Publications by authors named "Anna Teresa Palamara"

112 Publications

Dietary and Protective Factors to Halt or Mitigate Progression of Autoimmunity, COVID-19 and Its Associated Metabolic Diseases.

Int J Mol Sci 2021 Mar 19;22(6). Epub 2021 Mar 19.

Department of Systems Medicine, University of Rome "Tor Vergata", 00133 Rome, Italy.

COVID-19 is without any doubt the worst pandemic we have faced since the H1N1 virus outbreak. Even if vaccination against SARS-CoV-2 infection is becoming increasingly available, a more feasible approach for COVID-19 prevention and therapy is still needed. Evidence of a pathological link between metabolic diseases and severe forms of COVID-19 has stimulated critical reflection and new considerations. In particular, an abnormal immune response observed in certain patients with SARS-CoV-2 infection suggested possible common predisposing risk factors with autoimmune diseases such as Type 1 Diabetes (T1D). Correct supplementation with dietary factors may be key to preventing and counteracting both the underlying metabolic impairment and the complications of COVID-19. A set of agents may inhibit the cytokine storm and hypercoagulability that characterize severe COVID-19 infection: vitamin D3, omega-3 polyunsaturated fatty acids, polyphenols like pterostilbene, polydatin and honokiol, which can activate anti-inflammatory and antioxidant sirtuins pathways, quercetin, vitamin C, zinc, melatonin, lactoferrin and glutathione. These agents could be highly beneficial for subjects who have altered immune responses. In this review, we discuss the antiviral and metabolic effects of these dietary factors and propose their combination for potential applications in the prevention and treatment of COVID-19. Rigorous studies will be fundamental for validating preventive and therapeutic protocols that could be of assistance to mitigate disease progression following SARS-CoV-2 infection.
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http://dx.doi.org/10.3390/ijms22063134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003583PMC
March 2021

Intracellular Redox-Modulated Pathways as Targets for Effective Approaches in the Treatment of Viral Infection.

Int J Mol Sci 2021 Mar 30;22(7). Epub 2021 Mar 30.

Department of Biomolecular Sciences, University of Urbino Carlo Bo, Via Saffi 2, 61029 Urbino (PU), Italy.

Host-directed therapy using drugs that target cellular pathways required for virus lifecycle or its clearance might represent an effective approach for treating infectious diseases. Changes in redox homeostasis, including intracellular glutathione (GSH) depletion, are one of the key events that favor virus replication and contribute to the pathogenesis of virus-induced disease. Redox homeostasis has an important role in maintaining an appropriate Th1/Th2 balance, which is necessary to mount an effective immune response against viral infection and to avoid excessive inflammatory responses. It is known that excessive production of reactive oxygen species (ROS) induced by viral infection activates nuclear factor (NF)-B, which orchestrates the expression of viral and host genes involved in the viral replication and inflammatory response. Moreover, redox-regulated protein disulfide isomerase (PDI) chaperones have an essential role in catalyzing formation of disulfide bonds in viral proteins. This review aims at describing the role of GSH in modulating redox sensitive pathways, in particular that mediated by NF-B, and PDI activity. The second part of the review discusses the effectiveness of GSH-boosting molecules as broad-spectrum antivirals acting in a multifaceted way that includes the modulation of immune and inflammatory responses.
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http://dx.doi.org/10.3390/ijms22073603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036776PMC
March 2021

: An Ancient Commensal with Weapons of a Pathogen.

Pathogens 2021 Mar 24;10(4). Epub 2021 Mar 24.

IRCCS San Raffaele Pisana, 00166 Rome, Italy.

is regarded as a life-threatening pathogen associated with community-acquired and nosocomial infections, mainly pneumonia. The rise in the number of antibiotic-resistant strains reduces effective therapies and increases mortality. Bacterial comparative genomic studies have unraveled the innate and acquired virulence factors of These virulence factors are involved in antibiotic resistance, environmental persistence, host-pathogen interactions, and immune evasion. Studies on host-pathogen interactions revealed that evolved different mechanisms to adhere to in order to invade host respiratory cells as well as evade the host immune system. In this review, we discuss current data on genetic features and virulence factors. An emphasis is given to the players in host-pathogen interaction in the respiratory tract. In addition, we report recent investigations into host defense systems using in vitro and in vivo models, providing new insights into the innate immune response to infections. Increasing our knowledge of pathogenesis may help the development of novel therapeutic strategies based on anti-adhesive, anti-virulence, and anti-cell to cell signaling pathways drugs.
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http://dx.doi.org/10.3390/pathogens10040387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063835PMC
March 2021

Investigation of (Nees) Engl. Oil and Its Main Components for Antiviral Activity.

Pharmaceuticals (Basel) 2021 Mar 9;14(3). Epub 2021 Mar 9.

Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, "Sapienza" Università di Roma, p.le Aldo Moro 5, I-00185 Rome, Italy.

The resinous exudate produced by (Nees) Engl. is commonly known as true myrrh and has been used since antiquity for several medicinal applications. Hundreds of metabolites have been identified in the volatile component of myrrh so far, mainly sesquiterpenes. Although several efforts have been devoted to identifying these sesquiterpenes, the phytochemical analyses have been performed by gas-chromatography/mass spectrometry (GC-MS) where the high temperature employed can promote degradation of the components. In this work, we report the extraction of by supercritical CO, an extraction method known for the mild extraction conditions that allow avoiding undesired chemical reactions during the process. In addition, the analyses of myrrh oil and of its metabolites were performed by HPLC and GC-MS. Moreover, we evaluated the antiviral activity against influenza A virus of the myrrh extracts, that was possible to appreciate after the addition of vitamin E acetate (α-tocopheryl acetate) to the extract. Further, the single main bioactive components of the oil of commercially available were tested. Interestingly, we found that both furanodienone and curzerene affect viral replication by acting on different steps of the virus life cycle.
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http://dx.doi.org/10.3390/ph14030243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999460PMC
March 2021

Acinetobacter baumannii Targets Human Carcinoembryonic Antigen-Related Cell Adhesion Molecules (CEACAMs) for Invasion of Pneumocytes.

mSystems 2020 Dec 22;5(6). Epub 2020 Dec 22.

