Papers by Ester Pernjak-Pugel
In vitro differentiated CD8 + T cells have been the primary focus of immunotherapy of cancer with... more In vitro differentiated CD8 + T cells have been the primary focus of immunotherapy of cancer with little focus on CD4 + T cells. Immunotherapy involving in vitro differentiated T cells given after lymphodepleting regimens significantly augments antitumor immunity in animals and human patients with cancer. However, the mechanisms by which lymphopenia augments adoptive cell therapy and the means of properly differentiating T cells in vitro are still emerging. We demonstrate that naive tumor/self-specific CD4 + T cells naturally differentiated into T helper type 1 cytotoxic T cells in vivo and caused the regression of established tumors and depigmentation in lymphopenic hosts. Therapy was independent of vaccination, exogenous cytokine support, CD8 + , B, natural killer (NK), and NKT cells. Proper activation of CD4 + T cells in vivo was important for tumor clearance, as naive tumor-specific CD4 + T cells could not completely treat tumor in lymphopenic common gamma chain ( c)-deficient hosts. c signaling in the tumor-bearing host was important for survival and proper differentiation of adoptively transferred tumor-specific CD4 + T cells. Thus, these data provide a platform for designing immunotherapies that incorporate tumor/self-reactive CD4 + T cells.
Congenital human cytomegalovirus (HCMV) occurs in 0.5–1 % of live births and approxi-mately 10 % ... more Congenital human cytomegalovirus (HCMV) occurs in 0.5–1 % of live births and approxi-mately 10 % of infected infants develop hearing loss. The mechanism(s) of hearing loss re-main unknown. We developed a murine model of CMV induced hearing loss in which murine cytomegalovirus (MCMV) infection of newborn mice leads to hematogenous spread of virus to the inner ear, induction of inflammatory responses, and hearing loss. Characteris-tics of the hearing loss described in infants with congenital HCMV infection were observed including, delayed onset, progressive hearing loss, and unilateral hearing loss in this model and, these characteristics were viral inoculum dependent. Viral antigens were present in the inner ear as were CD3+ mononuclear cells in the spiral ganglion and stria vascularis. Spiral ganglion neuron density was decreased after infection, thus providing a mechanism for hearing loss. The lack of significant inner ear histopathology and persistence of inflam-mation in cochlea ...
Cytomegalovirus (CMV) infection is the most common congenital viral infection in humans and the m... more Cytomegalovirus (CMV) infection is the most common congenital viral infection in humans and the major cause of wide-spread encephalitis and developmental abnormalities of the newborn brain which can lead to several neurological consequences. Infection with the human CMV (HCMV) in patients with normal immune function does not cause a clinically manifest disease. As the HCMV infection in pregnancy is often unrecognized, it represents an additional risk for development of congenital HCMV infection. Beside the direct cytopathic effect of CMV on neurons during neurogenesis, the presence of the virus in brain parenchyme leads to the activation of host inflammatory response and development of pathohistological lesions. Therefore, further studies should be focused on development of safe and effective vaccines and drugs that will reduce the risk of maternal infection and in case of virus transfer from mother to child have the ability to prevent the development of congenital CMV infection.
Cytomegalovirus (CMV) is the most significant infectious cause of congenital abnormalities of the... more Cytomegalovirus (CMV) is the most significant infectious cause of congenital abnormalities of the central nervous system including retardation, microcephaly, cerebellar atrophy, hearing loss and blindness. The pathogenesis of a viral infection has not been fully elucidate yet and it may arise either because of direct viral damage to neuronal cells or indirectly because of different humoral factors. We have established a model of murine CMV (MCMV) brain infection in newborn mice. This model was used to determine the effect of MCMV infection on neuronal development. We have focused our analysis on the cerebellum because the majority of its cells mature postnatally making it accessible for our examination. Moreover, cerebellum has distinct cytoarchitecture and migration pattern of its neuronal cells has been well defined therefore each developmental disruption is easy to follow. Newborn mice have been infected intraperitoneally with MCMV. The viral presence in the brain has been analys...
