Publications by authors named "Arnaldo Caruso"

134 Publications

Binding to PI(4,5)P is indispensable for secretion of B cell clonogenic HIV-1 matrix protein p17 variants.

J Biol Chem 2021 Jul 14:100934. Epub 2021 Jul 14.

Section of Microbiology, Department of Molecular and Translational Medicine, University of Brescia medical School, Brescia, Italy. Electronic address:

Human immunodeficiency virus type 1 (HIV-1) matrix protein p17 variants (vp17s) derived from non-Hodgkin lymphoma (NHL) tissues of HIV-1-seropositive (HIV) patients promote B cell growth by activating the Akt signaling pathway. It is fundamental to understand the role played by vp17s in producing a microenvironment that fosters lymphoma development and progression. Therefore, we asked whether vp17s could be secreted from infected cells in their biologically active form. In this study, we show that two B cell growth-promoting vp17s, NHL-a101 and NHL-a102, characterized by amino acid insertions at position 117-118 (Ala-Ala) or 125-126 (Gly-Asn), respectively, are secreted from HIV-1-infected Jurkat T-cells during the active phase of viral replication. Secretion of biologically active vp17s also occurred in HeLa cells nucleofected with a plasmid expressing the entire Gag gene, following proteolytic cleavage of the precursor Gag polyprotein (Pr55) by cellular aspartyl proteases. Binding of Pr55 to PI(4,5)P was indispensable for allowing the unconventional secretion of both wild-type p17 and vp17s. Indeed, here we demonstrate that inhibition of Pr55 binding to PI(4,5)P by using neomycin, or its enzymatic depletion achieved by overexpression of 5ptaseIV, significantly impair p17s secretion. We also demonstrated that heparan sulfate proteoglycans were involved in tethering p17s at the cell surface. This finding opens up an interesting way for investigating whether tethered p17s on the surface of HIV-1 reservoirs may represent a likely target for immune-mediated killing.
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http://dx.doi.org/10.1016/j.jbc.2021.100934DOI Listing
July 2021

SARS-CoV-2 B.1.617 Indian variants: Are electrostatic potential changes responsible for a higher transmission rate?

J Med Virol 2021 Jul 14. Epub 2021 Jul 14.

Center of of Genomics, Genetics and Biology, Siena, Italy.

Lineage B.1.617+, also known as G/452R.V3 and now denoted by WHO with the Greek letters δ and κ, is a recently described SARS-CoV-2 variant under investigation first identified in October 2020 in India. As of May 2021, three sublineages labeled as B.1.617.1 (κ), B.1.617.2 (δ), and B.1.617.3 have been already identified, and their potential impact on the current pandemic is being studied. This variant has 13 amino acid changes, three in its spike protein, which are currently of particular concern: E484Q, L452R, and P681R. Here, we report a major effect of the mutations characterizing this lineage, represented by a marked alteration of the surface electrostatic potential (EP) of the receptor-binding domain (RBD) of the spike protein. Enhanced RBD-EP is particularly noticeable in the B.1.617.2 (δ) sublineage, which shows multiple replacements of neutral or negatively charged amino acids with positively charged amino acids. We here hypothesize that this EP change can favor the interaction between the B.1.617+ RBD and the negatively charged ACE2, thus conferring a potential increase in the virus transmission.
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http://dx.doi.org/10.1002/jmv.27210DOI Listing
July 2021

: .

Euro Surveill 2021 06;26(25)

Department Infectious Diseases, Istituto Superiore di Sanità, Rome, Italy.

In September 2018 in Brescia province, northern Italy, an outbreak of Legionnaires' disease (LD) caused by serogroup 2 () occurred. The 33 cases (two fatal) resided in seven municipalities along the Chiese river. All cases were negative by urinary antigen test (UAT) and most were diagnosed by real-time PCR and serology. In only three cases, respiratory sample cultures were positive, and was identified and typed as sequence type (ST)1455. In another three cases, nested sequence-based typing was directly applied to respiratory samples, which provided allelic profiles highly similar to ST1455. An environmental investigation was undertaken immediately and water samples were collected from private homes, municipal water systems, cooling towers and the river. Overall, 533 environmental water samples were analysed and 34 were positive for . Of these, only three samples, all collected from the Chiese river, were ST1455. If and how the river water could have been aerosolised causing the LD cases remains unexplained. This outbreak, the first to our knowledge caused by , highlights the limits of UAT for LD diagnosis, underlining the importance of adopting multiple tests to ensure that serogroups other than serogroup 1, as well as other species, are identified.
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http://dx.doi.org/10.2807/1560-7917.ES.2021.26.25.2001961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8229375PMC
June 2021

Serosurvey in BNT162b2 vaccine-elicited neutralizing antibodies against authentic B.1, B.1.1.7, B.1.351, B.1.525 and P.1 SARS-CoV-2 variants.