IRCCS San Raffaele Pisana, Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, Rome, Italy.

Multidrug-resistant is regarded as a life-threatening pathogen mainly associated with nosocomial and community-acquired pneumonia. Here, we show that can bind the human carcinoembryonic antigen-related cell adhesion molecule (CEACAM) receptors CEACAM1, CEACAM5, and CEACAM6. This specific interaction enhances internalization in membrane-bound vacuoles, promptly decorated with Rab5, Rab7, and lipidated microtubule-associated protein light chain 3 (LC3). Dissecting intracellular signaling pathways revealed that infected pneumocytes trigger interleukin-8 (IL-8) secretion via the extracellular signal-regulated kinase (ERK)1/2 and nuclear factor-kappa B (NF-κB) signaling pathways for clearance. However, in CEACAM1-L-expressing cells, IL-8 secretion lasts only 24 h, possibly due to an -dependent effect on the CEACAM1-L intracellular domain. Conversely, the glycosylphosphatidylinositol-anchored CEACAM5 and CEACAM6 activate the c-Jun NH-terminal kinase (JNK)1/2-Rubicon-NOX2 pathway, suggestive of LC3-associated phagocytosis. Overall, our data show for the first time novel mechanisms of adhesion to and invasion of pneumocytes by via CEACAM-dependent signaling pathways that eventually lead to bacterial killing. These findings suggest that CEACAM upregulation could put patients at increased risk of lower respiratory tract infection by This work shows for the first time that binds to carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), CEACAM5, and CEACAM6. This binding significantly enhances internalization within alveolar host cell epithelia. Intracellular trafficking involves typical Rab5 and Rab7 vacuolar proteins as well as light chain 3 (LC3) and slowly progresses to bacterial killing by endosome acidification. CEACAM engagement by leads to distinct and specific downstream signaling pathways. The CEACAM1 pathway finely tunes interleukin-8 (IL-8) secretion, whereas CEACAM5 and CEACAM6 mediate LC3-associated phagocytosis. The present study provides new insights into -host interactions and could represent a promising therapeutic strategy to reduce pulmonary infections caused by this pathogen.
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http://dx.doi.org/10.1128/mSystems.00604-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762790PMC
December 2020

SARS-CoV-2: Comparative analysis of different RNA extraction methods.

J Virol Methods 2021 01 4;287:114008. Epub 2020 Nov 4.

San Raffaele Roma Open University, 00166 Rome, Italy; IRCCS San Raffaele Pisana, 00166 Rome, Italy.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiologic agent of the COVID-19 pandemic. Although other diagnostic methods have been introduced, detection of viral genes on oro- and nasopharyngeal swabs by reverse-transcription real time-PCR (rRT-PCR) assays is still the gold standard. Efficient viral RNA extraction is a prerequisite for downstream performance of rRT-PCR assays. Currently, several automatic methods that include RNA extraction are available. However, due to the growing demand, a shortage in kit supplies could be experienced in several labs. For these reasons, the use of different commercial or in-house protocols for RNA extraction may increase the possibility to analyze high number of samples. Herein, we compared the efficiency of RNA extraction of three different commercial kits and an in-house extraction protocol using synthetic ssRNA standards of SARS-CoV-2 as well as in oro-nasopharyngeal swabs from six COVID-19-positive patients. It was concluded that tested commercial kits can be used with some modifications for the detection of the SARS-CoV-2 genome by rRT-PCR approaches, although with some differences in RNA yields. Conversely, EXTRAzol reagent was the less efficient due to the phase separation principle at the basis of RNA extraction. Overall, this study offers alternative suitable methods to manually extract RNA that can be taken into account for SARS-CoV-2 detection.
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http://dx.doi.org/10.1016/j.jviromet.2020.114008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7640895PMC
January 2021

Structural Analysis of Merkel Cell Polyomavirus (MCPyV) Viral Capsid Protein 1 (VP1) in HIV-1 Infected Individuals.

Int J Mol Sci 2020 Oct 27;21(21). Epub 2020 Oct 27.

Department of Public Health and Infectious Diseases, "Sapienza" University of Rome, 00185 Rome, Italy.

Merkel cell polyomavirus (MCPyV) viral protein 1 (VP1) is the capsid protein that mediates virus attachment to host cell receptors and is the major immune target. Given the limited data on MCPyV VP1 mutations, the VP1 genetic variability was examined in 100 plasma and 100 urine samples from 100 HIV+ individuals. Sequencing of VP1 DNA in 17 urine and 17 plasma specimens, simultaneously MCPyV DNA positive, revealed that 27 samples displayed sequences identical to VP1 of MCC350 strain. VP1 from two urine specimens had either Thr47Ser or Ile115Phe substitution, whereas VP1 of one plasma contained Asp69Val and Ser251Phe substitutions plus deletion (∆) of Tyr79. VP1 DNA in the remaining samples had mutations encoding truncated protein. Three-dimensional prediction models revealed that Asp69Val, Ser251Phe, and Ile115Phe caused neutral effects while Thr47Ser and Tyr79∆ produced a deleterious effect reducing VP1 stability. A549 cells infected with urine or plasma samples containing full-length VP1 variants with substitutions, sustained viral DNA replication and VP1 expression. Moreover, medium harvested from these cells was able to infect new A549 cells. In cells infected by samples with truncated VP1, MCPyV replication was hampered. In conclusion, MCPyV strains with unique mutations in the gene are circulating in HIV+ patients. These strains display altered replication efficiency compared to the MCC350 prototype strain in A549 cells.
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http://dx.doi.org/10.3390/ijms21217998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7663277PMC
October 2020

16S Metagenomics Reveals Dysbiosis of Nasal Core Microbiota in Children With Chronic Nasal Inflammation: Role of Adenoid Hypertrophy and Allergic Rhinitis.

