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Biomedical subjects

H Everett

Publications and source records attributed to H Everett.

16 recordsLinked to original sources
PubMed2006

The TRAF3-binding site of human molluscipox virus FLIP molecule MC159 is critical for its capacity to inhibit Fas-induced apoptosis.

Members of the viral Flice/caspase-8 inhibitory protein (v-FLIP) family prevent induction of apoptosis by death receptors through inhibition of the processing and activation of procaspase-8 and -10 at the level of the receptor-associated death-inducing signaling complex (DISC). Here, we have addressed the molecular function of the v-FLIP member MC159 of the human molluscum contagiosum virus. MC159 FLIP powerfully inhibited both caspase-dependent and caspase-independent cell death induced by Fas. The C-terminal region of MC159 bound TNF receptor-associated factor (TRAF)3, was necessary for optimal TRAF2 binding, and mediated the recruitment of both TRAFs into the Fas DISC. TRAF-binding-deficient mutants of MC159 showed impaired inhibition of FasL-induced caspase-8 processing and Fas internalization, and had reduced antiapoptotic activity. Our findings provide evidence that a MC159/TRAF2/TRAF3 complex regulates a new aspect of Fas signaling, and identify MC159 FLIP as a molecule that targets multiple features of Fas-induced cell death.

Apoptosis↗
PubMed2000

M11L: a novel mitochondria-localized protein of myxoma virus that blocks apoptosis of infected leukocytes.

M11L, a novel 166-amino acid membrane-associated protein expressed by the poxvirus, myxoma virus, was previously found to modulate apoptosis after infection of rabbit leukocytes. Furthermore, infection of rabbits with an M11L knockout virus unexpectedly produced lesions with a profound proinflammatory phenotype. We show here that M11L is antiapoptotic when expressed independently of other viral proteins, and is directed specifically to mitochondria by a short COOH-terminal region that is necessary and sufficient for targeting. This targeting region consists of a hydrophobic domain flanked by basic amino acid residues, adjacent to a positively charged tail. M11L blocks staurosporine-induced apoptosis by preventing mitochondria from undergoing a permeability transition, and the mitochondrial localization of this protein is essential for this function. We show that M11L is specifically required to inhibit the apoptotic response of monocytes/macrophages during virus infection, as cells of this lineage undergo apoptosis when infected with the M11L knockout virus. As monocyte apoptosis is uniquely proinflammatory, we propose that this observation reconciles the paradoxical proapoptotic and proinflammatory phenotypes of the M11L knockout virus. We suggest that apoptosis of tissue macrophages represents an important antiviral defense, and that the inhibition of apoptosis by viral proteins can be directed in a cell-specific fashion.

Amino Acid Sequence↗
PubMed1999

Use of chemokine receptors by poxviruses.

Chemokine receptors serve as portals of entry for certain intracellular pathogens, most notably human immunodeficiency virus (HIV). Myxoma virus is a member of the poxvirus family that induces a lethal systemic disease in rabbits, but no poxvirus receptor has ever been defined. Rodent fibroblasts (3T3) that cannot be infected with myxoma virus could be made fully permissive for myxoma virus infection by expression of any one of several human chemokine receptors, including CCR1, CCR5, and CXCR4. Conversely, infection of 3T3-CCR5 cells can be inhibited by RANTES, anti-CCR5 polyclonal antibody, or herbimycin A but not by monoclonal antibodies that block HIV-1 infection or by pertussis toxin. These findings suggest that poxviruses, like HIV, are able to use chemokine receptors to infect specific cell subtypes, notably migratory leukocytes, but that their mechanisms of receptor interactions are distinct.

3T3 Cells↗
PubMed1999

Apoptosis: an innate immune response to virus infection.

Viruses can induce apoptosis of infected cells either directly, to assist virus dissemination, or by inadvertently triggering cellular sensors that initiate cell death. Cellular checkpoints that can function as 'alarm bells' to transmit pro-apoptotic signals in response to virus infections include death receptors, protein kinase R, mitochondrial membrane potential, p53 and the endoplasmic reticulum.

Animals↗
PubMed1999

Immunomodulation by viruses: the myxoma virus story.

Myxoma virus is a poxvirus pathogen of rabbits that has evolved to replicate successfully in the presence of an active immune response by an infected host. To accomplish this, the virus has developed a variety of strategies to avoid detection by or obstruct specific aspects of the antiviral response whose consolidated action is antagonistic to virus survival. We describe two distinct viral strategies carried out by viral proteins with which myxoma virus subverts the host immune response. The first strategy is the production of virus-encoded proteins known as viroceptors or virokines that mimic host receptors or cytokines. These seek to actively block extracellular immune signals required for effective virus clearance and produce a local environment in the infected tissue that is "virus friendly". The second strategy, carried out by intracellular viral proteins, seeks to retard the innate antiviral responses such as apoptosis, and hinder attempts by the infected cell to communicate with the cellular arm of the immune system. By studying these viral strategies of immune evasion, the myxoma system can provide insights into virus-host interactions and also provide new insights into the complex immune system.

Amino Acid Sequence↗
PubMed1998

Virus-encoded receptors for cytokines and chemokines.