Emerg Microbes Infect 2021 Dec;10(1):1241-1243

Section of Microbiology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.

In this study, we show that BNT162b2 vaccine-elicited antibodies efficiently neutralize SARS-CoV-2 authentic viruses belonging to B.1, B.1.1.7, B.1.351, B.1.525 and P.1 lineages. Interestingly, the neutralization of B.1.1.7 and B.1.525 lineages was significantly higher, whereas the neutralization of B.1.351 and P.1 lineages was robust but significantly lower as compared to B.1 lineage. Following our findings, we consider that the BNT162b2 vaccine offers protection against the current prevailing variants of SARS-CoV-2.
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http://dx.doi.org/10.1080/22221751.2021.1940305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8216260PMC
December 2021

Viral Proteins as Emerging Cancer Therapeutics.

Cancers (Basel) 2021 May 3;13(9). Epub 2021 May 3.

Section of Microbiology, Department of Molecular and Translational Medicine, University of Brescia Medical School, 25123 Brescia, Italy.

Viruses are obligatory intracellular parasites that originated millions of years ago. Viral elements cover almost half of the human genome sequence and have evolved as genetic blueprints in humans. They have existed as endosymbionts as they are largely dependent on host cell metabolism. Viral proteins are known to regulate different mechanisms in the host cells by hijacking cellular metabolism to benefit viral replication. Amicable viral proteins, on the other hand, from several viruses can participate in mediating growth retardation of cancer cells based on genetic abnormalities while sparing normal cells. These proteins exert discreet yet converging pathways to regulate events like cell cycle and apoptosis in human cancer cells. This property of viral proteins could be harnessed for their use in cancer therapy. In this review, we discuss viral proteins from different sources as potential anticancer therapeutics.
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http://dx.doi.org/10.3390/cancers13092199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8125098PMC
May 2021

SARS-CoV-2 shifting transmission dynamics and hidden reservoirs potentially limit efficacy of public health interventions in Italy.

Commun Biol 2021 04 21;4(1):489. Epub 2021 Apr 21.

Medical Statistic and Molecular Epidemiology Unit, University of Biomedical Campus, Rome, Italy.

We investigated SARS-CoV-2 transmission dynamics in Italy, one of the countries hit hardest by the pandemic, using phylodynamic analysis of viral genetic and epidemiological data. We observed the co-circulation of multiple SARS-CoV-2 lineages over time, which were linked to multiple importations and characterized by large transmission clusters concomitant with a high number of infections. Subsequent implementation of a three-phase nationwide lockdown strategy greatly reduced infection numbers and hospitalizations. Yet we present evidence of sustained viral spread among sporadic clusters acting as "hidden reservoirs" during summer 2020. Mathematical modelling shows that increased mobility among residents eventually catalyzed the coalescence of such clusters, thus driving up the number of infections and initiating a new epidemic wave. Our results suggest that the efficacy of public health interventions is, ultimately, limited by the size and structure of epidemic reservoirs, which may warrant prioritization during vaccine deployment.
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http://dx.doi.org/10.1038/s42003-021-02025-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060392PMC
April 2021

Possible Impact of Severe Acute Respiratory Syndrome Coronavirus-2 Control Measures in Reducing Colonization by Gram-negative Bacteria and Candida spp. in a Neonatal Intensive Care Unit.

Pediatr Infect Dis J 2021 05;40(5):e211-e213

Department of Molecular and Translational Medicine, Institute of Microbiology, University of Brescia-ASST Spedali Civili di Brescia, Brescia, Italy.

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http://dx.doi.org/10.1097/INF.0000000000003092DOI Listing
May 2021

Serological Response to SARS-CoV-2 in Health Care Workers Employed in a Large Tertiary Hospital in Lombardy, Northern Italy.

Microorganisms 2021 Feb 25;9(3). Epub 2021 Feb 25.

University Department of Infectious and Tropical Diseases, University of Brescia and ASST Spedali Civili, 25123 Brescia, Italy.

Background: COVID-19 pandemic is requesting unprecedented efforts by health-care workers (HCWs) in all countries, and especially in Italy during the first semester of 2020.

Methods: This is a retrospective, observational study conducted at the Spedali Civili General Hospital, in Brescia, Northern Italy during the SARS CoV-2 pandemic in the first semester of 2020. Serum samples from HCWs were tested for SARS-CoV-2 spike protein-specific antibodies. An online survey was used to collect demographic, clinical, and epidemiological data.

