Publications by authors named "Rachele Bigi"

13 Publications

  • Page 1 of 1

Multiple Sclerosis and SARS-CoV-2: Has the Interplay Started?

Front Immunol 2021 27;12:755333. Epub 2021 Sep 27.

Centre for Experimental Neurological Therapies (CENTERS), Department of Neurosciences, Mental Health and Sensory Organs, Sapienza University of Rome, Rome, Italy.

Current knowledge on Multiple Sclerosis (MS) etiopathogenesis encompasses complex interactions between the host's genetic background and several environmental factors that result in dysimmunity against the central nervous system. An old-aged association exists between MS and viral infections, capable of triggering and sustaining neuroinflammation through direct and indirect mechanisms. The novel Coronavirus, SARS-CoV-2, has a remarkable, and still not fully understood, impact on the immune system: the occurrence and severity of both acute COVID-19 and post-infectious chronic illness (long COVID-19) largely depends on the host's response to the infection, that echoes several aspects of MS pathobiology. Furthermore, other MS-associated viruses, such as the Epstein-Barr Virus (EBV) and Human Endogenous Retroviruses (HERVs), may enhance a mechanistic interplay with the novel Coronavirus, with the potential to interfere in MS natural history. Studies on COVID-19 in people with MS have helped clinicians in adjusting therapeutic strategies during the pandemic; similar efforts are being made for SARS-CoV-2 vaccination campaigns. In this Review, we look over 18 months of SARS-CoV-2 pandemic from the perspective of MS: we dissect neuroinflammatory and demyelinating mechanisms associated with COVID-19, summarize pathophysiological crossroads between MS and SARS-CoV-2 infection, and discuss present evidence on COVID-19 and its vaccination in people with MS.
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http://dx.doi.org/10.3389/fimmu.2021.755333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8503550PMC
October 2021

MAIT Cells and Microbiota in Multiple Sclerosis and Other Autoimmune Diseases.

Microorganisms 2021 May 24;9(6). Epub 2021 May 24.

Centre for Experimental Neurological Therapies (CENTERS), Department of Neurosciences, Mental Health and Sensory Organs, Sapienza University of Rome, 00189 Rome, Italy.

The functions of mucosal-associated invariant T (MAIT) cells in homeostatic conditions include the interaction with the microbiota and its products, the protection of body barriers, and the mounting of a tissue-repair response to injuries or infections. Dysfunction of MAIT cells and dysbiosis occur in common chronic diseases of inflammatory, metabolic, and tumor nature. This review is aimed at analyzing the changes of MAIT cells, as well as of the microbiota, in multiple sclerosis and other autoimmune disorders. Common features of dysbiosis in these conditions are the reduced richness of microbial species and the unbalance between pro-inflammatory and immune regulatory components of the gut microbiota. The literature concerning MAIT cells in these disorders is rather complex, and sometimes not consistent. In multiple sclerosis and other autoimmune conditions, several studies have been done, or are in progress, to find correlations between intestinal permeability, dysbiosis, MAIT cell responses, and clinical biomarkers in treated and treatment-naïve patients. The final aims are to explain what activates MAIT cells in diseases not primarily infective, which interactions with the microbiota are potentially pathogenic, and their dynamics related to disease course and disease-modifying treatments.
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http://dx.doi.org/10.3390/microorganisms9061132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8225125PMC
May 2021

A Case of Double Standard: Sex Differences in Multiple Sclerosis Risk Factors.

Int J Mol Sci 2021 Apr 2;22(7). Epub 2021 Apr 2.

Centre for Experimental Neurological Therapies (CENTERS), Department of Neurosciences, Mental Health and Sensory Organs, Sapienza University of Rome, 00189 Rome, Italy.