Objective: Sex steroid hormones influence the components of both innate and adaptive immunity, re... more Objective: Sex steroid hormones influence the components of both innate and adaptive immunity, resulting in differences of immune responses between genders. Moreover, hormonal changes associated with pregnancy modify the severity of some infections and diseases. Progesteron has been proved as an inhibitor of antiviral immunity in both human and animal studies. Cytomegalovirus (CMV), a hepesvirus, is a ubiquitous pathogen and can be isolated from all body fluids of patients undergoing primary infection. CMV infection in gonads is predominantly described in immunocompromised patients and its role in gonadal insufficiency is still not completely elucidated. The aim of this study was to test whether sex hormones change the course and immunosurveillance of murine CMV (MCMV) infection in BALB/c mice. Methods: Female mice were treated with PMSG and hCG to trigger ovulation and luteinization. Virgin animals as well as pregnant ones were intravenously infected with MCMV and sacrificed daily from 1st to 10th day post infection. Viral titers in various organs were analyzed using a standard plaque forming assay. Virus spread was examined using immunohistochemistry. Progesterone levels in plasma were measured using Progesterone EIA kit. Results: MCMV successfully infected ovarian tissue in immunocompetent mice. Numerous infected cells were detected predominantly in corpora lutea, while follicles were free from infection. Our results showed higher susceptibility of pregnant mice to MCMV infection in various organs examined, while ovaries of pregnant mice showed delay in clearance of productive infection as compared to non-pregnant animals. The infection induced a strong innate immune response in corpora lutea which was predominantly comprised of infiltrating macrophages, while CD4+ and CD8+ T cells seemed to play a minor role. Increased plasma progesterone levels were observed in infected mice as compared to controls. Conclusions: Our study provides a new insight into the pathogenesis of MCMV infection in female reproductive tissue as well as its dependence on sex steroid environment. An elevated progesterone level underpins virus replication. These findings could bring evidence for the role of CMV infection in the pathogenesis of gonadal dysfunction.
PLoS Pathogens, 2013
Infection of the developing fetus with human cytomegalovirus (HCMV) is a major cause of central n... more Infection of the developing fetus with human cytomegalovirus (HCMV) is a major cause of central nervous system disease in infants and children; however, mechanism(s) of disease associated with this intrauterine infection remain poorly understood. Utilizing a mouse model of HCMV infection of the developing CNS, we have shown that peripheral inoculation of newborn mice with murine CMV (MCMV) results in CNS infection and developmental abnormalities that recapitulate key features of the human infection. In this model, animals exhibit decreased granule neuron precursor cell (GNPC) proliferation and altered morphogenesis of the cerebellar cortex. Deficits in cerebellar cortical development are symmetric and global even though infection of the CNS results in a non-necrotizing encephalitis characterized by widely scattered foci of virusinfected cells with mononuclear cell infiltrates. These findings suggested that inflammation induced by MCMV infection could underlie deficits in CNS development. We investigated the contribution of host inflammatory responses to abnormal cerebellar development by modulating inflammatory responses in infected mice with glucocorticoids. Treatment of infected animals with glucocorticoids decreased activation of CNS mononuclear cells and expression of inflammatory cytokines (TNFa, IFN-b and IFNc) in the CNS while minimally impacting CNS virus replication. Glucocorticoid treatment also limited morphogenic abnormalities and normalized the expression of developmentally regulated genes within the cerebellum. Importantly, GNPC proliferation deficits were normalized in MCMV infected mice following glucocorticoid treatment. Our findings argue that host inflammatory responses to MCMV infection contribute to deficits in CNS development in MCMV infected mice and suggest that similar mechanisms of disease could be responsible for the abnormal CNS development in human infants infected in-utero with HCMV.
This paper presents the need of diagnosing Neurological disorders related to Alzheimer's disease ... more This paper presents the need of diagnosing Neurological disorders related to Alzheimer's disease (AD) as well as Parkinson Disease (PD) by analyzing both EEG and Speech Signal. Research papers discuss about the various approaches in the analysis of Alzheimer's disease by extracting the electrical activity of brain signals. EEG systems are widely used to extract brain signals as they are quite capable of measuring Electrical activities of the brain but possess very poor spatial resolution and will be contaminated with various artifacts. Current Surveys indicate that about 70%-90% of patients suffering with Parkinson's disease exhibit dysphonic (Impairment in speaking ability) symptoms; thereby speech signal analysis is widely used to diagnose PD. Due to ambient environment, motion artifacts the speech quality may be varied which may result in wrong diagnosis. Even though researchers propose various risk factors for effective analysis of AD and PD using EEG and Speech signals the above stated limitations of EEG and Speech Signal can lead to a fault diagnosis of the diseases and may lead to subtle manifestation of defects. An efficient diagnostic system is therefore necessary to diagnose these Neurological disorders more effectively analyzing EEG and speech signal. This paper addresses the different techniques and methodologies incorporated in diagnosing the Neurological disorders such as AD and PD using EEG and Speech signal which provides a better insight to carry out the further research by developing an efficient integrated algorithm for diagnosing the above stated Neurological disorders using both EEG and Speech Signal.
