confocal-imaging-double-stranded-rna-pattern-recognition-receptors

Confocal Imaging of Double-Stranded RNA and Pattern Recognition Receptors in Negative-Sense RNA Virus Infection

Double-stranded (ds) RNA is produced as a replicative intermediate during RNA virus infection. Recognition of dsRNA by host pattern recognition receptors ...

University of Texas Medical Branch

university of texas medical branch

Although an association between Lassa fever (LF) and sudden-onset sensorineural hearing loss (SNHL) was confirmed clinically in 1990, the prevalence of LF-induced SNHL in endemic countries is still underestimated. LF, a viral hemorrhagic fever disease caused by Lassa virus (LASV), is endemic in West Africa, causing an estimated 500,000 cases and 5,000 deaths per year. Sudden-onset SNHL, one complication of LF, occurs in approximately one-third of survivors and constitutes a neglected public health and social burden. In the endemic countries, where access to hearing aids is limited, SNHL results in a decline of the quality of life for those affected. In addition, hearing loss costs Nigeria approximately 43 million dollars per year. The epidemiology of LF-induced SNHL has not been characterized well. The complication of LF induced by SNHL is also an important consideration for vaccine development and treatments. However, research into the mechanism has been hindered by the lack of autopsy samples and relevant small animal models. Recently, the first animal model that mimics the symptoms of SNHL associated with LF was developed. Preliminary data from the new animal model as well as the clinical case studies support the mechanism of immune-mediated injury that causes SNHL in LF patients. This article summarizes clinical findings of hearing loss in LF patients highlighting the association between LASV infection and SNHL as well as the potential mechanism(s) for LF-induced SNHL. Further research is necessary to identify the mechanism and the epidemiology of LF-induced SNHL.

Lassa fever-induced sensorineural hearing loss: A neglected public health and social burden.

An important step in the initiation of the innate immune response to virus infection is the recognition of non-self, viral RNA, including double-stranded RNA (dsRNA), by cytoplasmic pattern recognition receptors (PRRs). For many positive-sense RNA viruses and DNA viruses, the production of viral dsRNA, and the interaction of viral dsRNA and PRRs are well characterized. However, for negative-sense RNA viruses, viral dsRNA was thought to be produced at low to undetectable levels and PRR recognition of viral dsRNA is still largely unclear. In the case of arenaviruses, the nucleocaspid protein (NP) has been identified to contain an exoribonuclease activity that preferentially degrades dsRNA in biochemical studies. Nevertheless, pathogenic New World (NW) arenavirus infections readily induce an interferon (IFN) response in a RIG-I dependent manner, and also activate the dsRNA-dependent Protein Kinase R (PKR). To better understand the innate immune response to pathogenic arenavirus infection, we used a newly identified dsRNA-specific antibody that efficiently detects viral dsRNA in negative-sense RNA virus infected cells. dsRNA was detected in NW arenavirus infected cells colocalizing with virus NP in immunofluorescence assay. Importantly, the dsRNA signals also colocalized with cytoplasmic PRRs, namely, PKR, RIG-I and MDA-5, as well as with the phosphorylated, activated form of PKR in infected cells. Our data clearly demonstrate the PRR recognition of dsRNA and their activation in NW arenavirus infected cells. These findings provide new insights into the interaction between NW arenaviruses and the host innate immune response.

Visualization of Double-Stranded RNA Colocalizing With Pattern Recognition Receptors in Arenavirus Infected Cells.

Lassa fever (LF) outbreaks in Nigeria mostly occur in rural areas and during the dry season, peaking between December through February. Fever is a cardinal presenting feature among the myriad manifestations of LF. Thirty four patients with clinical diagnosis of LF were analyzed. However, only 11 (32%) LASV infections were confirmed by RT-PCR. The 2016 LF outbreak showed a preferential urban occurrence and a high case fatality. Fever (≥38°C) was not detected in over a fourth of the patients at the time of examination. Bleeding diathesis was the most common presentation while abdominal pain and headache were present in more than half of the confirmed cases. Changes in the geographical distribution and clinical presentation may have implications for disease control efforts and the risk of transmission, both locally and internationally. In order to guide interventions, public health authorities should be aware that the epidemic patterns may be changing.

Elizabeth Mateer

Department of Pathology and Institute for Human Infections and Immunity

University of Texas Medical Branch

Confocal Imaging of Double-Stranded RNA and Pattern Recognition Receptors in Negative-Sense RNA Virus Infection

Elizabeth Mateer

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Department of Pathology and Institute for Human Infections and Immunity

University of Texas Medical Branch

Confocal Imaging of Double-Stranded RNA and Pattern Recognition Receptors in Negative-Sense RNA Virus Infection

Department of Pathology and Institute for Human Infections and Immunity