Multiple sclerosis is a complex, multifactorial, dysimmune disease prevalent in women. Its etiopathogenesis is extremely intricate, since each risk factor behaves as a variable that is interconnected with others. In order to understand these interactions, sex must be considered as a determining element, either in a protective or pathological sense, and not as one of many variables. In particular, sex seems to highly influence immune response at chromosomal, epigenetic, and hormonal levels. Environmental and genetic risk factors cannot be considered without sex, since sex-based immunological differences deeply affect disease onset, course, and prognosis. Understanding the mechanisms underlying sex-based differences is necessary in order to develop a more effective and personalized therapeutic approach.
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http://dx.doi.org/10.3390/ijms22073696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037645PMC
April 2021

SARS-CoV-2 meta-interactome suggests disease-specific, autoimmune pathophysiologies and therapeutic targets.

F1000Res 2020 17;9:992. Epub 2020 Aug 17.

Department of Neurosciences, Mental Health and Sensory Organs, Sapienza University of Rome, Rome, 00189, Italy.

Severe coronavirus disease 2019 (COVID-19) is associated with multiple comorbidities and is characterized by an auto-aggressive inflammatory state leading to massive collateral damage. To identify preventive and therapeutic strategies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it is important to ascertain the molecular interactions between virus and host, and how they translate into disease pathophysiology. We matched virus-human protein interactions of human coronaviruses and other respiratory viruses with lists of genes associated with autoimmune diseases and comorbidities associated to worse COVID-19 course. We then selected the genes included in the statistically significant intersection between SARS-CoV-2 network and disease associated gene sets, identifying a meta-interactome. We analyzed the meta-interactome genes expression in samples derived from lungs of infected humans, and their regulation by IFN-β. Finally, we performed a drug repurposing screening to target the network's most critical nodes. We found a significant enrichment of SARS-CoV-2 interactors in immunological pathways and a strong association with autoimmunity and three prognostically relevant conditions (type 2 diabetes, coronary artery diseases, asthma), that present more independent physiopathological subnetworks. We observed a reduced expression of meta-interactome genes in human lungs after SARS-CoV-2 infection, and a regulatory potential of type I interferons. We also underscored multiple repurposable drugs to tailor the therapeutic strategies. Our data underscored a plausible genetic background that may contribute to the distinct observed pathophysiologies of severe COVID-19. Also, these results may help identify the most promising therapeutic targets and treatments for this condition.
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http://dx.doi.org/10.12688/f1000research.25593.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791351PMC
January 2021

Reworking GWAS Data to Understand the Role of Nongenetic Factors in MS Etiopathogenesis.

Genes (Basel) 2020 01 14;11(1). Epub 2020 Jan 14.

Centre for Experimental Neurological Therapies (CENTERS), Department of Neurosciences, Mental Health and Sensory Organs, Sapienza University of Rome, 00189 Rome, Italy.

Genome-wide association studies have identified more than 200 multiple sclerosis (MS)-associated loci across the human genome over the last decade, suggesting complexity in the disease etiology. This complexity poses at least two challenges:
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http://dx.doi.org/10.3390/genes11010097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017269PMC
January 2020

Kinome profiling of non-Hodgkin lymphoma identifies Tyro3 as a therapeutic target in primary effusion lymphoma.

Proc Natl Acad Sci U S A 2019 08 25;116(33):16541-16550. Epub 2019 Jul 25.

Department of Microbiology and Immunology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599;

Non-Hodgkin lymphomas (NHLs) make up the majority of lymphoma diagnoses and represent a very diverse set of malignancies. We sought to identify kinases uniquely up-regulated in different NHL subtypes. Using multiplexed inhibitor bead-mass spectrometry (MIB/MS), we found Tyro3 was uniquely up-regulated and important for cell survival in primary effusion lymphoma (PEL), which is a viral lymphoma infected with Kaposi's sarcoma-associated herpesvirus (KSHV). Tyro3 was also highly expressed in PEL cell lines as well as in primary PEL exudates. Based on this discovery, we developed an inhibitor against Tyro3 named UNC3810A, which hindered cell growth in PEL, but not in other NHL subtypes where Tyro3 was not highly expressed. UNC3810A also significantly inhibited tumor progression in a PEL xenograft mouse model that was not seen in a non-PEL NHL model. Taken together, our data suggest Tyro3 is a therapeutic target for PEL.
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http://dx.doi.org/10.1073/pnas.1903991116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697815PMC
August 2019

Targeting mTOR with MLN0128 Overcomes Rapamycin and Chemoresistant Primary Effusion Lymphoma.

mBio 2019 02 19;10(1). Epub 2019 Feb 19.

