, Cell Biology, Cancer Biology, DNA, Autoimmune diseases, Interferon, Cell nucleus, IFI, Enzyme Linked Immunosorbent Assay, Extracellular Space, Autoantibodies, Cell Membrane, and Human Umbilical Vein Endothelial Cells
Research Interests: Biology, Kidney transplantation, Histology, Immunohistochemistry, Clinical Biochemistry, and 15 moreApoptosis, Medicine, Clinical Chemistry, Italy, Cytogenetics, Humans, Female, Male, Polymerase Chain Reaction, Aged, Middle Aged, Basal cell carcinoma, Papillomavirus Infections, Medical and Health Sciences, and Modern Pathology
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Objective Several studies have shown the presence of anti-IFI16 antibodies in systemic lupus erythematosus (SLE), Sjögren Syndrome (SjS), systemic sclerosis (SSc) and other autoimmune diseases. However, the significance of anti-IFI16... more
Objective Several studies have shown the presence of anti-IFI16 antibodies in systemic lupus erythematosus (SLE), Sjögren Syndrome (SjS), systemic sclerosis (SSc) and other autoimmune diseases. However, the significance of anti-IFI16 antibodies in SLE has not been fully characterized. The aim of this study was to investigate associations between anti-IFI16 antibodies and clinical and serologic parameters of SLE. Methods An enzyme-linked immunosorbent assay (ELISA) kit was used to measure anti-IFI16 antibodies in the sera of 168 SLE patients, 46 patients with any type of primary glomerulonephritis (GN) and 182 healthy controls (HCs). Associations between anti-IFI16 antibodies and clinical and serologic parameters of SLE were statistically evaluated using both univariate and multivariate analysis. Results Significantly higher anti-IFI16 titres were observed in SLE patients compared to both non-SLE GN and HCs (median levels: 270.1 U/ml vs 132.1 U/ml, p = 0.001, and 52.9 U/ml, p
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Intrinsic immune mechanisms mediated by constitutively expressed proteins termed “restriction factors” provide frontline antiviral defense. We recently demonstrated that the DNA sensor IFI16 restricts human cytomegalovirus (HCMV)... more
Intrinsic immune mechanisms mediated by constitutively expressed proteins termed “restriction factors” provide frontline antiviral defense. We recently demonstrated that the DNA sensor IFI16 restricts human cytomegalovirus (HCMV) replication by downregulating viral early and late but not immediate-early mRNAs and their protein expression. We show here that at an early time point during the in vitro infection of low-passage-number human embryonic lung fibroblasts, IFI16 binds to HCMV DNA. However, during a later phase following infection, IFI16 is mislocalized to the cytoplasmic virus assembly complex (AC), where it colocalizes with viral structural proteins. Indeed, upon its binding to pUL97, IFI16 undergoes phosphorylation and relocalizes to the cytoplasm of HCMV-infected cells. ESCRT (endosomal sorting complex required for transport) machinery regulates the translocation of IFI16 into the virus AC by sorting and trafficking IFI16 into multivesicular bodies (MVB), as demonstrated b...
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The human cytomegalovirus (HCMV) US12 gene family comprises a set of 10 contiguous genes (US12 to US21), each encoding a predicted seven-transmembrane protein and whose specific functions have yet to be ascertained. While inactivation of... more
The human cytomegalovirus (HCMV) US12 gene family comprises a set of 10 contiguous genes (US12 to US21), each encoding a predicted seven-transmembrane protein and whose specific functions have yet to be ascertained. While inactivation of individual US12 family members in laboratory strains of HCMV has not been found to affect viral replication in fibroblasts, inactivation of US16 was reported to increase replication in microvascular endothelial cells. Here, we investigate the properties of US16 further by ascertaining the expression pattern of its product. A recombinant HCMV encoding a tagged version of the US16 protein expressed a 33-kDa polypeptide that accumulated with late kinetics in the cytoplasmic virion assembly compartment. To elucidate the function(s) of pUS16, we generated US16-deficient mutants in the TR clinical strain of HCMV. According to previous studies, inactivation of US16 had no effect on viral replication in fibroblasts. In contrast, the US16-deficient viruses e...