Front Cell Infect Microbiol 2020 2;10:458. Epub 2020 Sep 2.

Department of Public Health and Infectious Diseases, Microbiology Section, "Sapienza" University of Rome, Rome, Italy.

Allergic rhinitis (AR) and adenoid hypertrophy (AH) are, in children, the main cause of partial or complete upper airway obstruction and reduction in airflow. However, limited data exist about the impact of the increased resistance to airflow, on the nasal microbial composition of children with AR end AH. Allergic rhinitis (AR) as well as adenoid hypertrophy (AH), represent extremely common pathologies in this population. Their known inflammatory obstruction is amplified when both pathologies coexist. In our study, the microbiota of anterior nares of 75 pediatric subjects with AR, AH or both conditions, was explored by 16S rRNA-based metagenomic approach. Our data show for the first time, that in children, the inflammatory state is associated to similar changes in the microbiota composition of AR and AH subjects respect to the healthy condition. Together with such alterations, we observed a reduced variability in the between-subject biodiversity on the other hand, these same alterations resulted amplified by the nasal obstruction that could constitute a secondary risk factor for dysbiosis. Significant differences in the relative abundance of specific microbial groups were found between diseased phenotypes and the controls. Most of these taxa belonged to a stable and quantitatively dominating component of the nasal microbiota and showed marked potentials in discriminating the controls from diseased subjects. A pauperization of the nasal microbial network was observed in diseased status in respect to the number of involved taxa and connectivity. Finally, while stable co-occurrence relationships were observed within both control- and diseases-associated microbial groups, only negative correlations were present between them, suggesting that microbial subgroups potentially act as maintainer of the eubiosis state in the nasal ecosystem. In the nasal ecosystem, inflammation-associated shifts seem to impact the more intimate component of the microbiota rather than representing the mere loss of microbial diversity. The discriminatory potential showed by differentially abundant taxa provide a starting point for future research with the potential to improve patient outcomes. Overall, our results underline the association of AH and AR with the impairment of the microbial interplay leading to unbalanced ecosystems.
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http://dx.doi.org/10.3389/fcimb.2020.00458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492700PMC
September 2020

Ca -dependent release of ATP from astrocytes affects herpes simplex virus type 1 infection of neurons.

Glia 2021 Jan 20;69(1):201-215. Epub 2020 Aug 20.

Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, Italy.

Astrocytes provide metabolic support for neurons and modulate their functions by releasing a plethora of neuroactive molecules diffusing to neighboring cells. Here we report that astrocytes also play a role in cortical neurons' vulnerability to Herpes simplex virus type-1 (HSV-1) infection through the release of extracellular ATP. We found that the interaction of HSV-1 with heparan sulfate proteoglycans expressed on the plasma membrane of astrocytes triggered phospholipase C-mediated IP -dependent intracellular Ca transients causing extracellular release of ATP. ATP binds membrane purinergic P2 receptors (P2Rs) of both neurons and astrocytes causing an increase in intracellular Ca concentration that activates the Glycogen Synthase Kinase (GSK)-3β, whose action is necessary for HSV-1 entry/replication in these cells. Indeed, in co-cultures of neurons and astrocytes HSV-1-infected neurons were only found in proximity of infected astrocytes releasing ATP, whereas in the presence of fluorocitrate, an inhibitor of astrocyte metabolism, switching-off the HSV-1-induced ATP release, very few neurons were infected. The addition of exogenous ATP, mimicking that released by astrocytes after HSV-1 challenge, restored the ability of HSV-1 to infect neurons co-cultured with metabolically-inhibited astrocytes. The ATP-activated, P2R-mediated, and GSK-3-dependent molecular pathway underlying HSV-1 infection is likely shared by neurons and astrocytes, given that the blockade of either P2Rs or GSK-3 activation inhibited infection of both cell types. These results add a new layer of information to our understanding of the critical role played by astrocytes in regulating neuronal functions and their response to noxious stimuli including microbial agents via Ca -dependent release of neuroactive molecules.
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http://dx.doi.org/10.1002/glia.23895DOI Listing
January 2021

Fecal microRNAs as Innovative Biomarkers of Intestinal Diseases and Effective Players in Host-Microbiome Interactions.

Cancers (Basel) 2020 Aug 5;12(8). Epub 2020 Aug 5.

Research Laboratories, Bambino Gesù Children's Hospital, IRCCS, 00146 Rome, Italy.

Over the past decade, short non-coding microRNAs (miRNAs), including circulating and fecal miRNAs have emerged as important modulators of various cellular processes by regulating the expression of target genes. Recent studies revealed the role of miRNAs as powerful biomarkers in disease diagnosis and for the development of innovative therapeutic applications in several human conditions, including intestinal diseases. In this review, we explored the literature and summarized the role of identified dysregulated fecal miRNAs in intestinal diseases, with particular focus on colorectal cancer (CRC) and celiac disease (CD). The aim of this review is to highlight one fascinating aspect of fecal miRNA function related to gut microbiota shaping and bacterial metabolism influencing. The role of miRNAs as "messenger" molecules for inter kingdom communications will be analyzed to highlight their role in the complex host-bacteria interactions. Moreover, whether fecal miRNAs could open up new perspectives to develop novel suitable biomarkers for disease detection and innovative therapeutic approaches to restore microbiota balance will be discussed.
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http://dx.doi.org/10.3390/cancers12082174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463924PMC
August 2020

FimH and Anti-Adhesive Therapeutics: A Disarming Strategy Against Uropathogens.

Antibiotics (Basel) 2020 Jul 10;9(7). Epub 2020 Jul 10.

Department of Public Health and Infectious Diseases, Sapienza University of Rome, 00185 Rome, Italy.