UNC Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA

Primary effusion lymphoma (PEL) is caused by Kaposi's sarcoma-associated herpesvirus (KSHV). PEL has a highly active mTOR pathway, which makes mTOR a potential therapeutic target. MLN0128 is an ATP-competitive inhibitor of mTOR that has entered clinical trials for solid tumors. Our results demonstrated that MLN0128 has a greater effect on inhibiting proliferation than the allosteric mTOR inhibitor rapamycin. MLN0128 has ∼30 nM 50% inhibitory concentration (IC) across several PEL cell lines, including PEL that is resistant to conventional chemotherapy. MLN0128 induced apoptosis in PEL, whereas rapamycin induced G arrest, consistent with a different mechanism of action. MLN0128 inhibited phosphorylation of mTOR complex 1 and 2 targets, while rapamycin only partially inhibited mTOR complex 1 targets. PEL xenograft mouse models treated with MLN0128 showed reduced effusion volumes in comparison to the vehicle-treated group. Rapamycin-resistant (RR) clones with an IC for rapamycin 10 times higher than the parental IC emerged consistently after rapamycin exposure as a result of transcriptional adaptation. MLN0128 was nevertheless capable of inducing apoptosis in these RR clones. Our results suggest that MLN0128 might offer a new approach to the treatment of chemotherapy-resistant PEL. Primary effusion lymphoma (PEL) is an aggressive and incurable malignancy, which is usually characterized by lymphomatous effusions in body cavities without tumor masses. PEL has no established treatment and a poor prognosis, with a median survival time shorter than 6 months. PEL usually develops in the context of immunosuppression, such as HIV infection or post-organ transplantation. The optimal treatment for PEL has not been established, as PEL is generally resistant to traditional chemotherapy. The molecular drivers for PEL are still unknown; however, PEL displays a constitutively active mammalian target of rapamycin (mTOR) pathway, which is critical for metabolic and cell survival mechanisms. Therefore, the evaluation of novel agents targeting the mTOR pathway could be clinically relevant for the treatment of PEL.
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http://dx.doi.org/10.1128/mBio.02871-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6381283PMC
February 2019

Extracellular vesicles from Kaposi Sarcoma-associated herpesvirus lymphoma induce long-term endothelial cell reprogramming.

PLoS Pathog 2019 02 4;15(2):e1007536. Epub 2019 Feb 4.

Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

Extracellular signaling is a mechanism that higher eukaryotes have evolved to facilitate organismal homeostasis. Recent years have seen an emerging interest in the role of secreted microvesicles, termed extracellular vesicles (EV) or exosomes in this signaling network. EV contents can be modified by the cell in response to stimuli, allowing them to relay information to neighboring cells, influencing their physiology. Here we show that the tumor virus Kaposi's Sarcoma-associated herpesvirus (KSHV) hijacks this signaling pathway to induce cell proliferation, migration, and transcriptome reprogramming in cells not infected with the virus. KSHV-EV activates the canonical MEK/ERK pathway, while not alerting innate immune regulators, allowing the virus to exert these changes without cellular pathogen recognition. Collectively, we propose that KSHV establishes a niche favorable for viral spread and cell transformation through cell-derived vesicles, all while avoiding detection.
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http://dx.doi.org/10.1371/journal.ppat.1007536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6361468PMC
February 2019

Epstein-Barr virus enhances genome maintenance of Kaposi sarcoma-associated herpesvirus.

Proc Natl Acad Sci U S A 2018 11 14;115(48):E11379-E11387. Epub 2018 Nov 14.

Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, NC 27599

Primary effusion lymphoma (PEL) is a B cell lymphoma that is always associated with Kaposi's sarcoma-associated herpesvirus (KSHV) and in many cases also with Epstein-Barr virus (EBV); however, the requirement for EBV coinfection is not clear. Here, we demonstrate that adding exogenous EBV to KSHV single-positive PEL leads to increased KSHV genome maintenance and KSHV latency-associated nuclear antigen (LANA) expression. To show that EBV was necessary for naturally coinfected PEL, we nucleofected KSHV/EBV PEL cell lines with an EBV-specific CRISPR/Cas9 plasmid to delete EBV and observed a dramatic decrease in cell viability, KSHV genome copy number, and LANA expression. This phenotype was reversed by expressing Epstein-Barr nuclear antigen 1 (EBNA-1) , even though EBNA-1 and LANA do not colocalize in infected cells. This work reveals that EBV EBNA-1 plays an essential role in the pathogenesis of PEL by increasing KSHV viral load and LANA expression.
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http://dx.doi.org/10.1073/pnas.1810128115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6275488PMC
November 2018

Kaposi's Sarcoma-Associated Herpesvirus Latency Locus Renders B Cells Hyperresponsive to Secondary Infections.

J Virol 2018 10 12;92(19). Epub 2018 Sep 12.

Department of Microbiology and Immunology, Programs in Global Oncology and Virology, Lineberger Comprehensive Cancer Center and Center for AIDS Research, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Kaposi's sarcoma-associated herpesvirus (KSHV) induces B cell hyperplasia and neoplasia, such as multicentric Castleman's disease (MCD) and primary effusion lymphoma (PEL). To explore KSHV-induced B cell reprogramming , we expressed the KSHV latency locus, inclusive of all viral microRNAs (miRNAs), in B cells of transgenic mice in the absence of the inhibitory FcγRIIB receptor. The BALB/c strain was chosen as this is the preferred model to study B cell differentiation. The mice developed hyperglobulinemia, plasmacytosis, and B lymphoid hyperplasia. This phenotype was ameliorated by everolimus, which is a rapamycin derivative used for the treatment of mantle cell lymphoma. KSHV latency mice exhibited hyperresponsiveness to the T-dependent (TD) antigen mimic anti-CD40 and increased incidence of pristane-induced inflammation. Lastly, the adaptive immunity against a secondary infection with Zika virus (ZIKV) was markedly enhanced. These phenotypes are consistent with KSHV lowering the activation threshold of latently infected B cells, which may be beneficial in areas of endemicity, where KSHV is acquired in childhood and infections are common. Kaposi's sarcoma-associated herpesvirus (KSHV) establishes latency in B cells and is stringently linked to primary effusion lymphoma (PEL) and the premalignant B cell hyperplasia multicentric Castleman's disease (MCD). To investigate potential genetic background effects, we expressed the KSHV miRNAs in BALB/c transgenic mice. BALB/c mice are the preferred strain for B cell hybridoma development because of their propensity to develop predictable B cell responses to antigen. The BALB/c latency mice exhibited a higher incidence of B cell hyperplasia as well as sustained hyperglobulinemia. The development of neutralizing antibodies against ZIKV was augmented in BALB/c latency mice. Hyperglobulinemia was dampened by everolimus, a derivative of rapamycin, suggesting a role for mTOR inhibitors in managing immune activation, which is hallmark of KSHV infection as well as HIV infection.
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http://dx.doi.org/10.1128/JVI.01138-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6146794PMC
October 2018

Antimicrobial sulfonamides clear latent Kaposi sarcoma herpesvirus infection and impair MDM2-p53 complex formation.

J Antibiot (Tokyo) 2017 Aug 14;70(9):962-966. Epub 2017 Jun 14.

Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.