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Primary human embryo lung fibroblasts and adult diploid fibroblasts infected by the human cytomegalovirus (HCMV) display β-galactosidase (β-Gal) activity at neutral pH (senescence-associated β-Gal [SA-β-Gal] activity) and overexpression... more
Primary human embryo lung fibroblasts and adult diploid fibroblasts infected by the human cytomegalovirus (HCMV) display β-galactosidase (β-Gal) activity at neutral pH (senescence-associated β-Gal [SA-β-Gal] activity) and overexpression of the plasminogen activator inhibitor type 1 (PAI-1) gene, two widely recognized markers of the process designated premature cell senescence. This activity is higher when cells are serum starved for 48 h before infection, a process that speeds and facilitates HCMV infection but that is insufficient by itself to induce senescence. Fibroblasts infected by HCMV do not incorporate bromodeoxyuridine, a prerequisite for the formal definition of senescence. At the molecular level, cells infected by HCMV, beside the accumulation of large amounts of the cell cycle regulators p53 and pRb, the latter in its hyperphosphorylated form, display a strong induction of the cyclin-dependent kinase inhibitor (cdki) p16 INK4a , a direct effector of the senescence phenot...
Research Interests: Virology, Cell Cycle, Gene expression, Biological Sciences, Humans, and 13 moreProcess Design, Cytomegalovirus, Phenotype, Cell Cycle regulation, Cytomegalovirus Infections, Cell Cycle Arrest, Virus infection, Embryos, Birth Defect, DNA Polymerase, Plasminogen Activator Inhibitor, Human Cytomegalovirus, and Medical and Health Sciences
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Research Interests: Immunology, Biology, Oxidative Stress, Apoptosis, Medicine, and 13 moreProtein synthesis, Signal Transduction, Humans, Reactive Oxygen Species, Vascular endothelium, Signal Transduction Pathway Models, Hydrogen Peroxide, Time Dependent, Endothelial cell, Cell Cycle Proteins, hin, real time polymerase chain reaction, and Reporter gene
Research Interests: Biology, Medicine, Cell Division, Biological Sciences, Cell Differentiation, and 15 moreHumans, Female, Male, Proteins, Interferon, Digestive System, Buffers, Epithelial cells, Protein isoforms, Citric Acid, Expression analysis, Protein Biosynthesis, Gene Expression Regulation, Interferon gamma, and Medical and Health Sciences
The interferon-inducible p200 family proteins consist of a group of homologous human and mouse proteins that have an N-terminal Pyrin domain and 1 or 2 partially conserved 200 amino acid long C-terminal domains (designated the HIN domain... more
The interferon-inducible p200 family proteins consist of a group of homologous human and mouse proteins that have an N-terminal Pyrin domain and 1 or 2 partially conserved 200 amino acid long C-terminal domains (designated the HIN domain or p200 X domain). These proteins display multifaceted activity due to their ability to bind to various target proteins (eg, transcription factors, signaling proteins, and tumor suppressor proteins) and modulate different cell functions. In addition to a role in interferon biology, increasing evidence supports a role for these proteins as regulators of various cell functions, including proliferation, differentiation, apoptosis, senescence, inflammasome assembly, and control of organ transplants. As a consequence, alterations in their expression and function may be of relevance in the pathogenesis of human diseases, such as systemic autoimmune syndromes, tumors, and degenerative diseases. This review summarizes the literature describing these data, highlights some of the important findings derived from recent studies, and speculates about future perspectives.