A number of viruses, particularly members of the poxvirus, herpesvirus and retrovirus families, have adapted to the vertebrate immune responses by capturing and modifying cellular genes which regulate the host immune system. Included among these host-derived virus genes are modified versions of receptors for cytokines or chemokines. Most of these receptor homologs, also called viroceptors, are either secreted glycoproteins or are located at the infected cell surface. Although these viroceptors can act in different ways, collectively they function by modifying the cytokine network to the advantage of the virus rather than the host.

Animals↗
PubMed1995

Interruption of cytokine networks by poxviruses: lessons from myxoma virus.

Myxoma virus is an infectious poxvirus pathogen that induces a virulent systemic disease called myxomatosis in European rabbits. The disease is rapidly and uniformly fatal to susceptible rabbits and is characterized by generalized dysfunction of cellular immunity and multiple interruptions of the host cytokine network. A number of virus genes are classified as virulence factors because virus constructs bearing targeted gene disruptions induce attenuated disease symptoms. Many of these genes encode proteins that interact directly with effector elements of the host immune system. Included among these immunosubversive viral proteins are secreted mimics of host ligands or regulators (virokines) and homologues of cellular cytokine receptors (viroceptors). Five examples of these immune modulator proteins encoded by myxoma virus are reviewed: (1) myxoma growth factor, a member of the epidermal growth factor ligand superfamily; (2) SERP-1, a secreted serine proteinase inhibitor; (3) M11L, a receptor-like surface protein; (4) T2, a tumor necrosis factor receptor homologue; and (5) T7, an interferon-gamma receptor homologue. The origin of viral strategies designed to subvert immune regulation by host cytokines is considered in the context of the biology of myxoma virus within immunocompetent hosts.

Animals↗
PubMed1993

Psychosexual dysfunction in women with gynaecological cancer following radical pelvic surgery.

OBJECTIVE: To assess the prevalence and severity of psychosexual dysfunction in women treated for cancer of the cervix and vulva by radical vulvectomy, Wertheim's hysterectomy and pelvic exenteration; and to identify the risk factors for sexual morbidity and ways in which it might be reduced. DESIGN: Retrospective study of patients by questionnaire and semistructured interview, 6 months to 5 years following surgery. SETTING: Gynaecology-Oncology Unit of a general hospital. PATIENTS: 105 English speaking women with gynaecological cancer. RESULTS: 90% of the women in relationships had been sexually active prior to surgery. Of this group, 24% had no sexual difficulties post-operatively; 66% of the latter still had problems more than 6 months later, and 15% of the latter never resumed intercourse (excluding those with a colpectomy). 82% of those aged less than 50 years who had had radiotherapy suffered sexual dysfunction. Lack of desire was the commonest problem, and half the women felt that their sexual relationship had deteriorated, yet only 16% felt that their marriage had worsened. Younger women were more likely to attribute personal and marital distress to their sexual problems. More information on sexual matters would have been liked by 28% of the women. CONCLUSIONS: Sexual dysfunction is common following radical pelvic surgery and tends to remain a chronic problem. As well as organic causes there is a strong psychogenic element brought about by loss of fertility, disfigurement, depression and anxiety about one's desirability as a sexual partner. The presence of a stable relationship before the diagnosis of cancer helps women cope better, and young single women are a very vulnerable group. Patients want more information on sexual matters and the provision of sexual counselling may improve outcome in the future.

Adult↗
PubMed1992

Psychosocial adjustment following major gynaecological surgery for carcinoma of the cervix and vulva.

One-hundred and five women had undergone major gynaecological surgery for carcinoma of the cervix and vulva were interviewed retrospectively to elicit post-operative psychosocial and psychosexual problems. This interview took place between 6 months and 5 yr after surgery. Responses to the Hospital Anxiety and Depression Scale indicated that 20% of the women were 'probable' cases of anxiety and 21% were 'definite' cases. On the depression scale, 18% were 'doubtful' cases and 14% were 'definite' cases. Scores on the scales were not associated with age of the woman, the type of operation or the time period between being interviewed and the operation. Two-thirds of the women who were sexually active prior to the operation indicated ongoing sexual problems when interviewed and the presence of these problems was found to be significantly associated with the woman's level of anxiety.

Adaptation, Psychological↗
PubMed1992

The care of patients undergoing surgery for gynaecological cancer: the need for information, emotional support and counselling.

This study was undertaken by interviewing 105 patients who had undergone major gynaecological surgery for carcinoma of the cervix or vulva in the previous 5 years. A high proportion of the women was still found to be depressed and anxious when interviewed and the majority reported chronic sexual problems. The women were asked if they had received enough information regarding their illness and its treatment, and a high proportion would have liked to have had more information on the after-effects of the operation, including physical, sexual and emotional aspects. Many of the younger women would have liked their partner to have been included in the discussions and 25% of the 40 partners who responded to the questionnaire would have liked more information on the illness and its treatment. The women also indicated their needs for emotional support, discussion and counselling.

Body Image↗
PubMedDate not supplied

Viral proteins and the mitochondrial apoptotic checkpoint.

Regulated cell death by apoptosis constitutes a primary host defense for counteracting invading viral pathogens. In recent years, advances in the field of apoptosis research have revealed that mitochondria and mitochondria-derived factors play a central role in regulating cellular commitment to apoptosis. Here we explore the role of viral proteins in modulating cell death pathways that are relayed via this mitochondrial checkpoint.

Animals↗