Kaposi sarcoma herpesvirus (KSHV), also known as human herpesvirus 8, is the causative agent of Kaposi sarcoma; this malignant angiosarcoma is usually treated with conventional antitumor agents that can control disease evolution, but do not clear the latent KSHV episome that binds to cellular DNA. Some commercial antibacterial sulfonamides were tested for the ability to suppress latent KSHV. Quantitative PCR (qPCR) and cytofluorometry assays were used for detecting both viral DNA and the latency factor LANA (latency-associated nuclear antigen) in BC3 cells, respectively. The capacity of sulfonamides to impair MDM2-p53 complex formation was detected by an enzyme-linked immunosorbent assay method. The analysis of variance was performed according to one-way analysis of variance with Fisher as a post hoc test. Here we show that sulfonamide antibiotics are able to suppress the KSHV latent state in permanently infected BC3 lymphoma cells and interfere with the formation of the MDM2-p53 complex that KSHV seemingly needs to support latency and to trigger tumor cell transformation. These findings detected a new molecular target for the activity of sulfonamides and offer a new potential perspective for treating KSHV-induced lymphoproliferative diseases.
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http://dx.doi.org/10.1038/ja.2017.67DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6002838PMC
August 2017

Epstein-Barr virus infection induces miR-21 in terminally differentiated malignant B cells.

Int J Cancer 2015 Sep 4;137(6):1491-7. Epub 2015 Mar 4.

Department of Experimental Medicine, La Sapienza University, Rome, Italy.

The association of Epstein-Barr virus (EBV) with plasmacytoid malignancies is now well established but how the virus influences microRNA expression in such cells is not known. We have used multiple myeloma (MM) cell lines to address this issue and find that an oncomiR, miR-21 is induced after in vitro EBV infection. The PU.1 binding site in miR-21 promoter was essential for its activation by the virus. In accordance with its noted oncogenic functions, miR-21 induction in EBV infected MM cells caused downregulation of p21 and an increase in cyclin D3 expression. EBV infected MM cells were highly tumorigenic in SCID mice. Given the importance of miR-21 in plasmacytoid malignancies, our findings that EBV could further exacerbate the disease by inducing miR-21 has interesting implications both in terms of diagnosis and future miR based therapeutical approaches for the virus associated plasmacytoid tumors.
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http://dx.doi.org/10.1002/ijc.29489DOI Listing
September 2015

Modulation of the Ca(2+) permeability of human endplate acetylcholine receptor-channel.

Cell Calcium 2011 Apr 5;49(4):272-8. Epub 2011 Apr 5.

Dipartimento di Fisiologia e Farmacologia, Sapienza Università di Roma, P.le A. Moro 5, I-00185 Roma, Italy.

In slow-channel congenital myasthenic syndrome, point mutations of the endplate acetylcholine receptor (AChR) prolong channel openings, leading to excessive Ca(2+) entry with ensuing endplate degeneration and myasthenic symptoms. The Ca(2+) permeability of the human endplate AChR-channel is quite high, and is further increased by two slow-channel mutations in its ɛ subunit, worsening the pathological cascade. To gain further support to the hypothesis that the ɛ subunit plays a crucial role in controlling Ca(2+) permeability of endplate AChR-channel, in this work we measured the fractional Ca(2+) current (P(f), i.e., the percentage of the total current carried by Ca(2+) ions) of a panel of AChR carrying slow-channel mutations in the α, β and ɛ subunits detected in patients (α(N217K), α(S226Y), α(C418W), β(V266A), β(V266M), ɛ(I257F), ɛ(V265A) and ɛ(L269F)). We confirm that only mutations in the ɛ subunit altered Ca(2+) permeability of AChR-channels, with ɛ(L269F) increasing P(f) (10% vs. 7% of wild type AChR) and ɛ(I257F) decreasing it (to 4.6%). We also found that, for ɛ(L269F)-AChR, the Ca(2+) permeability and ACh-induced cell death can be normalized by clinically relevant concentrations of salbutamol or verapamil, providing the first evidence that the Ca(2+) permeability of AChR-channels can be modulated and this treatment may provide protection against excitotoxic insults.
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http://dx.doi.org/10.1016/j.ceca.2011.03.002DOI Listing
April 2011
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