Chaperone-usher fimbrial adhesins are powerful weapons against the uropathogens that allow the establishment of urinary tract infections (UTIs). As the antibiotic therapeutic strategy has become less effective in the treatment of uropathogen-related UTIs, the anti-adhesive molecules active against fimbrial adhesins, key determinants of urovirulence, are attractive alternatives. The best-characterized bacterial adhesin is FimH, produced by uropathogenic (UPEC). Hence, a number of high-affinity mono- and polyvalent mannose-based FimH antagonists, characterized by different bioavailabilities, have been reported. Given that antagonist affinities are firmly associated with the functional heterogeneities of different FimH variants, several FimH inhibitors have been developed using ligand-drug discovery strategies to generate high-affinity molecules for successful anti-adhesion therapy. As clinical trials have shown d-mannose's efficacy in UTIs prevention, it is supposed that mannosides could be a first-in-class strategy not only for UTIs, but also to combat other Gram-negative bacterial infections. Therefore, the current review discusses valuable and effective FimH anti-adhesive molecules active against UTIs, from design and synthesis to in vitro and in vivo evaluations.
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http://dx.doi.org/10.3390/antibiotics9070397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400442PMC
July 2020

Multiple Herpes Simplex Virus-1 (HSV-1) Reactivations Induce Protein Oxidative Damage in Mouse Brain: Novel Mechanisms for Alzheimer's Disease Progression.

Microorganisms 2020 Jun 29;8(7). Epub 2020 Jun 29.

Department of Public Health and Infectious Diseases, Sapienza University of Rome, Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, 00185 Rome, Italy.

Compelling evidence supports the role of oxidative stress in Alzheimer's disease (AD) pathophysiology. Interestingly, Herpes simplex virus-1 (HSV-1), a neurotropic virus that establishes a lifelong latent infection in the trigeminal ganglion followed by periodic reactivations, has been reportedly linked both to AD and to oxidative stress conditions. Herein, we analyzed, through biochemical and redox proteomic approaches, the mouse model of recurrent HSV-1 infection we previously set up, to investigate whether multiple virus reactivations induced oxidative stress in the mouse brain and affected protein function and related intracellular pathways. Following multiple HSV-1 reactivations, we found in mouse brains increased levels of oxidative stress hallmarks, including 4-hydroxynonenal (HNE), and 13 HNE-modified proteins whose levels were found significantly altered in the cortex of HSV-1-infected mice compared to controls. We focused on two proteins previously linked to AD pathogenesis, i.e., glucose-regulated protein 78 (GRP78) and collapsin response-mediated protein 2 (CRMP2), which are involved in the unfolded protein response (UPR) and in microtubule stabilization, respectively. We found that recurrent HSV-1 infection disables GRP78 function and activates the UPR, whereas it prevents CRMP2 function in mouse brains. Overall, these data suggest that repeated HSV-1 reactivation into the brain may contribute to neurodegeneration also through oxidative damage.
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http://dx.doi.org/10.3390/microorganisms8070972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409037PMC
June 2020

The "Three Italy" of the COVID-19 epidemic and the possible involvement of SARS-CoV-2 in triggering complications other than pneumonia.

J Neurovirol 2020 06 16;26(3):311-323. Epub 2020 Jun 16.

Department of Public Health and Infectious Diseases, "Sapienza" University, P.le Aldo Moro, 5, 00185, Rome, Italy.

Coronavirus disease 2019 (COVID-19), first reported in Wuhan, the capital of Hubei, China, has been associated to a novel coronavirus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In March 2020, the World Health Organization declared the SARS-CoV-2 infection a global pandemic. Soon after, the number of cases soared dramatically, spreading across China and worldwide. Italy has had 12,462 confirmed cases according to the Italian National Institute of Health (ISS) as of March 11, and after the "lockdown" of the entire territory, by May 4, 209,254 cases of COVID-19 and 26,892 associated deaths have been reported. We performed a review to describe, in particular, the origin and the diffusion of COVID-19 in Italy, underlying how the geographical circulation has been heterogeneous and the importance of pathophysiology in the involvement of cardiovascular and neurological clinical manifestations.
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http://dx.doi.org/10.1007/s13365-020-00862-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297137PMC
June 2020

Redox-Modulating Agents in the Treatment of Viral Infections.

Int J Mol Sci 2020 Jun 8;21(11). Epub 2020 Jun 8.

Department of Public Health and Infectious Diseases, Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University of Rome, 00185 Rome, Italy.

Viruses use cell machinery to replicate their genome and produce viral proteins. For this reason, several intracellular factors, including the redox state, might directly or indirectly affect the progression and outcome of viral infection. In physiological conditions, the redox balance between oxidant and antioxidant species is maintained by enzymatic and non-enzymatic systems, and it finely regulates several cell functions. Different viruses break this equilibrium and induce an oxidative stress that in turn facilitates specific steps of the virus lifecycle and activates an inflammatory response. In this context, many studies highlighted the importance of redox-sensitive pathways as novel cell-based targets for therapies aimed at blocking both viral replication and virus-induced inflammation. In the review, we discuss the most recent findings in this field. In particular, we describe the effects of natural or synthetic redox-modulating molecules in inhibiting DNA or RNA virus replication as well as inflammatory pathways. The importance of the antioxidant transcription factor Nrf2 is also discussed. Most of the data reported here are on influenza virus infection. We believe that this approach could be usefully applied to fight other acute respiratory viral infections characterized by a strong inflammatory response, like COVID-19.
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http://dx.doi.org/10.3390/ijms21114084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312898PMC
June 2020

Experimental Data Based Machine Learning Classification Models with Predictive Ability to Select in Vitro Active Antiviral and Non-Toxic Essential Oils.

Molecules 2020 May 25;25(10). Epub 2020 May 25.

Rome Center for Molecular Design, Department of Drug Chemistry and Technology, Sapienza University, P.le Aldo Moro 5, 00185 Rome, Italy.

