Serena Delbue

Review on the relationship between human polyomaviruses-associated tumors and host immune system.

The polyomaviruses are small DNA viruses that can establish latency in the human host. The name polyomavirus is derived from the Greek roots poly-, which means “many,” and -oma, which means “tumours.” These viruses were originally isolated in mouse (mPyV) and in monkey (SV40). In 1971, the first human polyomaviruses BK and JC were isolated and subsequently demonstrated to be ubiquitous in the human population. To date, at least nine members of the Polyomaviridae family have been identified, some of them playing an etiological role in malignancies in immunosuppressed patients. Here, we describe the biology of human polyomaviruses, their nonmalignant and malignant potentials ability, and their relationship with the host immune response.

Search for genomic sequences of microbial agents in atherosclerotic plaques.

Atherosclerosis is a complex, multifactorial disease. Several studies have reported a possible association between infection with microbial agents and atherogenesis. Chlamydia pneumoniae (C. pneumoniae), Herpes Simplex Virus 1 (HSV1), Human Cytomegalovirus (HCMV), and Epstein Barr Virus (EBV) have been widely investigated for their possible role in atherosclerosis development, but the results obtained to date are contradictory. The aim of our study is to search DNA of the aforementioned infectious agents by means of Quantitative Real Time PCR in atherosclerotic plaques from carotid arteries obtained from 17 patients. Genomic sequences of C. pneumoniae, HSV1, HCMV were not found in any atherosclerotic lesion. Therefore, our results do not support the hypothesis of an association between these infectious agents and atherosclerosis. Conversely, three patients were found to be positive for EBV DNA, thus indicating that, at least in a limited number of patients, EBV could play a role in atherogenesis.

Specific protein profile in cerebrospinal fluid from HIV-1-positive cART-treated patients affected by neurological disorders

Cytokines/chemokines are involved in the immune response of infections, including HIV-1. We defined the profile of 48 cytokines/chemokines in cerebrospinal fluid from 18 cART patients with chronic HIV-1 infection by Luminex technology. Nine patients were affected with leukoencephalopathies: five with John Cunningham virus (JCV) + progressive multifocal leukoencephalopathy (PML) and four with JCV-not determined leukoencephalopathy (NDLE). In addition, nine HIV-1-positive patients with no neurological signs (NND) and five HIV-1-negative patients affected with acute disseminated encephalomyelitis (ADEM) were enrolled. Ten cytokines (IL-15, IL-3, IL-16, IL-18, CTACK, GRO1, SCF, MCP-1, MIF, SDF) were highly expressed in HIV-1-positive patients while IL-1Ra and IL-17 were present at a lower level. In addition, the levels of IL-17, IL-9, FGF-basic, MIP-1β, and MCP-1 were significantly higher (p < 0.05) in patients with neurological diseases (PML, NDLE, ADEM) with respect to NND. Focusing the attention to the cytokine profile in JCV + PML patients with respect to JCV-NDLE patients, only TNF-β was significantly downregulated (p < 0.05) in JCV + PML patients. This pilot study emphasized the role of immunoregulation in HIV-1-related neurological disorders during cART treatment.

Review on the role of the human Polyomavirus JC in the development of tumors

Almost one fifth of human cancers worldwide are associated with infectious agents, either bacteria or viruses, and this makes the possible association between infections and tumors a relevant research issue. We focused our attention on the human Polyomavirus JC (JCPyV), that is a small, naked DNA virus, belonging to the Polyomaviridae family. It is the recognized etiological agent of the Progressive Multifocal Leukoencephalopathy (PML), a fatal demyelinating disease, occurring in immunosuppressed individuals.JCPyV is able to induce cell transformation in vitro when infecting non-permissive cells, that do not support viral replication and JCPyV inoculation into small animal models and non human primates drives to tumor formation. The molecular mechanisms involved in JCPyV oncogenesis have been extensively studied: the main oncogenic viral protein is the large tumor antigen (T-Ag), that is able to bind, among other cellular factors, both Retinoblastoma protein (pRb) and p53 and to dysregulate the cell cycle, but also the early proteins small tumor antigen (t-Ag) and Agnoprotein appear to cooperate in the process of cell transformation.Consequently, it is not surprising that JCPyV genomic sequences and protein expression have been detected in Central Nervous System (CNS) tumors and colon cancer and an association between this virus and several brain and non CNS-tumors has been proposed. However, the significances of these findings are under debate because there is still insufficient evidence of a casual association between JCPyV and solid cancer development.In this paper we summarized and critically analyzed the published literature, in order to describe the current knowledge on the possible role of JCPyV in the development of human tumors.

