Angela Battistini's scientific contributionswhile working at Istituto Superiore di Sanità and other institutions
- Abstract: Exposure of a number of murine and human cell lines to low graded doses of cycloheximide (CXM) results in a pattern of protein synthesis consisting of enhanced and induced species. These can be divided into two main classes according to molecular weight (20-40 and 70-120 Kd), similar to what has been described for other agents that modify the physiological conditions of growth. In addition, the pronounced synthesis of a hitherto unreported 50-Kd protein species has been consistently observed... Show More
- Abstract: The pattern of Interferon (IFN) production in virus-infected cells has been compared with the rate of bulk cellular protein synthesis, on one hand, and with the synthesis of representative cell and virus proteins such as actin, the γ and the NP proteins of encephalomyocarditis (EMC) and Newcastle Disease (NDV) viruses, on the other hand. This was investigated under conditions of impaired protein synthesis such as i) high osmolarity media, ii) a virus-induced shut-off, and iii) in cells... Show More
- Abstract: Analysis of expression of the Friend murine leukemia virus (F-MuLV) and of the spleen focus forming virus (SFFV) has been undertaken in highly malignant interferon (IFN)-sensitive (745) and IFN-resistant (3Cl-8) Friend leukemia cells (FLC), serially passaged intraperitoneally in DBA/2 mice. In vivo passaged 745 cells, as well as the clones derived thereof, did not release Friend virus (FV). Western blot analysis of the plasma membrane fractions of the virus nonproducer 745 cells revealed the... Show More
- Abstract: The replication of Friend Leukemia virus (FLV) has been investigated in adhesive clones (FF) of Friend Leukemia cells which were selected via cultivation on top of human fibroblast monolayers. In these adhesive clones a shut-down of FLV production is observed under conditions of culture confluency; this finding is not due either to a reduced number of cell divisions nor to a defective expression of FLV genome as assessed by Northern blot and immunofluorescence studies. Ultrastructural... Show More
- Abstract: Infection of L929 murine cells with vesicular stomatitis virus (VSV) results in inhibition of host protein synthesis and appearance of membrane alterations at a time when cells are still actively engaged in viral protein synthesis. VSV temperature-sensitive (ts) mutants have been used to explore the role(s) played by the virus-coded proteins in the genesis of these effects. Cells were infected with each of fivets mutants representing the known complementation groups of VSV Indiana serotype,... Show More
- Abstract: The irreversible inhibition of overall protein synthesis induced by diphtheria toxin in mammalian cells is accompanied by a peculiar pattern of synthesized protein species during the early stages of cell intoxication. This pattern closely resembles patterns of synthesized protein species observed in cells treated with reversible inhibitors of protein synthesis acting at different levels. Synthesized proteins are in the Mr range of 70-100 and 20-40 kDa. A 50-kDa protein, the most represented... Show More
- Abstract: Exposure of a number of quiescent murine and human cell lines to low-graded doses of cycloheximide (CXM) results in a pattern of protein synthesis consisting of enhanced and induced species. This pattern is reminiscent of but not identical to that observed after several stress treatments [V. Sorrentino et al. (1985) J. Cell. Physiol. 125, 313]. A pattern identical to that seen after exposure to CXM is synthesized when cells are exposed to an hypertonic growth medium resulting in a full and... Show More
- Abstract: In FLC cultures exposed separately to three different murine IFN types (alpha1, beta, and gamma), IFN-β enhances chemically induced erythroid differentiation, whereas IFN-α1 and IFN-γ do not affect the differentiation process up to a threshold dosage, and then, at higher doses, they inhibit it. The observation that low doses of IFN-β are sufficient to induce the stimulatory effect may suggest a higher susceptibility of erythroid cells to this type of IFN. In regard to this point, it has... Show More
- Abstract: The interferons comprise a group of proteins first identified by their ability to protect cells against virus infections but also capable of influencing cellular physiology. They are synthesized and secreted by a variety of cell types in response to various inducers. Their effects include antiviral action, inhibition of cell proliferation, modulation of cell differentiation and activation of various cell types in immune system. This review aims to summarize the current state of biology of... Show More
- Abstract: Treatment of cells with interferons (IFNs) induces resistance to virus infection. The 2'-5'oligo A (2-5A) synthetase/RNase L is one of the pathways leading to translation inhibition induced by IFN treatment. A murine cDNA encoding the 43-kDa 2-5A synthetase was cloned and sequenced. NIH-3T3 cell clones transfected with this cDNA expressed the enzymatic activity to various extents and exhibited resistance to encephalomyocarditis virus (EMCV) but not to vesicular stomatitis virus replication.... Show More