In the last decade essential oils have attracted scientists with a constant increase rate of more than 7% as witnessed by almost 5000 articles. Among the prominent studies essential oils are investigated as antibacterial agents alone or in combination with known drugs. Minor studies involved essential oil inspection as potential anticancer and antiviral natural remedies. In line with the authors previous reports the investigation of an in-house library of extracted essential oils as a potential blocker of HSV-1 infection is reported herein. A subset of essential oils was experimentally tested in an in vitro model of HSV-1 infection and the determined ICs and CCs values were used in conjunction with the results obtained by gas-chromatography/mass spectrometry chemical analysis to derive machine learning based classification models trained with the partial least square discriminant analysis algorithm. The internally validated models were thus applied on untested essential oils to assess their effective predictive ability in selecting both active and low toxic samples. Five essential oils were selected among a list of 52 and readily assayed for IC and CC determination. Interestingly, four out of the five selected samples, compared with the potencies of the training set, returned to be highly active and endowed with low toxicity. In particular, sample CJM1 from was the most potent tested essential oil with the highest selectivity index (IC = 0.063 mg/mL, SI > 47.5). In conclusion, it was herein demonstrated how multidisciplinary applications involving machine learning could represent a valuable tool in predicting the bioactivity of complex mixtures and in the near future to enable the design of blended essential oil possibly endowed with higher potency and lower toxicity.
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http://dx.doi.org/10.3390/molecules25102452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288128PMC
May 2020

Herpes Simplex Virus-1 in the Brain: The Dark Side of a Sneaky Infection.

Trends Microbiol 2020 10 5;28(10):808-820. Epub 2020 May 5.

Institute of Translational Pharmacology, National Research Council, Rome, Italy.

Herpes simplex virus-1 (HSV-1) establishes latency preferentially in sensory neurons of peripheral ganglia. A variety of stresses can induce recurrent reactivations of the virus, which spreads and then actively replicates to the site of primary infection (usually the lips or eyes). Viral particles produced following reactivation can also reach the brain, causing a rare but severe form of diffuse acute infection, namely herpes simplex encephalitis. Most of the time, this infection is clinically asymptomatic. However, it was recently correlated with the production and accumulation of neuropathological biomarkers of Alzheimer's disease. In this review we discuss the different cellular and molecular mechanisms underlying the acute and long-term damage caused by HSV-1 infection in the brain.
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http://dx.doi.org/10.1016/j.tim.2020.03.003DOI Listing
October 2020

Merkel Cell Polyomavirus (MCPyV) in the Context of Immunosuppression: Genetic Analysis of Noncoding Control Region (NCCR) Variability among a HIV-1-Positive Population.

Viruses 2020 05 4;12(5). Epub 2020 May 4.

Department of Public Health and Infectious Diseases, "Sapienza" University, 00185 Rome, Italy.

Background: Since limited data are available about the prevalence of Merkel cell polyomavirus (MCPyV) and the genetic variability of its noncoding control region (NCCR) in the context of immunosuppression, this study aimed to investigate the distribution of MCPyV in anatomical sites other than the skin and the behavior of NCCR among an HIV-1-positive population.

Methods: Urine, plasma, and rectal swabs specimens from a cohort of 66 HIV-1-positive patients were collected and subjected to quantitative real-time polymerase chain reaction (qPCR) for MCPyV DNA detection. MCPyV-positive samples were amplified by nested PCR targeting the NCCR, and NCCRs alignment was carried out to evaluate the occurrence of mutations and to identify putative binding sites for cellular factors.

Results: MCPyV DNA was detected in 10/66 urine, in 7/66 plasma, and in 23/66 rectal samples, with a median value of 5 × 10 copies/mL, 1.5 × 10 copies/mL, and 2.3 × 10 copies/mL, respectively. NCCR sequence analysis revealed a high degree of homology with the MCC350 reference strain in urine, whereas transitions, transversions, and single or double deletions were observed in plasma and rectal swabs. In these latter samples, representative GTT and GTTGA insertions were also observed. Search for putative binding sites of cellular transcription factors showed that in several strains, deletions, insertions, or single base substitutions altered the NCCR canonical configuration.

Conclusions: Sequencing analysis revealed the presence of numerous mutations in the NCCR, including insertions and deletions. Whether these mutations may have an impact on the pathogenic features of the virus remains to be determined. qPCR measured on average a low viral load in the specimens analyzed, with the exception of those with the GTTGA insertion.
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http://dx.doi.org/10.3390/v12050507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291121PMC
May 2020

Glutathione increase by the n-butanoyl glutathione derivative (GSH-C4) inhibits viral replication and induces a predominant Th1 immune profile in old mice infected with influenza virus.

FASEB Bioadv 2019 May 13;1(5):296-305. Epub 2019 Mar 13.

Deparment of Public Health and Infectious Diseases Istituto Pasteur Italia-Fondazione Cenci-Bolognetti, Sapienza University of Rome Rome Italy.

During aging, glutathione (GSH) content declines and the immune system undergoes a deficiency in the induction of Th1 response. Reduced secretion of Th1 cytokines, which is associated with GSH depletion, could weaken the host defenses against viral infections. We first evaluated the concentration of GSH and cysteine in organs of old mice; then, the effect of the administration of the N-butanoyl GSH derivative (GSH-C4) on the response of aged mice infected with influenza A PR8/H1N1 virus was studied through the determination of GSH concentration in organs, lung viral titer, IgA and IgG1/IgG2a production, and Th1/Th2 cytokine profile. Old mice had lower GSH than young mice in organs. Also the gene expression of endoplasmic reticulum (ER) stress markers involved in GSH metabolism and folding of proteins, that is, Nrf2 and PDI, was reduced. Following infection, GSH content remained low and neither infection nor GSH-C4 treatment affected Nrf2 expression. In contrast, PDI expression was upregulated during infection and appeared counterbalanced by GSH-C4. Moreover, the treatment with GSH-C4 increased GSH content in organs, reduced viral replication and induced a predominant Th1 response. In conclusion, GSH-C4 treatment could be used in the elderly to contrast influenza virus infection by inducing immune response, in particular the Th1 profile.
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http://dx.doi.org/10.1096/fba.2018-00066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996388PMC
May 2019

Which is the best PML risk stratification strategy in natalizumab-treated patients affected by multiple sclerosis?

