Publications by authors named "Maria G Cusi"

8 Publications

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Type I interferons induced by endogenous or exogenous viral infections promote metastasis and relapse of leishmaniasis.

Proc Natl Acad Sci U S A 2017 05 24;114(19):4987-4992. Epub 2017 Apr 24.

Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland;

The presence of the endogenous RNA virus 1 (LRV1) replicating stably within some parasite species has been associated with the development of more severe forms of leishmaniasis and relapses after drug treatment in humans. Here, we show that the disease-exacerbatory role of LRV1 relies on type I IFN (type I IFNs) production by macrophages and signaling in vivo. Moreover, infecting mice with the LRV1-cured ( ) strain of parasites followed by type I IFN treatment increased lesion size and parasite burden, quantitatively reproducing the LRV1-bearing ( ) infection phenotype. This finding suggested the possibility that exogenous viral infections could likewise increase pathogenicity, which was tested by coinfecting mice with and lymphocytic choriomeningitis virus (LCMV), or the sand fly-transmitted arbovirus Toscana virus (TOSV). The type I IFN antiviral response increased the pathology of infection, accompanied by down-regulation of the IFN-γ receptor normally required for antileishmanial control. Further, LCMV coinfection of IFN-γ-deficient mice promoted parasite dissemination to secondary sites, reproducing the metastatic phenotype. Remarkably, LCMV coinfection of mice that had healed from infection induced reactivation of disease pathology, overriding the protective adaptive immune response. Our findings establish that type I IFN-dependent responses, arising from endogenous viral elements (dsRNA/LRV1), or exogenous coinfection with IFN-inducing viruses, are able to synergize with New World parasites in both primary and relapse infections. Thus, viral infections likely represent a significant risk factor along with parasite and host factors, thereby contributing to the pathological spectrum of human leishmaniasis.
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http://dx.doi.org/10.1073/pnas.1621447114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5441690PMC
May 2017

Gemcitabine, oxaliplatin, levofolinate, 5-fluorouracil, granulocyte-macrophage colony-stimulating factor, and interleukin-2 (GOLFIG) versus FOLFOX chemotherapy in metastatic colorectal cancer patients: the GOLFIG-2 multicentric open-label randomized phase III trial.

J Immunother 2014 Jan;37(1):26-35

*Radiotherapy Unit §Medical Oncology Unit, Department of Oncology, Microbiology Section ∥Department of Biotechnology ¶Rheumatology Unit, Department of Medicine #Pharmacy Unit, Siena University Hospital "Santa Maria alle Scotte", Istituto Toscano Tumory, Siena †Medical Oncology Unit ‡Department of Legal, Historical, Economic and Social Sciences-DSGSES, Magna Graecia University of Catanzaro ††Translational Medical Oncology Unit, "Magna Graecia" University and "Tommaso Campanella" Cancer Center, Campus "Salvatore Venuta," Catanzaro **Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples ‡‡Chemotherapy Unit, Department of Oncology, Florence University School of Medicine, Florence §§Medical Oncology Unit, Department of Oncology, Cagliari University School of Medicine, Cagliari ∥∥Medical Oncology Unit, Centro Oncologico Romagnolo, Forlì, Italy.

The GOLFIG-2 phase III trial was designed to compare the immunobiological activity and antitumor efficacy of GOLFIG chemoimmunotherapy regimen with standard FOLFOX-4 chemotherapy in frontline treatment of metastatic colorectal cancer (mCRC) patients. This trial was conceived on the basis of previous evidence of antitumor and immunomodulating activity of the GOLFIG regimen in mCRC. GOLFIG-2 is a multicentric open/label phase III trial (EUDRACT: 2005-003458-81). Chemo-naive mCRC patients were randomized in a 1:1 ratio to receive biweekly standard FOLFOX-4 or GOLFIG [gemcitabine (1000 mg/m(2), day 1); oxaliplatin (85 mg/m(2), day 2); levofolinate (100 mg/m(2), days 1-2), 5-fluorouracil (5-FU) (400 mg/m(2) in bolus followed by 24 h infusion at 800 mg/m(2),days 1-2), sc. GM-CSF (100 μg, days 3-7); sc. aldesleukin (0·5 MIU bi-daily, days 8-14 and 17-30)] treatments. The study underwent early termination because of poor recruitment in the control arm. After a median follow-up of 43.83 months, GOLFIG regimen showed superiority over FOLFOX in terms of progression-free survival [median 9·23 (95% confidence interval (CI), 6·9-11.5) vs. median 5.70 (95% CI, 3.38-8.02) months; hazard ratio (HR): 0.52 (95% CI, 0.35-0.77), P=0·002] and response rate [66.1% (95% CI, 0.41-0.73) vs. 37·0% (95% CI, 0.28-0.59), P=0.002], with a trend to longer survival [median 21.63 (95% CI, 18.09-25.18) vs. 14.57 mo (95% CI, 9.07-20.07); HR: 0·79 (95% CI, 0.52-1.21); P=0.28]. Patients in the experimental arm showed higher incidence of non-neutropenic fever (18.5%), autoimmunity signs (18.5%), an increase in the number of monocytes, eosinophils, CD4(+) T lymphocytes, natural killer cells, and a decrease in immunoregulatory (CD3(+)CD4(+)CD25(+)FoxP3(+)) T cells. Taken together, these findings provide proof-of-principle that GOLFIG chemoimmunotherapy may represent a novel reliable option for first-line treatment of mCRC.
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http://dx.doi.org/10.1097/CJI.0000000000000004DOI Listing
January 2014