- Abstract: Administration of highly purified preparations of murine interferon (IFN)-alpha 1, -alpha 4, -alpha 6, or -beta to Friend leukemia cells induced to differentiate by dimethyl sulfoxide leads to a 100% increase of benzidine-positive (B+) cells. Different efficiencies for the two IFN species have been observed; a 10-fold higher dose of IFN-alpha is needed for stimulation of hemoglobin production and inhibition of cell growth as compared with IFN-beta. Both species of IFN induce a substantial... Show More
- Abstract: Treatment of Friend erythroleukemia cells (FLC) with gamma interferon (IFN-gamma) in the presence of anti-IFN-beta antibodies reduces the effectiveness of the antiviral state and the induction of 2'-5'-oligoadenylate synthetase activity, indicating that the antiviral activity of IFN-gamma in FLC is in part mediated by the production of IFN-beta. Accordingly, IFN-gamma induces a less pronounced antiviral state in FLC resistant to IFN-alpha/beta than in wild-type cells. Moreover, while results... Show More
- Abstract: The effect of succinylacetone (SA), a highly specific inhibitor of ALA-dehydratase and heme synthesis, on hemoglobin (Hb) production, transferrin receptor (TfR), and ferritin expression was analyzed in differentiating Friend leukemia cells (FLC). This compound exerted a pronounced inhibitory effect not only on heme and Hb synthesis, but also on all the remaining above-mentioned parameters. In particular, SA induced: (1) a reduction of the level of alpha-globin mRNA; (2) a decreased number of... Show More
- Abstract: The effect of interferons (IFNs) type I (alpha/beta) and type II (gamma) on the stimulation of H2-Dd (class I) and beta 2 microglobulin genes transcription was analysed in IFN-sensitive (w.t.) and IFN-resistant Friend erythroleukemia cells (FLC). Type I IFN enhances the expression of H2-Dd and beta 2 microglobulin genes in w.t. FLC but does not modulate the expression of these genes in clones resistant to IFN-alpha/beta. IFN type II treatment of w.t. and IFN-alpha/beta resistant cell lines... Show More
- Abstract: The mechanisms that regulate the expression of the H chain of the iron storage protein ferritin in Friend erythroleukemia cells (FLCs) after exposure to hemin (ferric protoporphyrin IX), protoporphyrin IX, and ferric ammonium citrate (FAC) have been investigated. Administration of hemin increases the steady-state level of ferritin mRNA about 10-fold and that of ferritin protein expression 20-fold. Experiments with the transcriptional inhibitor actinomycin D and transfection studies... Show More
- Abstract: The clear involvement of the interferon (IFN) system in the regulation of differentiation justifies the advanced IFN clinical trials in “differentiation therapy” of cancer. By employing this strategy, it may be possible to specifically reprogram the phenotype of a tumor cell by inducing its terminal cell differentiation and, thus, the loss of its tumorigenic potential. The effects of IFNs on erythroid differentiation and the related mechanisms are reported. Administration of highly purified... Show More
- Abstract: Ferritin is an ubiquitous iron storage protein that plays a key role in determining the intracellular fate of iron. Therefore, ferritin synthesis is highly regulated by the iron status of the cell through post-transcriptional mechanisms that involve a specific high-affinity interaction between an iron-responsive element (IRE) in the 5' untranslated region of ferritin mRNA and a 98 kDa cytoplasmic protein, the iron-regulatory factor (IRF). The mechanisms that regulate the expression of the... Show More
- Abstract: Hemin and other metalloporphyrins are known as very versatile compounds in nature, because they are able to carry out numerous functions in a free state or in association with specific proteins. When Friend murine erythroleukemia cells are treated with IFN-beta plus 100 mu M hemin, the antiviral state is not observed, whereas the antiviral effect of IFN-gamma is unaffected by hemin treatment. This inhibitory effect of hemin is not restricted to erythroid cells. In fact, it is also observed... Show More
Publications citing this author (2416)
[Show abstract] [Hide abstract] ABSTRACT: The interferon regulatory factor (IRF) family consists of transcriptional regulators that exert multifaceted and versatile functions in multiple biological processes. Their crucial role as central mediators in the establishment and execution of host immunity in response to pathogen-derived signals downstream pattern recognition receptors (PRRs) makes IRFs a hallmark of the host antiviral response. They function as hub molecules at the crossroad of different signaling pathways for the induction of interferon (IFN) and inflammatory cytokines, as well as of antiviral and immunomodulatory genes even in an IFN-independent manner. By regulating the development and activity of immune cells, IRFs also function as a bridge between innate and adaptive responses. As such, IRFs represent attractive and compulsive targets in viral strategies to subvert antiviral signaling. In this study, we discuss current knowledge on the wide array of strategies put in place by pathogenic viruses to evade, subvert, and/or hijack these essential components of host antiviral immunity.