Mult Scler Relat Disord 2020 Jun 13;41:102008. Epub 2020 Feb 13.

Department of Public Health and Infectious Diseases, "Sapienza" University, P.le Aldo Moro, 5, 00185 Rome, Italy. Electronic address:

Background: The risk of progressive multifocal leukoencephalopathy (PML), a brain infection caused by John Cunningham virus (JCPyV), is the main limitation to the use of natalizumab, highly effective in the treatment of relapsing remitting multiple sclerosis (RRMS) patients. Establishing the PML risk against expected benefits represents an obligatory requirement of MS treatment algorithm. In order to achieve this goal, the aims of this study were to establish if JCPyV-DNA detection and non-coding control region (NCCR) arrangements could play a role of biomarkers, supporting anti-JCPyV antibodies measurement, actually the only parameter for PML risk stratification.

Methods: Thirty RRMS patients in treatment with natalizumab were enrolled. Urine and blood samples were collected according to this calendar: baseline (T0), 4 (T1), 8 (T2), 12 (T3), 16 (T4), 20 months (T5) after beginning of natalizumab therapy. After JCPyV DNA extraction, a specific quantitative-PCR (Q-PCR) and arrangements' analysis of NCCR and Viral Capsid Protein 1 (VP1) were carried out.

Results: Q-PCR detected JCPyV DNA in urine and blood from baseline (T0) to 20 natalizumab infusions (T5), although JC viral load in urine was significantly higher compared to viremia, at all selected time points. A contextual analysis of the anti-JCPyV-antibodies versus JCPyV-DNA detection revealed that viral DNA preceded the antibodies' presence in the serum. During the first year of natalizumab treatment, sequences isolated from blood displayed an archetype JCPyV NCCR structure with the occurrence of point mutations, whereas after one year NCCR re-organizations were observed in plasma and PBMC with duplication of NF-1 binding site in box F, duplication of box C and partial or total deletion of box D. VP1 analysis showed the amino acid change mutation S269F in plasma and S267L in PBMC, involving the receptor-binding region of VP1. Phylogenetic analysis suggested a stability and a similarity across different isolates of the JCPyV VP1.

Conclusions: We highly recommend considering JCPyV-DNA detection and NCCR re-organizations as viral biomarkers in order to accurately identify JCPyV-infected patients with a specific humoral response not yet detectable and to identify NCCR arrangements correlated with the onset of neurovirulent variants.
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http://dx.doi.org/10.1016/j.msard.2020.102008DOI Listing
June 2020

d-Mannose Treatment neither Affects Uropathogenic Properties nor Induces Stable FimH Modifications.

Molecules 2020 Jan 13;25(2). Epub 2020 Jan 13.

IRCCS San Raffaele Pisana, Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, 00166 Rome, Italy.

Urinary tract infections (UTIs) are mainly caused by uropathogenic (UPEC). Acute and recurrent UTIs are commonly treated with antibiotics, the efficacy of which is limited by the emergence of antibiotic resistant strains. The natural sugar d-mannose is considered as an alternative to antibiotics due to its ability to mask the bacterial adhesin FimH, thereby preventing its binding to urothelial cells. Despite its extensive use, the possibility that d-mannose exerts "antibiotic-like" activity by altering bacterial growth and metabolism or selecting FimH variants has not been investigated yet. To this aim, main bacterial features of the prototype UPEC strain CFT073 treated with d-mannose were analyzed by standard microbiological methods. FimH functionality was analyzed by yeast agglutination and human bladder cell adhesion assays. Our results indicate that high d-mannose concentrations have no effect on bacterial growth and do not interfere with the activity of different antibiotics. d-mannose ranked as the least preferred carbon source to support bacterial metabolism and growth, in comparison with d-glucose, d-fructose, and l-arabinose. Since small glucose amounts are physiologically detectable in urine, we can conclude that the presence of d-mannose is irrelevant for bacterial metabolism. Moreover, d-mannose removal after long-term exposure did not alter FimH's capacity to bind to mannosylated proteins. Overall, our data indicate that d-mannose is a good alternative in the prevention and treatment of UPEC-related UTIs.
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http://dx.doi.org/10.3390/molecules25020316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7024335PMC
January 2020

A simple, fast and reliable scan-based technique as a novel approach to quantify intracellular bacteria.

BMC Microbiol 2019 11 12;19(1):252. Epub 2019 Nov 12.

Department of Public Health and Infectious Diseases, Sapienza University of Rome, 00185, Rome, Italy.

Background: Quantification of intracellular bacteria is fundamental in many areas of cellular and clinical microbiology to study acute and chronic infections. Therefore, rapid, accurate and low-cost methods represent valuable tools in determining bacterial ability to persist and proliferate within eukaryotic cells.

Results: Herein, we present the first application of the immunofluorescence In-Cell Western (ICW) assay aimed at quantifying intracellular bacteria in in vitro infection models. The performance of this new approach was evaluated in cell culture infection models using three microorganisms with different lifestyles. Two facultative intracellular bacteria, the fast-growing Shigella flexneri and a persistent strain of Escherichia coli, as well as the obligate intracellular bacterium Chlamydia trachomatis were chosen as bacterial models. The ICW assay was performed in parallel with conventional quantification methods, i.e. colony forming units (CFUs) and inclusion forming units (IFUs). The fluorescence signal intensity values from the ICW assay were highly correlated to CFU/IFUs counting and showed coefficients of determination (R), ranging from 0,92 to 0,99.

Conclusions: The ICW assay offers several advantages including sensitivity, reproducibility, high speed, operator-independent data acquisition and overtime stability of fluorescence signals. All these features, together with the simplicity in performance, make this assay particularly suitable for high-throughput screening and diagnostic approaches.
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http://dx.doi.org/10.1186/s12866-019-1625-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849193PMC
November 2019

Glutathione and Nitric Oxide: Key Team Players in Use and Disuse of Skeletal Muscle.

Nutrients 2019 Sep 30;11(10). Epub 2019 Sep 30.