Results: Of the 1893 HCWs included, 433 (22.9%) were found seropositive for SARS-CoV-2 IgG. The cumulative prevalence of SARS-CoV-2 infection (antibodies production or past positive RT-PCR on nasal/throat swab) was 25.1% (475/1893). Fifty-six out of 433 (13%) seropositive participants declared to have been asymptomatic during the study period. The development of COVID-19 signs or symptoms is the main determinant of seropositivity (OR: 11.3, < 0.0001) along with their duration and severity. 40/290 (14.5%) HCWs with documented positive RT-PCR during the study period did not show any detectable antibody response. IgG levels positively correlate with age, COVID-19-compatible signs and symptoms experienced and their duration.

Conclusions: In this study, carried out in one of the most affected areas in Europe, we demonstrate that most HCWs with COVID-19 related symptoms develop a spike protein-specific antibodies with potential neutralizing effect.
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http://dx.doi.org/10.3390/microorganisms9030488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996483PMC
February 2021

Avian Reovirus P17 Suppresses Angiogenesis by Promoting DPP4 Secretion.

Cells 2021 Jan 28;10(2). Epub 2021 Jan 28.

Section of Microbiology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy.

Avian reovirus p17 (ARV p17) is a non-structural protein known to activate autophagy, interfere with gene transcription and induce a significant tumor cell growth inhibition in vitro and in vivo. In this study, we show that ARV p17 is capable of exerting potent antiangiogenic properties. The viral protein significantly inhibited the physiological angiogenesis of human endothelial cells (ECs) by affecting migration, capillary-like structure and new vessel formation. ARV p17 was not only able to suppress the EC physiological angiogenesis but also rendered ECs insensitive to two different potent proangiogenic inducers, such as VEGF-A and FGF-2 in the three-dimensional (3D) Matrigel and spheroid assay. ARV p17 was found to exert its antiangiogenic activity by upregulating transcription and release of the well-known tumor suppressor molecule dipeptidyl peptidase 4 (DPP4). The ability of ARV p17 to impact on angiogenesis is completely new and highlights the "two compartments" activity of the viral protein that is expected to hamper the tumor parenchymal/stromal crosstalk. The complex antitumor activities of ARV p17 open the way to a new promising field of research aimed to develop new therapeutic approaches for treating tumor and cancer metastasis.
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http://dx.doi.org/10.3390/cells10020259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911508PMC
January 2021

First detection of SARS-CoV-2 spike protein N501 mutation in Italy in August, 2020.

Lancet Infect Dis 2021 06 12;21(6):e147. Epub 2021 Jan 12.

Section of Microbiology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy. Electronic address:

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http://dx.doi.org/10.1016/S1473-3099(21)00007-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836831PMC
June 2021

Evolution toward beta common chain receptor usage links the matrix proteins of HIV-1 and its ancestors to human erythropoietin.

Proc Natl Acad Sci U S A 2021 01;118(2)

Department of Molecular and Translational Medicine, University of Brescia Medical School, 25123 Brescia, Italy;

The HIV-1 matrix protein p17 (p17) is a pleiotropic molecule impacting on different cell types. Its interaction with many cellular proteins underlines the importance of the viral protein as a major determinant of human specific adaptation. We previously showed the proangiogenic capability of p17. Here, by integrating functional analysis and receptor binding, we identify a functional epitope that displays molecular mimicry with human erythropoietin (EPO) and promotes angiogenesis through common beta chain receptor (βCR) activation. The functional EPO-like epitope was found to be present in the matrix protein of HIV-1 ancestors SIV originated in chimpanzees (SIVcpz) and gorillas (SIVgor) but not in that of HIV-2 and its ancestor SIVsmm from sooty mangabeys. According to biological data, evolution of the EPO-like epitope showed a clear differentiation between HIV-1/SIVcpz-gor and HIV-2/SIVsmm branches, thus highlighting this epitope on p17 as a divergent signature discriminating HIV-1 and HIV-2 ancestors. P17 is known to enhance HIV-1 replication. Similarly to other βCR ligands, p17 is capable of attracting and activating HIV-1 target cells and promoting a proinflammatory microenvironment. Thus, it is tempting to speculate that acquisition of an epitope on the matrix proteins of HIV-1 ancestors capable of triggering βCR may have represented a critical step to enhance viral aggressiveness and early human-to-human SIVcpz/gor dissemination. The hypothesis that the p17/βCR interaction and βCR abnormal stimulation may also play a role in sustaining chronic activation and inflammation, thus marking the difference between HIV-1 and HIV-2 in term of pathogenicity, needs further investigation.
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http://dx.doi.org/10.1073/pnas.2021366118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812818PMC
January 2021

The U94 Gene of Human Herpesvirus 6: A Narrative Review of Its Role and Potential Functions.