- A number of adaptor signaling proteins in the PRR cascade, including members of the IRF family, are activated by K63-linked ubiquitination. On the other hand, ubiquitinmediated degradation of IRFs is physiologically used as an effective mechanism to dampen IFN overexpression and/or to regulate IRF stability in physiological conditions (Higgs and Jefferies 2008;Battistini 2012;Davis and Gack 2015;Liu and others 2015). Thus, the multifaceted nature of the ubiquitination pathway for protein regulation makes it an attractive target of many viruses.
[Show abstract] [Hide abstract] ABSTRACT: For more than 50 years, Type I Interferon (IFN) has been recognized as critical in controlling viral infections. IFN is produced downstream germ-line encoded pattern recognition receptors (PRRs) upon engagement by pathogen-associated molecular patterns (PAMPs). As a result, hundreds of different interferon-stimulated genes (ISGs) are rapidly induced, acting in both autocrine and paracrine manner to build a barrier against viral replication and spread. ISGs encode proteins with direct antiviral and immunomodulatory activities affecting both innate and adaptive immune responses. During infection with viruses, as HIV-1, that can establish a persistent infection, IFN although produced, is not able to block the initial infection and a chronic IFN-mediated immune activation/inflammation becomes a pathogenic mechanism of disease progression. This review will briefly summarize when and how IFN is produced during HIV-1 infection and the way this innate immune response is manipulated by the virus to its own advantage to drive chronic immune activation and progression to AIDS. Copyright © 2014 Elsevier Ltd. All rights reserved.
- IFN production in response to PRR signaling essentially depends on the presence and activation of a family of transcription factors termed IRFs. Targeting of IRFs by HIV-1 represents a winning strategy to increase virus replication and spread and establishment of viral persistence and latency[14,16,58,59]. The IRF family is presently composed of nine mammalian members namely IRF-1-9, coded by distinct, but related genes that exert multifaceted versatile functions in the regulation of innate and adaptive immune responses. IRF-3 and IRF-7 are essential for the PRR-mediated IFN gene induction with their contribution varying depending on the cell type considered[57,58].
[Show abstract] [Hide abstract] ABSTRACT: The alteration of extracellular matrix (ECM) in cartilage during the pathological development of Osteoarthritis (OA) changes the biomechanical environment of chondrocytes, which further drives the progression of the disease in the presence of inflammation. Healthy cartilage matrix mainly contains collagen type II, which is degraded by matrix metalloproteinase13 (MMP13), an important molecules responsible for joint damage in OA. Cilostazol (6-[4-(1-cyclohexyl-1Htetrazol-5-yl)butoxy]-3,4- dihydro-2-(1H)-quinolinone) is a medication approved by the US Food and Drug Administration and used in the alleviation of the symptom of intermittent claudication in individuals with peripheral vascular disease. In this study, we reported that cilostazol is able to suppress the degradation of type II collagen in human chondrocytes induced by IL-1β. Mechanistically, cilostazol treatment leads to inhibiting the expression of IRF-1, thereby prevents the induction of MMP-13. Signal transducers and activator of transcription 1 (STAT1) has been reported to play an essential role in regulating the activation of IRF-1. Our results indicated that cilostazol supresses the activation of STAT1 by mitigating the phosphorylation of STAT1 at Ser727 and tyrosine phosphorylation of STAT1 at position 701 (Tyr701).