IRCCS San Raffaele 'La Pisana', 00166 Rome, Italy.

Glutathione (GSH) is the main non-enzymatic antioxidant playing an important role in detoxification, signal transduction by modulation of protein thiols redox status and direct scavenging of radicals. The latter function is not only performed against reactive oxygen species (ROS) but GSH also has a fundamental role in buffering nitric oxide (NO), a physiologically-produced molecule having-multifaceted functions. The efficient rate of GSH synthesis and high levels of GSH-dependent enzymes are characteristic features of healthy skeletal muscle where, besides the canonical functions, it is also involved in muscle contraction regulation. Moreover, NO production in skeletal muscle is a direct consequence of contractile activity and influences several metabolic myocyte pathways under both physiological and pathological conditions. In this review, we will consider the homeostasis and intersection of GSH with NO and then we will restrict the discussion on their role in processes related to skeletal muscle function and degeneration.
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http://dx.doi.org/10.3390/nu11102318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6836164PMC
September 2019

Role of Glutathionylation in Infection and Inflammation.

Nutrients 2019 Aug 20;11(8). Epub 2019 Aug 20.

IRCCS San Raffaele Pisana, Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, 00166 Rome, Italy.

Glutathionylation, that is, the formation of mixed disulfides between protein cysteines and glutathione (GSH) cysteines, is a reversible post-translational modification catalyzed by different cellular oxidoreductases, by which the redox state of the cell modulates protein function. So far, most studies on the identification of glutathionylated proteins have focused on cellular proteins, including proteins involved in host response to infection, but there is a growing number of reports showing that microbial proteins also undergo glutathionylation, with modification of their characteristics and functions. In the present review, we highlight the signaling role of GSH through glutathionylation, particularly focusing on microbial (viral and bacterial) glutathionylated proteins (GSSPs) and host GSSPs involved in the immune/inflammatory response to infection; moreover, we discuss the biological role of the process in microbial infections and related host responses.
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http://dx.doi.org/10.3390/nu11081952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6723385PMC
August 2019

Herpes Simplex Virus Type-1 Infection Impairs Adult Hippocampal Neurogenesis via Amyloid-β Protein Accumulation.

Stem Cells 2019 11 22;37(11):1467-1480. Epub 2019 Aug 22.

Institute of Human Physiology, Università Cattolica del Sacro Cuore, Rome, Italy.

We previously reported that Herpes simplex virus type-1 (HSV-1) infection of cultured neurons triggered intracellular accumulation of amyloid-β protein (Aβ) markedly impinging on neuronal functions. Here, we demonstrated that HSV-1 affects in vitro and in vivo adult hippocampal neurogenesis by reducing neural stem/progenitor cell (NSC) proliferation and their neuronal differentiation via intracellular Aβ accumulation. Specifically, cultured NSCs were more permissive for HSV-1 replication than mature neurons and, once infected, they exhibited reduced proliferation (assessed by 5'-bromo-deoxyuridine incorporation, Ki67 immunoreactivity, and Sox2 mRNA expression) and impaired neuronal differentiation in favor of glial phenotype (evaluated by immunoreactivity for the neuronal marker MAP2, the glial marker glial fibrillary astrocyte protein, and the expression of the proneuronal genes Mash1 and NeuroD1). Similarly, impaired adult neurogenesis was observed in the subgranular zone of hippocampal dentate gyrus of an in vivo model of recurrent HSV-1 infections, that we recently set up and characterized, with respect to mock-infected mice. The effects of HSV-1 on neurogenesis did not depend on cell death and were due to Aβ accumulation in infected NSCs. Indeed, they were: (a) reverted, in vitro, by the presence of either β/γ-secretase inhibitors preventing Aβ production or the specific 4G8 antibody counteracting the action of intracellular Aβ; (b) not detectable, in vivo, in HSV-1-infected amyloid precursor protein knockout mice, unable to produce and accumulate Aβ. Given the critical role played by adult neurogenesis in hippocampal-dependent memory and learning, our results suggest that multiple virus reactivations in the brain may contribute to Alzheimer's disease phenotype by also targeting NSCs. Stem Cells 2019;37:1467-1480.
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http://dx.doi.org/10.1002/stem.3072DOI Listing
November 2019

Polyomaviruses shedding in stool of patients with hematological disorders: detection analysis and study of the non-coding control region's genetic variability.

Med Microbiol Immunol 2019 Dec 2;208(6):845-854. Epub 2019 Aug 2.

Department of Public Health and Infectious Diseases, "Sapienza" University, P.le Aldo Moro, 5, 00185, Rome, Italy.

Fragmented data are available on the human polyomaviruses (HPyVs) prevalence in the gastrointestinal tract. Rearrangements in the non-coding control region (NCCR) of JCPyV and BKPyV have been extensively studied and correlated to clinical outcome; instead, little information is available for KIPyV, WUPyV and MCPyV NCCRs. To get insights into the role of HPyVs in the gastrointestinal tract, we investigated JCPyV, BKPyV, KIPyV, WUPyV and MCPyV distribution among hematological patients in concomitance with gastrointestinal symptoms. In addition, NCCRs and VP1 sequences were examined to characterize the strains circulating among the enrolled patients. DNA was extracted from 62 stool samples and qPCR was carried out to detect and quantify JCPyV, BKPyV, KIPyV, WUPyV and MCPyV genomes. Positive samples were subsequently amplified and sequenced for NCCR and VP1 regions. A phylogenetic tree was constructed aligning the obtained VP1 sequences to a set of reference sequences. qPCR revealed low viral loads for all HPyVs searched. Mono and co-infections were detected. A significant correlation was found between gastrointestinal complications and KIPyV infection. Archetype-like NCCRs were found for JCPyV and BKPyV, and a high degree of NCCRs stability was observed for KIPyV, WUPyV and MCPyV. Analysis of the VP1 sequences revealed a 99% identity with the VP1 reference sequences. The study adds important information on HPyVs prevalence and persistence in the gastrointestinal tract. Gastrointestinal signs were correlated with the presence of KIPyV, although definitive conclusions cannot be drawn. HPyVs NCCRs showed a high degree of sequence stability, suggesting that sequence rearrangements are rare in this anatomical site.
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http://dx.doi.org/10.1007/s00430-019-00630-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817764PMC
December 2019

Insights into the Periplasmic Proteins of AB5075 and the Impact of Imipenem Exposure: A Proteomic Approach.