Cells 2020 12 4;9(12). Epub 2020 Dec 4.

Section of Microbiology, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy.

Human herpesvirus 6 (HHV-6) is a β-herpesvirus that is highly prevalent in the human population. HHV-6 comprises two recognized species (HHV-6A and HHV-6B). Despite different cell tropism and disease association, HHV-6A/B show high genome homology and harbor the conserved U94 gene, which is limited to HHV-6 and absent in all the other human herpesviruses. U94 has key functions in the virus life cycle and associated diseases, having demonstrated or putative roles in virus replication, integration, and reactivation. During natural infection, U94 elicits an immune response, and the prevalence and extent of the anti-U94 response are associated with specific diseases. Notably, U94 can entirely reproduce some virus effects at the cell level, including inhibition of cell migration, induction of cytokines and HLA-G expression, and angiogenesis inhibition, supporting a direct U94 role in the development of HHV-6-associated diseases. Moreover, specific U94 properties, such as the ability to modulate angiogenesis pathways, have been exploited to counteract cancer development. Here, we review the information available on this key HHV-6 gene, highlighting its potential uses.
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http://dx.doi.org/10.3390/cells9122608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762089PMC
December 2020

Evolution patterns of SARS-CoV-2: Snapshot on its genome variants.

Biochem Biophys Res Commun 2021 01 6;538:88-91. Epub 2020 Nov 6.

Medical Statistic and Molecular Epidemiology Unit, University of Biomedical Campus, Rome, Italy. Electronic address:

An acute respiratory syndrome (COVID-19), caused by a novel coronavirus (SARS-CoV-2) with a high rate of morbidity and elevate mortality, has emerged as one of the most important threats to humankind in the last centuries. Rigorous determination of SARS-CoV-2 infectivity is very difficult owing to the continuous evolution of the virus, with its single nucleotide polymorphism (SNP) variants and many lineages. However, it is urgently necessary to study the virus in depth, to understand the mechanism of its pathogenicity and virulence, and to develop effective therapeutic strategies. The present contribution summarizes in a succinct way the current knowledge on the evolutionary and structural features of the virus, with the aim of clarifying its mutational pattern and its possible role in the ongoing pandemic.
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http://dx.doi.org/10.1016/j.bbrc.2020.10.102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836704PMC
January 2021

Advances in CMV Management: A Single Center Real-Life Experience.

Front Cell Dev Biol 2020 27;8:534268. Epub 2020 Oct 27.

Chair of Hematology, Bone Marrow Transplant Unit, ASST-Spedali Civili Brescia, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.

CMV infection is a major challenge in allogeneic stem cell transplantation (allo-SCT). The changing landscape in CMV management includes the introduction of letermovir in prophylaxis of high-risk patients and the source of CMV DNA monitoring (plasma-PL vs. whole blood-WB), for pre-emptive therapy (PET) initiation. We report here how our real-life experience in CMV management evolved, following letermovir registration. We focus on: (i) the effects of systematic use of letermovir for CMV prophylaxis in high-risk patients, (ii) the results of a longitudinal comparison of CMV DNAemia monitoring in PL and WB. From December 2018 to April 2020, 60 allo-SCTs have been performed in our center (LET ), of whom 45 received letermovir in prophylaxis from day 0 to day + 100, because of recipient positivity of anti CMV IgG. These patients were compared with a cohort of 41 allo-SCTs performed between November 2017 and November 2018 (NO LET ). Firstly, the incidence of CMV clinically significant infections, CMV disease, bacterial infections, proven/probable fungal infections, hospital re-admissions after allo-SCT by day + 100 in the two ERA were 8 vs. 44% ( = 0.0006), 2 vs. 12% ( = 0.02), 37 vs. 56% ( = 0.05), 8 vs. 19% ( = 0.09), and 23 vs. 39% ( = 0.09), respectively. By day + 180 these differences were 17 vs. 68% ( < 0.00001), 2 vs. 12% ( = 0.02), 45 vs. 78% ( = 0.09), 8 vs. 22% ( = 0.05), and 40 vs. 66% ( = 0.01), respectively. Secondly, from February to May 2019, we comparatively measured CMV DNA from WB and PL and we confirmed that there is a linear correlation between CMV DNA level in WB and PL (Spearman's test = 0.86). Moreover, CMV DNAemia at the time of PET in the 12 patients with a clinically significant CMV infection was higher in WB vs. PL (5.202 vs. 4.981 copies/ml, = 0.1). Our real-life experience confirms that: (i) letermovir is highly effective, leading to a significant drop in CMV clinically significant infections and CMV-related complications by day + 100 and + 180 after allo-SCT; (ii) WB may be an effective alternative to PL as a source for CMV DNA monitoring, as a linear correlation of DNAemia was confirmed between WB and PL, even if the CMV DNAemia at PET initiation was comparable in the two sources.
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http://dx.doi.org/10.3389/fcell.2020.534268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7652755PMC
October 2020