- The immunofluorescence study verified this finding at the protein levels. Signal transducers and activator of transcription 1 (STAT1) has been reported to play an essential role in regulating the activation of IRF-1 . In addition, it has been reported that cAMP could completely inhibit STAT1 activation .
[Show abstract] [Hide abstract] ABSTRACT: A number of chemical compounds have been shown to induce liver tumors in mice but not in other species. While several mechanisms for this species-specific tumorigenicity have been proposed, no definitive mechanism has been established. We examined the effects of the nongenotoxic rodent hepatic carcinogen, WY-14,643, in male mice from a high liver tumor susceptible strain (C3H/HeJ), and from a low tumor susceptible strain (C57BL/6). WY-14,643, a PPARα activator induced widespread increases in the expression of some endogenous retroelements, namely members of LTR and LINE elements in both strains. The expression of a number of known retroviral defense genes was also elevated. We also demonstrated that basal immune-mediated viral defense was elevated in C57BL/6 mice (the resistant strain) and that WY-14,643 further activated those immuno-defense processes. We propose that the previously reported >100X activity of retroelements in mice drives mouse-specific tumorigenicity. We also propose that C57BL/6’s competent immune to retroviral activation allows it to remove cells before the activation of these elements can result in significant chromosomal insertions and mutation. Finally, we showed that WY-14,643 treatment induced gene signatures of DNA recombination in the sensitive C3H/HeJ strain.
- Amongst the top regulators showing increased activity are interferon gamma, the interferon alpha/beta group, IL10 and tumor necrosis factor (S2 Excel File). All of these genes are deeply tied to the body's response to retroviral infection and are also known to be stimulated by TLR4 activation. In addition, we found the expression of several host restriction factors, including Trim5, Trim12a, Trim30a, and Trim30d, to be significantly elevated (Trim5:2.4e-5,
- Estrogens induce the accumulation of PIAS3 mRNA in multiple myeloma (MM) cells and increase the physical association of PIAS3 with Stat3, which is suggested to represent a possible mechanism for estrogen-mediated inhibition of IL-6-inducible MM cell proliferation (Wang et al. 2001b). Interestingly, downregulation or upregulation of PIAS protein expression that correlates with increased or decreased STAT activity, respectively, has been associated with many distinct clinical conditions, such as anaplastic lymphoma kinase-positive T/null-cell lymphoma, acute hepatic failure and cystic fibrosis (Kamohara et al. 2000, Kelley and Elmer 2000), as well as with physiological processes such as macrophage maturation (Coccia et al. 2002). Down-regulation of PIASy expression has also been detected in association with stage progression in chronic myeloid leukemia (Ohmine et al. 2001), and GBP/PIAS1 is down-regulated in RAS-transformed cells (Zuber et al. 2000).
[Show abstract] [Hide abstract] ABSTRACT: IL-18 is a pleiotropic and multifunctional cytokine that belongs to the IL-1 family. It is produced as a biologically inactive precursor, which is cleaved into its active mature form mainly by caspase-1. The caspase becomes active from its inactive precursor (procaspase-1) upon assembly of an inflammasome. Because of IL-18’s potential pro-inflammatory and tissue destructive effects, its biological activities are tightly controlled in the body by its naturally occurring antagonist called IL-18BP. The antagonist is produced in the body both constitutively and in response to an increased production of IL-18 as a negative feedback mechanism. Under physiological conditions, most of IL-18 in the circulation is bound with IL-18BP and is inactive. However, an imbalance in the production of IL-18 and its antagonist (an increase in the production of IL-18 with a decrease, no increase or an insufficient increase in the production of IL-18BP) has been described in many chronic inflammatory diseases in humans. The imbalance results in an increase in the concentrations of free IL-18 (unbound with its antagonist) resulting in increased biological activities of the cytokine that contribute towards pathogenesis of the disease. In this article, we provide an overview of the current biology of IL-18 and its antagonist, discuss how the imbalance occurs in HIV infections and how it contributes towards development of AIDS and other non-AIDS-associated clinical conditions occurring in HIV-infected individuals undergoing combination anti-retroviral therapy (cART). Finally, we discuss challenges facing immunotherapeutic strategies aimed at restoring balance between IL-18 and its antagonist in these patients.
