Cooperative Chikungunya Virus Membrane Fusion and Its Substoichiometric Inhibition by CHK-152 Antibody

Chikungunya virus (CHIKV) presents a major burden on healthcare systems worldwide, but specific treatment remains unavailable. Attachment and fusion of CHIKV to the host cell membrane is mediated by the E1/E2 protein spikes. We used an in vitro single-particle fusion assay to study the effect of the potent, neutralizing antibody CHK-152 on CHIKV binding and fusion. We find that CHK-152 shields the virions, inhibiting interaction with the target membrane and inhibiting fusion. The analysis of the ratio of bound antibodies to epitopes implied that CHIKV fusion is a highly cooperative process. Further, dissociation of the antibody at lower pH results in a finely balanced kinetic competition between inhibition and fusion, suggesting a window of opportunity for the spike proteins to act and mediate fusion, even in the presence of the antibody

Early Events in Chikungunya Virus Infection-From Virus Cell Binding to Membrane Fusion

Chikungunya virus (CHIKV) is a rapidly emerging mosquito-borne alphavirus causing millions of infections in the tropical and subtropical regions of the world. CHIKV infection often leads to an acute self-limited febrile illness with debilitating myalgia and arthralgia. A potential long-term complication of CHIKV infection is severe joint pain, which can last for months to years. There are no vaccines or specific therapeutics available to prevent or treat infection. This review describes the critical steps in CHIKV cell entry. We summarize the latest studies on the virus-cell tropism, virus-receptor binding, internalization, membrane fusion and review the molecules and compounds that have been described to interfere with virus cell entry. The aim of the review is to give the reader a state-of-the-art overview on CHIKV cell entry and to provide an outlook on potential new avenues in CHIKV research

Unravelling the spirits’ message: a study of help-seeking steps and explanatory models among patients suffering from spirit possession in Uganda

As in many cultures, also in Uganda spirit possession is a common idiom of distress associated with traumatic experiences. In the DSM-IV and -5, possession trance disorders can be classified as dissociative disorders. Dissociation in Western countries is associated with complicated, time-consuming and costly therapies. Patients with spirit possession in SW Uganda, however, often report partial or full recovery after treatment by traditional healers. The aim of this study is to explore how the development of symptoms concomitant help-seeking steps, and explanatory models (EM) eventually contributed to healing of patients with spirit possession in SW Uganda. Illness narratives of 119 patients with spirit possession referred by traditional healers were analysed using a mixed-method approach. Treatments of two-thirds of the patients were unsuccessful when first seeking help in the medical sector. Their initially physical symptoms subsequently developed into dissociative possession symptoms. After an average of two help-seeking steps, patients reached a healing place where 99% of them found satisfactory EM and effective healing. During healing sessions, possessing agents were summoned to identify themselves and underlying problems were addressed. Often-mentioned explanations were the following: neglect of rituals and of responsibilities towards relatives and inheritance, the call to become a healer, witchcraft, grief, and land conflicts. The results demonstrate that traditional healing processes of spirit possession can play a role in restoring connections with the supra-, inter-, intra-, and extra-human worlds. It does not always seem necessary to address individual traumatic experiences per se, which is in line with other research in this field. The study leads to additional perspectives on treatment of trauma-related dissociation in Western countries and on developing effective mental health services in low -and middle-income countries

Broadly Neutralizing Alphavirus Antibodies Bind an Epitope on E2 and Inhibit Entry and Egress

SummaryWe screened a panel of mouse and human monoclonal antibodies (MAbs) against chikungunya virus and identified several with inhibitory activity against multiple alphaviruses. Passive transfer of broadly neutralizing MAbs protected mice against infection by chikungunya, Mayaro, and O’nyong’nyong alphaviruses. Using alanine-scanning mutagenesis, loss-of-function recombinant proteins and viruses, and multiple functional assays, we determined that broadly neutralizing MAbs block multiple steps in the viral lifecycle, including entry and egress, and bind to a conserved epitope on the B domain of the E2 glycoprotein. A 16 Å resolution cryo-electron microscopy structure of a Fab fragment bound to CHIKV E2 B domain provided an explanation for its neutralizing activity. Binding to the B domain was associated with repositioning of the A domain of E2 that enabled cross-linking of neighboring spikes. Our results suggest that B domain antigenic determinants could be targeted for vaccine or antibody therapeutic development against multiple alphaviruses of global concern

Hendrick Schull: Knuppels, messen en wijn op de Sont

Collective identities and transnational networks in medieval and early modern Europe, 1000-180

Are symptoms of spirit possessed patients covered by the DSM-IV or DSM-5 criteria for possession trance disorder? A mixed-method explorative study in Uganda

Introduction and aims As in many cultures, spirit possession is a common idiom of distress in Uganda. The DSM-IV contains experimental research criteria for dissociative and possession trance disorder (DTD and PTD), which are under review for the DSM-5. In the current proposed categories of the DSM-5, PTD is subsumed under dissociative identity disorder (DID) and DTD under dissociative disorders not elsewhere classified. Evaluation of these criteria is currently urgently required. This study explores the match between local symptoms of spirit possession in Uganda and experimental research criteria for PTD in the DSM-IV and proposed criteria for DID in the DSM-5. Methods A mixed-method approach was used combining qualitative and quantitative research methods. Local symptoms were explored of 119 spirit possessed patients, using illness narratives and a cultural dissociative symptoms’ checklist. Possible meaningful clusters of symptoms were inventoried through multiple correspondence analysis. Finally, local symptoms were compared with experimental criteria for PTD in the DSM-IV and proposed criteria for DID in the DSM-5. Results and conclusion Illness narratives revealed different phases of spirit possession, with passive-influence experiences preceding the actual possession states. Multiple correspondence analysis of symptoms revealed two dimensions: ‘passive’ and ‘active’ symptoms. Local symptoms, such as changes in consciousness, shaking movements, and talking in a voice attributed to spirits, match with DSM-IV-PTD and DSM-5-DID criteria. Passive-influence experiences, such as feeling influenced or held by powers from outside, strange dreams, and hearing voices, deserve to be more explicitly described in the proposed criteria for DID in the DSM-5. The suggested incorporation of PTD in DID in the DSM-5 and the envisioned separation of DTD and PTD in two distinctive categories have disputable aspects