B-cell clonogenic activity of HIV-1 p17 variants is driven by PAR1-mediated EGF transactivation.

Cancer Gene Ther 2021 Jun 22;28(6):649-666. Epub 2020 Oct 22.

Section of Microbiology, Department of Molecular and Translational Medicine, University of Brescia, 25123, Brescia, Italy.

Combined antiretroviral therapy (cART) for HIV-1 dramatically slows disease progression among HIV individuals. Currently, lymphoma represents the main cause of death among HIV-1-infected patients. Detection of p17 variants (vp17s) endowed with B-cell clonogenic activity in HIV-1-seropositive patients with lymphoma suggests their possible role in lymphomagenesis. Here, we demonstrate that the clonogenic activity of vp17s is mediated by their binding to PAR1 and to PAR1-mediated EGFR transactivation through Gq protein. The entire vp17s-triggered clonogenic process is MMPs dependent. Moreover, phosphoproteomic and bioinformatic analysis highlighted the crucial role of EGFR/PI3K/Akt pathway in modulating several molecules promoting cancer progression, including RAC1, ABL1, p53, CDK1, NPM, Rb, PTP-1B, and STAT1. Finally, we show that a peptide (F1) corresponding to the vp17s functional epitope is sufficient to trigger the PAR1/EGFR/PI3K/Akt pathway and bind PAR1. Our findings suggest novel potential therapeutic targets to counteract vp17-driven lymphomagenesis in HIV patients.
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http://dx.doi.org/10.1038/s41417-020-00246-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203498PMC
June 2021

Mycoplasma infection may complicate the clinical course of SARS-Co-V-2 associated Kawasaki-like disease in children.

Clin Immunol 2020 12 16;221:108613. Epub 2020 Oct 16.

Institute of Microbiology and Virology, Department of Molecular and Translational Medicine, University of Brescia-ASST Spedali Civili of Brescia, Brescia, Italy.

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http://dx.doi.org/10.1016/j.clim.2020.108613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7561565PMC
December 2020

A persistently replicating SARS-CoV-2 variant derived from an asymptomatic individual.

J Transl Med 2020 09 23;18(1):362. Epub 2020 Sep 23.

Department of Molecular and Translational Medicine, Section of Microbiology, University of Brescia, Brescia, Italy.

Background: Since the first outbreak of SARS-CoV-2, the clinical characteristics of the Coronavirus Disease 2019 (COVID-19) have been progressively changed. Data reporting a viral intra-host and inter-host evolution favouring the appearance of mild SARS-CoV-2 strains are since being accumulating. To better understand the evolution of SARS-CoV-2 pathogenicity and its adaptation to the host, it is therefore crucial to investigate the genetic and phenotypic characteristics of SARS-CoV-2 strains circulating lately in the epidemic.

Methods: Nasopharyngeal swabs have been analyzed for viral load in the early (March 2020) and late (May 2020) phases of epidemic in Brescia, Italy. Isolation of SARS-CoV-2 from 2 high viral load specimens identified on March 9 (AP66) and on May 8 (GZ69) was performed on Vero E6 cells. Amount of virus released was assessed by quantitative PCR. Genotypic characterization of AP66 and GZ69 was performed by next generation sequencing followed by an in-depth in silico analysis of nucleotide mutations.

Results: The SARS-CoV-2 GZ69 strain, isolated in May from an asymptomatic healthcare worker, showed an unprecedented capability of replication in Vero E6 cells in the absence of any evident cytopathic effect. Vero E6 subculturing, up to passage 4, showed that SARS-CoV-2 GZ69 infection was as productive as the one sustained by the cytopathic strain AP66. Whole genome sequencing of the persistently replicating SARS-CoV-2 GZ69 has shown that this strain differs from the early AP66 variant in 9 nucleotide positions (C2939T; C3828T; G21784T; T21846C; T24631C; G28881A; G28882A; G28883C; G29810T) which lead to 6 non-synonymous substitutions spanning on ORF1ab (P892S; S1188L), S (K74N; I95T) and N (R203K, G204R) proteins.