- Furthermore, as discussed above, IRF-1 is absolutely required for transcriptional activation of the IL-18BP gene. The transcriptional factor is also required for viral replication, as the HIV LTRs have IRF-1-binding sites . In the cells undergoing viral replication, IRF-1 may be preferentially used for viral replication resulting in a decreased production of IL-18BP.
[Show abstract] [Hide abstract] ABSTRACT: Originally identified as regulators of the type I Interferon system, the nine mammalian members of the Interferon Regulatory Factor (IRF) family are transcriptional regulators with multiple biologic functions, among which the best known are those involved in initiating and regulating many aspect of host immunity, downstream pattern recognition receptors in response to cell injuries. In addition, these versatile proteins also regulate cell differentiation, cell growth and apoptosis in several cell types, and when mutated or disregulated significantly contribute to susceptibility to and progression of several cancers. IRF-1 is the most versatile member of the family, not essential for IFN gene expression and implicated in a variety of cellular functions spanning from the development and function of various immune cells to tumor suppression activity. IRF-3, IRF-7 and Irf-9 are more specifically involved in IFN induction and antiviral responses while IRF-5 is the regulator of inflammatory cytokines expression downstream pattern recognition receptors and IRF-6 is implicated in epithelial differentiation. IRF-8 as IRF-1 is considered a tumor suppressor gene, while IRF-2 and IRF-4 have generally oncogenic activity. The present review focuses principally on the current knowledge on IRF genetic characteristics, including mutations, polymorphisms and epigenetic regulation that are implicated in oncogenesis.
- Some existing chemotherapies already target metabolic enzymes while developing new cancer drugs that interfere with metabolism is an expanding area of research [186,187]. To date little is known on the role of IRFs in metabolic homeostasis even if an involvement in the regulation/interference with some metabolic pathways, linked to IRF-mediated immune responses, is emerging, as recently discussed . Thus, future studies aimed at the elucidation of the full range of target genes triggered by IRFs as well as of IRF cross-talk with other transcriptional regulators, functional deregulation of their activation, epigenetic regulation and significance of IRF polymorphisms in the context of tumorigenesis, by using system biology strategies, will aid in defining an holistic understanding of IRF activities with important therapeutic implications.
[Show abstract] [Hide abstract] ABSTRACT: Aim of the study The gastrointestinal peptide hormone ghrelin (Ghr) was discovered in 1999 as the endogenous ligand for the growth hormone secretagogue receptor (GHSR-1a). It is a pleiotropic peptide that modulates a wide spectrum of biological activities, such as growth hormone (GH) release, feeding stimulation, adiposity and cardiovascular actions. The presence of Ghr mRNA in the iris and ciliary body (CB) epithelium was recently demonstrated in animal models, where a possible myorelaxing effect on the iris muscles has been suggested. Based on these observations, the aim of our study was to investigate the Ghr and GHSR-1a expression and localization in the normal human eye. Five different ciliary body/iris samples from normal eyes were subjected to western blot analysis. Immunohistochemical detection was performed on three enucleated eyes. Twenty aqueous humor (AqH) samples obtained from patients submitted to cataract surgery were analyzed with an ELISA for the presence of Ghr. Ghr and GHSR-1a were co-expressed by the pigmented epithelium (PE) of the CB, by the retinal pigmented epithelium (RPE) and by the anterior limiting layer (ALL) of the iris. No reaction was detected at the subepithelial level in the ciliary or pupillae smooth muscle cells. The AqH samples were positive for the presence of Ghr. This study provides the first evidence that Ghr and GHSR-1a are expressed in the human eye by specific cells. The understanding of the functional role of Ghr at the human eye level needs more efforts and investigation, but a hypothetical action on the GH retinal synthesis and/or on the circadian clock system could be suggested.
- The protein concentration was evaluated by the Bradford method. The lysate samples (35 μg) were separated by SDS-PAGE and blotted, as previously described [13,14] . The membranes were incubated overnight at 4 °C with a rabbit polyclonal anti GHSR1-a (Abcam, 1:1000) or anti-Ghr (Abcam, 1:500) and probed with a horse-radishperoxidase-conjugated anti-rabbit secondary antibody (Abcam, 1:2000).