Toscana virus epidemiology: from Italy to beyond.

Open Virol J 2010 Apr 22;4:22-8. Epub 2010 Apr 22.

Department of Molecular Biology, Microbiology Section, University of Siena, Policlinico "S. Maria alle Scotte", Siena, Italy.

Toscana virus (TOSV) is an arthropod-borne virus which is transmitted to humans by Phlebotomus spp sandflies. Infection is the cause of brain injuries, such as aseptic meningitis and meningoencephalitis, in Italy mainly during the summer. More recently some unusual clinical manifestations due to TOSV with severe sequelae, such as ischemic complications and hydrocephalus, have been reported. TOSV represents an important emerging pathogen and its presence is being investigated in several European countries on the Mediterranean basin, including Italy, France, Spain, Portugal and Cyprus. Phylogenetic analysis has distinguished two genotypes of TOSV, A and B; the first is circulating mainly in Italy and the second in Spain, indicating a different geographic distribution possibly related to the vector. This distribution, evolving with the climate, globalization and habitat modification, has implications for the epidemiology of TOSV.
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http://dx.doi.org/10.2174/1874357901004020022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2879028PMC
April 2010

Immunological characterization of respiratory syncytial virus N protein epitopes recognized by human cytotoxic T lymphocytes.

Viral Immunol 2007 Sep;20(3):399-406

Microbiology Section, Department of Molecular Biology, University of Siena, Siena, Italy.

Virus-specific cytotoxic T lymphocytes (CTLs) are crucial for the control of respiratory syncytial virus (RSV) infection. This study has identified CTL epitopes of the RSV N protein in healthy subjects. We screened the primary structure of the N protein for HLA-A 0201-binding amino acid consensus motifs, identifying three peptides designated as N-RSV1, N-RSV2, and N-RSV3. These peptides were used to generate CTL lines by stimulating human HLA-A 02.01 peripheral blood mononuclear cells (PBMCs) in vitro. These CTL lines were then characterized by performing CTL chromium release assays and IFN-gamma secretion detection by intracellular cytokine staining. N-RSV1 and N-RSV3 peptides elicited the strongest cytolytic activity against RSV-infected cells and they could be useful epitopes for the analysis of CTL responses to RSV and for understanding immune-induced disease pathogenesis.
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http://dx.doi.org/10.1089/vim.2007.0041DOI Listing
September 2007

Search for Chlamydia pneumoniae genes and their expression in atherosclerotic plaques of carotid arteries.

J Med Microbiol 2001 Mar;50(3):228-232

Department of Molecular Biology, Microbiology Section, *Institute of Infectious Diseases and †Institute of Heart Surgery, Ospedale 'Le Scotte', University of Siena, Siena, Italy and ‡Laboratory of Virology, Centre Hospitalier Universitaire, Nancy, France.

Samples of atherosclerotic tissue from 58 patients undergoing carotid surgery were analysed by tissue culture and PCR for Chlamydia pneumoniae; PCR was performed to detect Omp1, 16S rRNA and HSP-70 genes. To understand the active pathogenic role of C. pneumoniae, a reverse transcriptase-PCR (RT-PCR) assay was applied to detect the specific RNAs expressed either in the replicative form, or in the cryptic form found in chronic infection. The C. pneumoniae omp1 gene, encoding the major outer-membrane protein (MOMP), was detected in 13 of 58 samples. Among these, the result was confirmed in 11 samples after amplification of a further target, the 16S rRNA, and the presence of the HSP-70 gene, encoding heat-shock protein 70, was revealed in only five cases. All the samples were negative for evidence of specific RNAs by RT-PCR. The presence of genomic DNA and absence of specific RNAs in atherosclerotic tissue samples suggests a lack of an active metabolic or persistent infective role for C. pneumoniae. Thus, traces of C. pneumoniae DNA in these samples could be due to a degradative pathway of the host defensive cellular and biochemical mechanisms.
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http://dx.doi.org/10.1099/0022-1317-50-3-228DOI Listing
March 2001