Conclusions: Identification of the peculiar SARS-CoV-2 GZ69 strain in the late Italian epidemic highlights the need to better characterize viral variants circulating among asymptomatic or paucisymptomatic individuals. The current approach could unravel the ways for future studies aimed at analyzing the selection process which favours viral mutations in the human host.
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http://dx.doi.org/10.1186/s12967-020-02535-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509824PMC
September 2020

May we learn a useful lesson from prevention rules against severe acute respiratory coronavirus virus 2 (SARS-CoV-2)?

Infect Control Hosp Epidemiol 2020 Sep 23:1-2. Epub 2020 Sep 23.

Department of Molecular and Translational Medicine, Institute of Microbiology, University of Brescia-ASST Spedali Civili di Brescia, Brescia, Italy.

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http://dx.doi.org/10.1017/ice.2020.1228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591741PMC
September 2020

and SARS-CoV-2 Co-Infection: A Common Feature in Transplant Recipients?

Vaccines (Basel) 2020 Sep 18;8(3). Epub 2020 Sep 18.

Institute of Microbiology, Department of Molecular and Translational Medicine, University of Brescia-ASST Spedali Civili di Brescia, 25123 Brescia, Italy.

COVID-19 might potentially give rise to a more severe infection in solid organ transplant recipients due to their chronic immunosuppression. These patients are at a higher risk of developing concurrent or secondary bacterial and fungal infections. Co-infections can increase systemic inflammation influencing the prognosis and the severity of the disease, and can in turn lead to an increased need of mechanical ventilation, antibiotic therapy and to a higher mortality. Here we describe, for the first time in Europe, a fatal case of co-infection between SARS-CoV-2 and in a kidney transplant recipient.
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http://dx.doi.org/10.3390/vaccines8030544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565862PMC
September 2020

Methotrexate inhibits SARS-CoV-2 virus replication "in vitro".

J Med Virol 2021 03 28;93(3):1780-1785. Epub 2020 Sep 28.

Department of Biotechnology and Biosciences, ISBE.IT-SYSBIO/Centre of Systems Biology, University of Milano Bicocca, Milano, Italy.

In early 2020 the new respiratory syndrome COVID-19 (caused by the zoonotic SARS-CoV-2 virus) spread like a pandemic, starting from Wuhan, China, causing severe economic depression. Despite some advances in drug treatments of medical complications in the later stages of the disease, the pandemic's death toll is tragic, as no vaccine or specific antiviral treatment is currently available. By using a systems approach, we identify the host-encoded pathway, which provides ribonucleotides to viral RNA synthesis, as a possible target. We show that methotrexate, an FDA-approved inhibitor of purine biosynthesis, potently inhibits viral RNA replication, viral protein synthesis, and virus release. The effective antiviral methotrexate concentrations are similar to those used for established human therapies using the same drug. Methotrexate should be most effective in patients at the earliest appearance of symptoms to effectively prevent viral replication, diffusion of the infection, and possibly fatal complications.
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http://dx.doi.org/10.1002/jmv.26512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891346PMC
March 2021

Detection of a hypermucoviscous Klebsiella pneumoniae co-producing NDM-5 and OXA-48 carbapenemases with sequence type 383, Brescia, Italy.

Int J Antimicrob Agents 2020 Oct 4;56(4):106130. Epub 2020 Aug 4.

Institute of Microbiology, Department of Molecular and Translational Medicine, University of Brescia-Spedali Civili, Brescia, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.ijantimicag.2020.106130DOI Listing
October 2020

Molecular Tracing of SARS-CoV-2 in Italy in the First Three Months of the Epidemic.

Viruses 2020 07 24;12(8). Epub 2020 Jul 24.

Department of Biomedical and Clinical Sciences Luigi Sacco, University of Milan, 20157 Milan, Italy.

The aim of this study is the characterization and genomic tracing by phylogenetic analyses of 59 new SARS-CoV-2 Italian isolates obtained from patients attending clinical centres in North and Central Italy until the end of April 2020. All but one of the newly-characterized genomes belonged to the lineage B.1, the most frequently identified in European countries, including Italy. Only a single sequence was found to belong to lineage B. A mean of 6 nucleotide substitutions per viral genome was observed, without significant differences between synonymous and non-synonymous mutations, indicating genetic drift as a major source for virus evolution. tMRCA estimation confirmed the probable origin of the epidemic between the end of January and the beginning of February with a rapid increase in the number of infections between the end of February and mid-March. Since early February, an effective reproduction number (R) greater than 1 was estimated, which then increased reaching the peak of 2.3 in early March, confirming the circulation of the virus before the first COVID-19 cases were documented. Continuous use of state-of-the-art methods for molecular surveillance is warranted to trace virus circulation and evolution and inform effective prevention and containment of future SARS-CoV-2 outbreaks.
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http://dx.doi.org/10.3390/v12080798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7472216PMC
July 2020

Human Metapneumovirus Establishes Persistent Infection in Lung Microvascular Endothelial Cells and Primes a Th2-Skewed Immune Response.