[Show abstract] [Hide abstract] ABSTRACT: Visceral leishmaniasis, caused by a protozoan parasite Leishmania donovani, is still a threat to mankind due to treatment failure, drug-resistance and co-infection with HIV. The limitations of first line drugs have led to the development of new strategies to combat this dreaded disease. Recently, we have shown the immunomodulatory property of Ara-LAM, a TLR2 ligand, against leishmanial pathogenesis. In this study, we have extended our study to the effect of Ara-LAM on regulatory Tcells in a murine model of VL. We observed that, Ara-LAM treated infected BALB/c mice showed a strong host-protective Th1 immune response due to reduced IL-10 and TGF-β production, along with marked decrease in CD4(+) CD25(+) Foxp3(+) GITR(+) CTLA4(+) regulatory Tcell (Treg) generation and activation. The reduction in Foxp3 expression was due to effective modulation of TGF-β induced SMAD signaling in Treg cells by Ara-LAM. Moreover, we demonstrated that Ara-LAM induced IRF1 expression in the Treg cells, which negatively regulated foxp3 gene transcription, resulting in the reduced immunosuppressive activity of Treg cells. Interestingly, irf1 gene knock down completely abrogated the effect of Ara-LAM on Treg cells. Thus, these findings provide detailed mechanistic insight into Ara-LAM mediated modulation of Treg cells, which might be helpful in combating VL. © FEMS 2015. All rights reserved. For permissions, please e-mail: firstname.lastname@example.org.
- IRF1, a key regulator of IFNγ mediated Th1 response, can act as both transcriptional activator and repressor depending on stimulations (Kirchhoff et al. 2000; Nishikawa et al. 2005; Lal et al. 2011 ). A similar report suggests that IRF-1 can directly repress Foxp3 expression and Treg cell development (Fragale et al. 2008; Lal et al. 2011 ). Commensurate with this, our observations showed that Ara-LAM treatment induced IRF1expression in both CD4 + CD25 + Treg cells and CD4 + CD25 − T responder cells.
[Show abstract] [Hide abstract] ABSTRACT: Insulin resistance caused by a high-fat diet induces type 2 diabetes and its complications. In this study, we investigated gene expression changes in peripheral leukocytes with insulin resistance by conducting microarray analyses in rats with high-fat diet-induced insulin resistance. After assessing insulin resistance in rats by an oral glucose tolerance test, we performed microarray analyses using peripheral leukocytes from normal rats and insulin-resistant rats after fasting. Real-time RT-PCR analyses were performed for several upregulated genes in the microarray data after fasting and at 3h after a single oral glucose load. Feeding rats a high-fat diet for 77days induced moderate insulin resistance. Microarray analysis showed that the high-fat diet enhances many genes related to leukocyte activation. These upregulated genes included genes related to host defense, and many genes related to G-protein-coupled receptor/tyrosine receptor signaling. Moreover, many genes, such as Anxa1, S100a8, Il22ra2, Gng10, Csf3r and Cd302, showed further upregulation of their expression after a single oral glucose load. Exposure to high glucose and/or tumor necrosis factor-α which is known to be a factor that induces insulin resistance, enhanced the mRNA levels of DUSP1, ANXA1, IL1B, S100A8, IL22RA2, S100A9 and IRF1 in human monocyte-like U937 cells. These results suggest that the expression of genes related to leukocyte activation in peripheral leukocytes is associated with the development of moderate insulin resistance.
- Recent studies have shown that CEACAM1 activates its target genes by acting as a substrate in the insulin receptor cascade (Najjar, 2002). IRF1 is a transcription factor that regulates the differentiation of leukocytes, such as macrophages and neutrophils, regulates the functions of type Ι and type ΙΙ interferons, and plays a role in host protection (Coccia et al., 2001; Lee et al., 2007). Considering the present results and those in previous reports, the enhanced insulin resistance induced by feeding rats a high-fat diet increased the expression of many cytokine/ chemokine-related genes and G-protein-coupled receptor/tyrosine receptor-related genes, particularly at 3 h after glucose administration .
[Show abstract] [Hide abstract] ABSTRACT: Cytokines, because of their nature of soluble mediators, represent key elements in mediating and tuning the immune response against Mycobacterium tuberculosis.•Mycobacterium tuberculosis orchestrates the cytokine storm to induce or evade host immune responses.•Granuloma formation is tightly regulated by lung-secreted cytokines.•Perturbation of cytokine signaling represents a critical checkpoint of the immune response against Mycobacterium tuberculosis.•Understanding the balance between pro- and anti-inflammatory cytokines is crucial for developing more effective measures of immune intervention against tuberculosis.