Int J Mol Sci 2019 Jul 13;20(14). Epub 2019 Jul 13.

Department of Public Health and Infectious Diseases, Sapienza University of Rome, 00185 Rome, Italy.

Carbapenem-resistant strains cause life-threatening infections due to the lack of therapeutic options. Although the main mechanisms underlying antibiotic-resistance have been extensively studied, the general response to maintain bacterial viability under antibiotic exposure deserves to be fully investigated. Since the periplasmic space contains several proteins with crucial cellular functions, besides carbapenemases, we decided to study the periplasmic proteome of the multidrug-resistant (MDR) AB5075 strain, grown in the absence and presence of imipenem (IMP). Through the proteomic approach, 65 unique periplasmic proteins common in both growth conditions were identified: eight proteins involved in protein fate, response to oxidative stress, energy metabolism, antibiotic-resistance, were differentially expressed. Among them, ABUW_1746 and ABUW_2363 gene products presented the tetratricopeptide repeat motif, mediating protein-protein interactions. The expression switch of these proteins might determine specific protein interactions to better adapt to changing environmental conditions. ABUW_2868, encoding a heat shock protein likely involved in protection against oxidative stress, was upregulated in IMP-exposed bacteria. Accordingly, the addition of periplasmic proteins from cultured with IMP increased bacterial viability in an antioxidant activity assay. Overall, this study provides the first insights about the composition of the periplasmic proteins of a MDR strain, its biological response to IMP and suggests possible new targets to develop alternative antibiotic drugs.
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http://dx.doi.org/10.3390/ijms20143451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679007PMC
July 2019

Erratum to "Counteraction of HCV-Induced Oxidative Stress Concurs to Establish Chronic Infection in Liver Cell Cultures".

Oxid Med Cell Longev 2019 18;2019:3712969. Epub 2019 Apr 18.

Istituto Superiore di Sanità, Center for Gender-Specific Medicine, Rome, Italy.

[This corrects the article DOI: 10.1155/2019/6452390.].
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http://dx.doi.org/10.1155/2019/3712969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6501126PMC
April 2019

Counteraction of HCV-Induced Oxidative Stress Concurs to Establish Chronic Infection in Liver Cell Cultures.

Oxid Med Cell Longev 2019 13;2019:6452390. Epub 2019 Feb 13.

Istituto Superiore di Sanità, Center for Gender-Specific Medicine, Rome, Italy.

Hepatitis C virus (HCV) is a blood-borne pathogen causing acute and chronic hepatitis. A significant number of people chronically infected with HCV develop cirrhosis and/or liver cancer. The pathophysiologic mechanisms of hepatocyte damage associated with chronic HCV infection are not fully understood yet, mainly due to the lack of an system able to recapitulate the stages of infection . Several studies underline that HCV virus replication depends on redox-sensitive cellular pathways; in addition, it is known that virus itself induces alterations of the cellular redox state. However, the exact interplay between HCV replication and oxidative stress has not been elucidated. In particular, the role of reduced glutathione (GSH) in HCV replication and infection is still not clear. We set up an system, based on low m.o.i. of Huh7.5 cell line with a HCV infectious clone (J6/JFH1), that reproduced the acute and persistent phases of HCV infection up to 76 days of culture. We demonstrated that the acute phase of HCV infection is characterized by the elevated levels of reactive oxygen species (ROS) associated in part with an increase of NADPH-oxidase transcripts and activity and a depletion of GSH accompanied by high rates of viral replication and apoptotic cell death. Conversely, the chronic phase is characterized by a reestablishment of reduced environment due to a decreased ROS production and increased GSH content in infected cells that might concur to the establishment of viral persistence. Treatment with the prooxidant auranofin of the persistently infected cultures induced the increase of viral RNA titer, suggesting that a prooxidant state could favor the reactivation of HCV viral replication that in turn caused cell damage and death. Our results suggest that targeting the redox-sensitive host-cells pathways essential for viral replication and/or persistence may represent a promising option for contrasting HCV infection.
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http://dx.doi.org/10.1155/2019/6452390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6393922PMC
May 2019

Recurrent herpes simplex virus-1 infection induces hallmarks of neurodegeneration and cognitive deficits in mice.

PLoS Pathog 2019 03 14;15(3):e1007617. Epub 2019 Mar 14.

Department of Public Health and Infectious Diseases, Sapienza University of Rome, Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Rome, Italy.

Herpes simplex virus type 1 (HSV-1) is a DNA neurotropic virus, usually establishing latent infections in the trigeminal ganglia followed by periodic reactivations. Although numerous findings suggested potential links between HSV-1 and Alzheimer's disease (AD), a causal relation has not been demonstrated yet. Hence, we set up a model of recurrent HSV-1 infection in mice undergoing repeated cycles of viral reactivation. By virological and molecular analyses we found: i) HSV-1 spreading and replication in different brain regions after thermal stress-induced virus reactivations; ii) accumulation of AD hallmarks including amyloid-β protein, tau hyperphosphorylation, and neuroinflammation markers (astrogliosis, IL-1β and IL-6). Remarkably, the progressive accumulation of AD molecular biomarkers in neocortex and hippocampus of HSV-1 infected mice, triggered by repeated virus reactivations, correlated with increasing cognitive deficits becoming irreversible after seven cycles of reactivation. Collectively, our findings provide evidence that mild and recurrent HSV-1 infections in the central nervous system produce an AD-like phenotype and suggest that they are a risk factor for AD.
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http://dx.doi.org/10.1371/journal.ppat.1007617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6417650PMC
March 2019