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The human interferon (IFN)-inducible IFI16 protein is a member of the 200-amino acid repeat family encoded by the HIN-200 genes. Forced IFI16 expression in normal human endothelial cells (ECs) inhibits cell growth and tube morphogenesis... more
The human interferon (IFN)-inducible IFI16 protein is a member of the 200-amino acid repeat family encoded by the HIN-200 genes. Forced IFI16 expression in normal human endothelial cells (ECs) inhibits cell growth and tube morphogenesis of ECs through the triggering of apoptosis by caspase-2 and caspase-3 via nuclear factor-κB (NF-κB) complex activation. Accumulating evidence suggests that tumor-derived ECs (TECs) possess a distinct and unique phenotype compared with normal ECs, and they may be able to acquire resistance to antiangiogenic agents such as IFNs. However, few functional studies are available on cultured TEC. In the present study, we have demonstrated that TEC obtained from tumors of various histological origin, namely kidney (Eck25), breast (B-TEC), and head and neck (HN4), continued to proliferate and generate microtubules on Matrigel following IFI16 overexpression. In contrast to normal ECs, they were resistant to apoptosis triggered by caspase-2 and caspase-3 activation via the NF-κB complex. At the molecular level, when overexpressed in TEC, IFI16 appeared unable to regulate NF-κB activity and lead to caspase activation. Altogether, these results indicate that TECs display abnormal responses, in terms of survival and angiogenic properties, to an antiproliferative and antiangiogenic IFN-inducible gene such as IFI16.
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We have used yeast two-hybrid screening to isolate cDNA-encoding proteins interacting with the protein encoded by the interferon (IFN)-inducible gene Ifi204. Four independent overlapping clones were isolated from an NIH3T3 cDNA library.... more
We have used yeast two-hybrid screening to isolate cDNA-encoding proteins interacting with the protein encoded by the interferon (IFN)-inducible gene Ifi204. Four independent overlapping clones were isolated from an NIH3T3 cDNA library. The largest clone encoded a protein (1203 amino acids in length) sharing 94% identity with the C-terminal portion of the human translocated promoter region (Tpr) protein. Northern blot analysis revealed a 7.5-kilobase mRNA present in both mouse and human cell lines. In addition, in vivo interaction was demonstrated by coimmunoprecipitation experiments. Anti-Tpr polyclonal monospecific antibodies (Ab) used for immunofluorescence staining labeled the nuclear envelope (NE) in a punctate pattern characteristic of nucleoporins and also yielded staining throughout the nuclear interior. The intranuclear Tpr occurred in apparently discrete foci. When superimposed on optical sections obtained with anti-p204 Abs, these colocalized, with the sole exception of the nucleolar compartment stained by the anti-p204 Abs only. Although the specific function of Tpr is not defined, it appears to mediate p204 translocation from the cytoplasmic to the nuclear compartment following IFN treatment.
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Research Interests: Regeneration, Skeletal muscle biology, Calcium, Biological Chemistry, Biological Sciences, and 15 moreCell line, Fluorescence in situ hybridization, Mice, Animals, Biological, CHEMICAL SCIENCES, Molecular cloning, Fluorescent Antibody Technique, Rats, Myocardium, X chromosome, Amino Acid Sequence, Cytoplasm, Molecular Sequence Data, and Medical and Health Sciences
Type I interferons (IFNs) are key cytokines endowed with antiviral and immunomodulatory activities. The human type I IFN family consists of 13 subtypes of IFNa, a single IFNb subtype, plus IFNε, IFNk, and IFNv. Type I IFNs exert their... more
Type I interferons (IFNs) are key cytokines endowed with antiviral and immunomodulatory activities. The human type I IFN family consists of 13 subtypes of IFNa, a single IFNb subtype, plus IFNε, IFNk, and IFNv. Type I IFNs exert their biological activities via interaction with a heterodimeric receptor complex – a cell surface receptor composed of two subunits, namely IFNaR1 and IFNaR2. Ligand binding initiates a transcriptional program that leads to the expression of the IFN-regulated genes (IRGs) responsible for the multifaceted activity of type I IFNs. Optimal outcomes of these cytokines are achieved through regulation of the nature, strength, and duration of IFN production; IFN–receptor interaction; and specific signaling pathways that are modulated in a cell type–specific manner. When virus-infected cells are exposed to IFN, they develop what is known as an 'antiviral state,' regulated by the IRGs, in which the viral life cycle is blocked or impaired. However, viruses have developed an impressive array of tactics to circumvent IFN-mediated antiviral responses. Type I IFNs also induce a broad spectrum of cell activities, including cell proliferation and differentiation, angiogenesis, and immunomodulation, regulated by the release of mediators relevant for the innate and adaptive immune responses. Detailed knowledge about how these pathways are regulated will, in turn, further our understanding of the roles of IFN pathways in the pathogenesis of infectious and inflammatory diseases and cancer.