Varicella zoster virus-associated polyradiculoneuritis

We describe a case of polyradiculoneuritis in an elderly patient with pleocytosis, raised proteins in CSF, and varicella zoster virus (VZV) DNA in the CSF without cutaneous rash. ### Case description. A 79-year-old man presented in September 2008 with subacute onset of lower limb flaccid paralysis, the day after an episode of diarrhea with hyperthermia. His medical history included HCV-related hepatitis. The neurologic examination showed flaccid paraplegia with areflexia and decreased temperature, pain, and vibration sensation. Electroneurography/electromyography examination showed multifocal demyelinating polyneuropathy with proximal damage, prevalently at the lower limbs. The CSF examination, 10 days after the onset of the symptoms, showed lymphocytic pleocytosis (224 cells/mm3, normal value 45%). A search for herpes simplex virus 1–2, VZV, Epstein-Barr virus, cytomegalovirus, human …

Review on the immunotherapy strategies against metastatic colorectal carcinoma

Colorectal cancer (CRC) is one of the most common malignancies throughout the world and the leading cause of cancer-related mortality in Western countries. Recent progress in CRC treatment options, such as surgery, chemotherapy, radiotherapy and target therapy, has improved the prognosis, but advanced disease with recurrence or distant metastasis is usually incurable and has an unfavorable prognosis. The introduction of immunotherapy-associated strategies, both active and passive, to the treatment of CRC aims to overcome the limits of classical treatments. We review the state of the art for CRC with respect to different immunotherapeutic approaches, such as the use of cancer vaccines and/or adoptive cellular therapy, their most current advances and limitations and perspectives for further improvements.

SV40 Infection of Mesenchymal Stromal Cells From Wharton's Jelly Drives the Production of Inflammatory and Tumoral Mediators

The Mesenchymal Stromal Cells from umbilical cord Whartons jelly (WJSCs) are a source of cells with high potentiality for the treatment of human immunological disorders. Footprints of the oncogenic viruses Simian Virus 40 (SV40) and JC Virus (JCPyV) have been recently detected in human WJSCs specimens. The aim of this study is to evaluate if WJSCs can be efficiently infected by these Polyomaviruses and if they can potentially exert tumoral activity. Cell culture experiments indicated that WJSCs could sustain both SV40 and JCPyV infections. A transient and lytic replication was observed for JCPyV, while SV40 persistently infected WJSCs over a long period of time, releasing a viral progeny at low titer without evident cytopathic effect (CPE). Considering the association between SV40 and human tumors and the reported ability of the oncogenic viruses to drive the host innate immune response to cell transformation, the expression profile of a large panel of immune mediators was evaluated in supernatants by the Bioplex platform. RANTES, IL‐3, MIG, and IL‐12p40, involved in chronic inflammation, cells differentiation, and transformation, were constantly measured at high concentration comparing to control. These findings represent a new aspect of SV40 biological activity in the humans, highlighting its interaction with specific host cellular pathways. In view of these results, it seems to be increasingly urgent to consider Polyomaviruses in the management of WJSCs for their safely use as promising therapeutic source. J. Cell. Physiol. 232: 3060–3066, 2017.

Upregulation of integrin expression on monocytes in multiple sclerosis patients treated with natalizumab

Natalizumab is a humanized monoclonal antibody against the α4 subunit of VLA-4 integrin that is used to treat conditions such as multiple sclerosis (MS). Although its effects on lymphocytes have been widely described, little is known about its effects on monocytes. Here we described the effects of natalizumab treatment on peripheral blood monocytes from a small cohort of MS patients in terms of relative frequencies and surface integrin (CD49d and CD18) expression. We showed that natalizumab treatment altered the surface integrin expression on monocyte subsets in the peripheral compartment, suggesting a role for them as mediators of natalizumab effects.