- The production of IL-12 and type I IFN, namely IFN-, by DC is considered critical for the polarization of CD4 + T lymphocytes toward a Th1 pattern . The Mtb-driven induction of IFN-and IL-12p35 is dependent on IFN regulatory factor (IRF)-3 activation  , while no induction was observed when human DC were challenged with Bacillus Calmette-Guérin (BCG) . In line with this finding, Watson and colleagues  have recently demonstrated that the activation of cytosolic receptors via extracellular Mtb DNA induces signaling through the STING/TANK-binding kinase (TBK) 1/IRF3 axis, resulting in IFN-production.
[Show abstract] [Hide abstract] ABSTRACT: HIV-1 infection has been transformed by combined anti-retroviral therapy (ART), changing a universally fatal infection into a controllable infection. However, major obstacles for an HIV-1 cure exist. The HIV latent reservoir, which exists in resting CD4+ T cells, is not impacted by ART, and can reactivate when ART is interrupted or ceased. Additionally, multi-drug resistance can arise. One alternate approach to conventional HIV-1 drug treatment that is being explored involves gene therapies utilizing RNA-directed gene regulation. Commonly known as RNA interference (RNAi), short interfering RNA (siRNA) induce gene silencing in conserved biological pathways, which require a high degree of sequence specificity. This review will provide an overview of the silencing pathways, the current RNAi technologies being developed for HIV-1 gene therapy, current clinical trials, and the challenges faced in progressing these treatments into clinical trials.
- It is thought the majority of the virus reservoir is in a latent form , mediated by a series of epigenetic mechanisms . Virus in the latent reservoir has the potential to reactivate from latency upon activation of these cells by antigen or changes in the local inflammatory milieu [18,19]. Thus, this source of virus represents the major barrier to curing HIV.
[Show abstract] [Hide abstract] ABSTRACT: Despite Imatinib (IM), a selective inhibitor of Bcr-Abl, having led to improved prognosis in Chronic Myeloid Leukemia (CML) patients, acquired resistance and long-term adverse effects is still being encountered. There is, therefore, urgent need to develop alternative strategies to overcome drug resistance. According to the molecules expressed on their surface, exosomes can target specific cells. Exosomes can also be loaded with a variety of molecules, thereby acting as a vehicle for the delivery of therapeutic agents. In this study, we engineered HEK293T cells to express the exosomal protein Lamp2b, fused to a fragment of Interleukin 3 (IL3). The IL3 receptor (IL3-R) is overexpressed in CML blasts compared to normal hematopoietic cells and thus is able to act as a receptor target in a cancer drug delivery system. Here we show that IL3L exosomes, loaded with Imatinib or with BCR-ABL siRNA, are able to target CML cells and inhibit in vitro and in vivo cancer cell growth.
- In this study we generated targeted exosomes able to deliver Imatinib or BCR-ABL siRNA to CML cells in order to overcome pharmacological resistance (Figure 1A). It is known that interleukin-3 receptor (IL3-R) is overexpressed on CML and AML (acute myeloid leukemia) blasts while expressed at low levels or absent on normal hematopoietic stem cells, suggesting that IL3-R could serve as a receptor target in a cancer drug delivery system using exosomes to deliver drugs or siRNA to inhibit BCR-ABL. Here we show that modified exosomes, containing IL3-Lamp2B, and loaded with Imatinib, are able to specifically target tumor cells in vivo, leading to a the reduction in tumor size.
- These findings are in agreement with Iken et al. (2006) who observed an unusually low frequency of HCV-specific T-cells in the liver and peripheral blood of CHC patients. Moreover, Ciccaglione et al. (2007) deduced that HCV persistence in most infected individuals is associated with the ability of the virus to evade the host immune response at local and systemic levels and that the virus is capable of replicating in immune cells, effector cells and hepatocytes, which are the main target of HCV replication. Shete et al. (2010) previously reported that the CD3 + T-cell count was lower in EBVinfected patients compared to control individuals.
Istituto Superiore di Sanità
- Laboratory of Virology