Periodicum Biologorum
Background and purpose: The incidence of gastric cancer decreases but despite declining, it still... more Background and purpose: The incidence of gastric cancer decreases but despite declining, it still remains the second cause of death of all malignan-cies worldwide. Morphometric methods are independent prognostic variables in various cancers and there have been encouraging results in using it for estimating the prognosis of gastric cancer. Aim of this study was to evaluate the influence of nuclear area (morphometric method), on the survival of patients with intestinal type of gastric cancer. Materials and methods: Seventy-four patients who had undergone gastric resections for adenocarcinoma of the stomach in the University Hospital Center, Rijeka, Croatia, were analyzed in this study. None had received pre-operative radiotherapy or chemotherapy. Age, gender, tumor size, tumor depth into the stomach wall (T-category) presence or absence of metastases to regional lymph nodes (N-category) or distant organs (M-category) and nuclear area of tumor cells were estimated. All patients were fo...
Journal of General Virology, 1979
Macrophages harvested from the peritoneal cavities of mice of several strains were permissive to ... more Macrophages harvested from the peritoneal cavities of mice of several strains were permissive to infection with murine cytomegalovirus (MCMV). Macrophages from six mouse strains released equivalent amounts of plaque-forming virus into the culture fluids and cells from three mouse strains scored similarly in numbers of infectious centres. Twenty to 5o% of the infected macrophages obtained after thioglycollate activation formed infectious centres. When studied by in situ hybridization, more than 82% of infected macrophages (with or without thioglycollate activation) contained MCMV DNA. Macrophages obtained from latently infected mice were examined for their content of MCMV. Using co-cultivation assays, MCMV was frequently recovered from thioglycollate activated macrophages harvested from latently infected mice but only rarely recovered from non-activated macrophages. MCMV DNA-mouse DNA hybridization assays revealed four to seven virus genome DNA copies per ioo cells. These studies indicate that macrophages harvested from mice susceptible (BALB/cSt) or resistant (C3H) to MCMV infection replicated virus equivalently and that macrophages are a reservoir of MCMV during latent and chronic infections. Activation of macrophages may be one of the important steps leading to the exacerbation of in vivo latent infections.
Book of Abstracts - HDBMB2019 - Crossroads in Life Sciences, 2019
Hepatitis is a major clinical complication of human CMV infections. We have investigated the path... more Hepatitis is a major clinical complication of human CMV infections. We have investigated the pathogenesis of murine cytomegalovirus-induced hepatitis during lethal and sublethal-infection. While numerous organs and tissues were capable of supporting virus replication, the highest virus titers and most significant morphological changes occurred in liver and spleen. Lethal dose infection resulted in confluent necrosis of the liver and loss of liver function, which correlated with high levels of virus replication in this organ. In mice given a sublethal dose, immune control mechanisms could limit virus replication in the liver by the 5th post-infection day and liver function recovered. Depletion of T cells led severe loss of liver function and death in mice given an otherwise sublethal dose. Virus infection also resulted in a profound, dose-dependent depletion of spleen cell populations. Furthermore, virus infection led to suppression of delayed-type hypersensitivity responses, indicat...
Congenital human cytomegalovirus (HCMV) infection is the most common viral cause of long-term neu... more Congenital human cytomegalovirus (HCMV) infection is the most common viral cause of long-term neurodevelopmental sequelae, including mental retardation, microcephaly and sensorineural hearing loss. As HCMV does not cross the species barrier, we employed a mouse model in which newborn mice are infected by intraperitoneal (i.p.) inoculation of mouse cytomegalovirus (MCMV). Following infection the virus disseminates to the central nervous system (CNS) and replicates in the brain parenchyma. CNS infection leads to the activation of resident microglial cells and the recruitment of peripheral immune cells. In addition, the virus induces delay in cerebellar growth. In our model of congenital MCMV infection, the initial neuroimmune responses are dominated by activation of resident microglial cells and the influx of NK cells, whose appearance coincides with detection of the virus in the brain. The number of NK cells in the CNS peaked at day 8 post infection (p.i.). In addition, we also obser...
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Papers by Ester Pernjak-Pugel