Microorganisms 2020 May 30;8(6). Epub 2020 May 30.

Section of Microbiology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy.

(HMPV) is a major cause of lower respiratory tract infections. HMPV infection has been hypothesized to alter dendritic cell (DC) immune response; however, many questions regarding HMPV pathogenesis within the infected lung remain unanswered. Here, we show that HMPV productively infects human lung microvascular endothelial cells (L-HMVECs). The release of infectious virus occurs for up to more than 30 days of culture without producing overt cytopathic effects and medium derived from persistently HMPV-infected L-HMVECs (secretome) induced monocyte-derived DCs to prime naïve CD4 T-cells toward a Th2 phenotype. Moreover, we demonstrated that infected secretomes trigger DCs to up-regulate OX40L expression and OX40L neutralization abolished the pro-Th2 effect that is induced by HMPV-secretome. We clarified secretome from HMPV by size exclusion and ultracentrifugation with the aim to characterize the role of viral particles in the observed pro-Th2 effect. In both cases, the percentage of IL-4-producing cells and expression of OX40L returned at basal levels. Finally, we showed that HMPV, , could reproduce the ability of secretome to prime pro-Th2 DCs. These results suggest that HMPV, persistently released by L-HMVECs, might take part in the development of a skewed, pro-Th2 lung microenvironment.
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http://dx.doi.org/10.3390/microorganisms8060824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357125PMC
May 2020

Steroid-Responsive Encephalitis in Coronavirus Disease 2019.

Ann Neurol 2020 08 9;88(2):423-427. Epub 2020 Jun 9.

Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.

Coronavirus disease 2019 (COVID-19) infection has the potential for targeting the central nervous system, and several neurological symptoms have been described in patients with severe respiratory distress. Here, we described the case of a 60-year-old patient with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection but only mild respiratory abnormalities who developed an akinetic mutism attributable to encephalitis. Magnetic resonance imaging was negative, whereas electroencephalography showed generalized theta slowing. Cerebrospinal fluid analyses during the acute stage were negative for SARS-CoV-2, positive for pleocytosis and hyperproteinorrachia, and showed increased interleukin-8 and tumor necrosis factor-α concentrations. Other infectious or autoimmune disorders were excluded. A progressive clinical improvement along with a reduction of cerebrospinal fluid parameters was observed after high-dose steroid treatment, thus arguing for an inflammatory-mediated brain involvement related to COVID-19. ANN NEUROL 2020;88:423-427.
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http://dx.doi.org/10.1002/ana.25783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7276848PMC
August 2020

Management of a Case of Peritonitis Due to Infection Following Pelvic Inflammatory Disease (PID).

Antibiotics (Basel) 2020 04 18;9(4). Epub 2020 Apr 18.

Department of Molecular and Translational Medicine, Institute of Microbiology, University of Brescia-Spedali Civili, 25123 Brescia, Italy.

Pelvic inflammatory disease (PID), a serious infection in sexually active women, is one of the reasons for which females seek care in emergency departments and therefore represents an important public health problem. PID is the result of an endocervical infection with different microorganisms, which then ascend to the endometrium and fallopian tubes. Symptoms of PID may be mild and aspecific, making its diagnosis difficult. However, this clinical condition requires effective antibiotic treatment to reduce incidence of complications and late sequelae. We describe here a case of peritonitis as a complication of pelvic inflammatory disease (PID) due to infection in a 49-year-old woman who presented at the Emergency Department with acute abdominal pain.
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http://dx.doi.org/10.3390/antibiotics9040193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235818PMC
April 2020

Detection of microbial contamination in dialysis water and gastrointestinal endoscopes by the Uro4 HB&L™ system.

J Infect Public Health 2020 Jul 12;13(7):1054-1056. Epub 2020 Apr 12.

Institute of Microbiology, Department of Molecular and Translational Medicine, University of Brescia-Spedali Civili, Brescia, Italy.

