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J Virol ; 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-32051278


Arenaviruses Lassa (LASV), Junín (JUNV) and Machupo (MACV) can cause severe and fatal diseases in humans. Although these pathogens are closely related, the host immune responses to these virus infections differs remarkably with direct implications in viral pathogenesis. LASV infection is immunosuppressive with very low level interferon response. In contrast, JUNV and MACV infections stimulate a robust IFN response in a RIG-I-dependent manner and readily activate PKR, a known host dsRNA sensor. In response to infection with RNA viruses, host non-self RNA sensors recognize viral-derived dsRNA as danger signals and initiate innate immune responses. Arenavirus nucleoproteins (NPs) contain a highly conserved exoribonuclease (ExoN) motif, through which LASV NP has been shown to degrade virus-derived immunostimulatory dsRNA in biochemical assays. In this study, we for the first time present evidence that LASV restricts dsRNA accumulation during infection. Although JUNV and MACV NPs also have the ExoN motif, dsRNA readily accumulated in infected cells and often co-localized with dsRNA sensors. Moreover, LASV co-infection diminished the dsRNA accumulation and IFN response in JUNV-infected cells. Disruption of LASV NP ExoN with mutation led to dsRNA accumulation and impaired LASV replication in minigenome systems. Importantly, both LASV NP and RNA polymerase L protein were required to diminish dsRNA accumulation and IFN response in JUNV infection. For the first time, we discovered a collaboration between LASV NP ExoN and L protein in limiting dsRNA accumulation. Our new findings provide mechanistic insights into the differential host innate immune responses to highly pathogenic arenavirus infections.SignificanceArenavirus NPs contain a highly conserved DEDDh ExoN motif, through which LASV NP degrades virus-derived, immunostimulatory dsRNA in biochemical assays to eliminate the danger signal and inhibit innate immune response. Nevertheless, the function of NP ExoN in arenavirus infection remains to be defined. In this study, we discovered that LASV potently restricts dsRNA accumulation during infection and minigenome replication. In contrast, although the NPs of JUNV and MACV also harbor the ExoN motif, dsRNA readily formed during JUNV and MACV infections accompanied by IFN and PKR responses. Interestingly, LASV NP alone was not sufficient to limit dsRNA accumulation. Instead, both LASV NP and L protein were required to restrict immunostimulatory dsRNA accumulation. Our findings provide novel and important insights to the mechanism for the distinct innate immune response to these highly pathogenic arenaviruses and open new directions for future studies.

Genome ; 62(12): 785-792, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31491336


Carbapenem-resistant bacteria have quickly become a worldwide concern in nosocomial infections. Of the seven known carbapenemases, four have been shown to be particularly problematic: KPC, NDM, IMP, and VIM. To date, many local and species- or carbapenemase-specific epidemiological studies have been performed, which often focus on the organism itself. This report attempts to perform an inclusive (encompass both species and carbapenemase) epidemiologic study using publicly available plasmid sequences from NCBI. In this report, the gene content of these various plasmids has been characterized, replicon types of the plasmids identified, and the global spread and species promiscuity of the plasmids analyzed. Additionally, support to several groups targeting plasmid maintenance and transfer mechanisms to slow the spread of resistance plasmids is given.