Patients undergoing haemodialysis are exposed to a great volume of dialysis water and therefore its microbial analysis is important for patient safety. Furthermore, microbial surveillance is reported in several guidelines as a necessary means to identify contamination of gastrointestinal endoscopes in order to reduce the potential of infection risk. Here we evaluated the Uro4 HB&L™ automated system to detect microbial contamination in dialysis water and gastrointestinal endoscopes. A total of 222 samples were collected during a six month period. Dialysis water and gastrointestinal endoscopes were evaluated both with the reference culture methods and the Uro4 HB&L system. Bacterial identification was performed using a matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS). The results show that the Uro4 HB&L system has high specificity but a lesser sensitivity than traditional culture method, even if it might allow the identification of more exigent bacteria in terms of nutrition. The Uro4 HB&L system gives positive results in less time than culture method but the possibility to generate false negative results imposes that it should be associated with a traditional 48h agar culture.
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http://dx.doi.org/10.1016/j.jiph.2020.02.037DOI Listing
July 2020

Role of Autophagy in Von Willebrand Factor Secretion by Endothelial Cells and in the In Vivo Thrombin-Antithrombin Complex Formation Promoted by the HIV-1 Matrix Protein p17.

Int J Mol Sci 2020 Mar 16;21(6). Epub 2020 Mar 16.

Department of Molecular and Translational Medicine, Section of Microbiology, University of Brescia Medical School, 25123 Brescia, Italy.

Although the advent of combined antiretroviral therapy has substantially improved the survival of HIV-1-infected individuals, non-AIDS-related diseases are becoming increasingly prevalent in HIV-1-infected patients. Persistent abnormalities in coagulation appear to contribute to excess risk for a broad spectrum of non-AIDS defining complications. Alterations in coagulation biology in the context of HIV infection seem to be largely a consequence of a chronically inflammatory microenvironment leading to endothelial cell (EC) dysfunction. A possible direct role of HIV-1 proteins in sustaining EC dysfunction has been postulated but not yet investigated. The HIV-1 matrix protein p17 (p17) is secreted from HIV-1-infected cells and is known to sustain inflammatory processes by activating ECs. The aim of this study was to investigate the possibility that p17-driven stimulation of human ECs is associated with increased production of critical coagulation factors. Here we show the involvement of autophagy in the p17-induced accumulation and secretion of von Willebrand factor (vWF) by ECs. In vivo experiments confirmed the capability of p17 to exert a potent pro-coagulant activity soon after its intravenous administration.
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http://dx.doi.org/10.3390/ijms21062022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139864PMC
March 2020

Presence of V72I, G123S and R127K Integrase Inhibitor polymorphisms could reduce ART effectiveness: a retrospective longitudinal study.

HIV Res Clin Pract 2020 02 6;21(1):24-33. Epub 2020 Mar 6.

Department of Infectious and Tropical Diseases, University of Brescia and ASST Spedali Civili Hospital, Brescia, Italy.

Structural aspects of HIV-1 integrase complex and role of integrase minor mutations and polymorphisms in ART effectiveness is still unknown. The objective of this study was to assess the 24 and 48 weeks (W) effectiveness of ART regimens in patients with Integrase Inhibitors (InSTI) minor mutations and polymorphisms receiving InSTI-based regimens. We enrolled all ART-naïve or InSTI-naïve HIV-infected patients, with a baseline InSTI genotypic resistances test between 2011 and 2016. We analyzed integrase resistance mutations using the Stanford University HIV Drug Resistance Database (HIVdb Program, version 6.3.0). The outcome was virological response at 24 and 48 W of follow up (FU) according to snapshot analysis. We defined virological failure as two consecutive HIV-RNA > 50 copies/ml, or one >1000 copies/ml. Patients were divided in those presenting InSTI minor mutations (Group 1), and those with only polymorphisms or wild type (Group 2). We enrolled 83 patients. 81 patients reached 24 W of FU: 2/20 (10%) and 4/61 (6.5%) showed virological failure in Group 1 and 2 respectively. 66 patients reached 48 W of FU: 0/17 (0%) and 2/49 (4%) showed virological failure in Group 1 and 2 respectively. Interestingly, patients with polymorphisms G123S and R127K had higher risk of failure at 24 W (respectively, relative risk - RR - 36, IQR 2.1-613, p = 0.01; RR 36, IQR 2.1-613, p = 0.01) and patients with V72I had an higher risk of failure both at 24 W (RR 6.52, IQR 1.29-32.9, p = 0.02) and 48 W (RR 21.1, IQR 1.07-414, p = 0.04). Our study showed that the presence of V72I, G123S and R127K polymorphisms could play a role in reducing InSTI effectiveness.
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http://dx.doi.org/10.1080/25787489.2020.1734753DOI Listing
February 2020
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