Comparative analysis of disease pathogenesis and molecular mechanisms of New World and Old World arenavirus infections.

University of Minnesota.
Journal of General Virology (Impact Factor: 3.53). 09/2013; DOI: 10.1099/vir.0.057000-0
Source: PubMed

ABSTRACT Arenaviruses can cause fatal human haemorrhagic fever (HF) diseases for which vaccines and therapies are extremely limited. Both the New World (NW) and Old World (OW) groups of arenaviruses contain HF-causing pathogens. Although these two groups share many similarities, important differences with regards to pathogenicity and molecular mechanisms of virus infection exist. These closely related pathogens share many characteristics, including genome structure, viral assembly, natural host selection, and the ability to interfere with innate immune signalling. However, members of the NW and OW viruses appear to use different receptors for cellular entry as well as different mechanisms of virus internalization. General differences in disease signs and symptoms and pathological lesions in patients infected with either the NW or OW arenaviruses are also noted and discussed herein. While both the OW Lassa virus (LASV) and the NW Junin (JUNV) can cause disruption of the vascular endothelium, which is an important pathological feature of HF, the immune responses to these related pathogens seem to be quite distinct. Whereas LASV infection results in an overall generalized immune suppression, patients infected with JUNV seem to develop a cytokine storm. Additionally, the type of immune response required for recovery and clearance of the virus is different between the NW and OW infections. These differences may be important to allow the viruses to evade host immune detection. Understanding these differences will aid the development of new vaccines and treatment strategies against deadly haemorrhagic fever viral infections.

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    • "tavirus - infected patients in the Old and New World include high fever , hemorrhages , thrombocytopenia , abdominal pain , flu - like symptoms , and finally organ failure – symptoms known to be also caused by many other hemorrhagic fever viruses including arena - , filo - , and flaviviruses ( Kortepeter et al . , 2011 ; Heinz and Stiasny , 2012 ; McLay et al . , 2014 ) . Recent outbreaks of zoonotic diseases , like MERS coronavirus on the Arabian Peninsula ( de Groot et al . , 2013 ) or Ebola virus in West Africa ( Baize et al . , 2014 ) , demonstrate a high necessity for intensive studies of highly pathogenic zoonotic viruses in order to be prepared for their emergence and major outbreaks . Here we"
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    ABSTRACT: Hantaviruses are members of the Bunyaviridae family carried by small mammals and causing human hemorrhagic fevers worldwide. In Western Africa, where a variety of hemorrhagic fever viruses occurs, indigenous hantaviruses have been molecularly found in animal reservoirs such as rodents, shrews, and bats since 2006. To investigate the human contact to hantaviruses carried by these hosts and to assess the public health relevance of hantaviruses for humans living in the tropical rainforest regions of Western and Central Africa, we performed a cross-sectional seroprevalence study in the region of Taï National Park in Côte d´Ivoire and the Bandundu region near the Salonga National Park in the Democratic Republic of Congo. Serum samples were initially screened with enzyme-linked immunosorbent assays using nucleoproteins of several hantaviruses as diagnostic antigens. Positive results were confirmed by Western blotting and immunofluorescence testing. Seroprevalence rates of 3.9% (27/687) and 2.4% (7/295), respectively, were found in the investigated regions in Côte d´Ivoire and the Democratic Republic of Congo. In Côte d´Ivoire, this value was significantly higher than the seroprevalence rates previously reported from the neighboring country Guinea as well as from South Africa. Our study indicates an exposure of humans to hantaviruses in West and Central African tropical rainforest areas. In order to pinpoint the possible existence and frequency of clinical disease caused by hantaviruses in this region of the world, systematic investigations of patients with fever and renal or respiratory symptoms are required.
    Frontiers in Microbiology 05/2015; 6. DOI:10.3389/fmicb.2015.00518 · 3.94 Impact Factor
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    ABSTRACT: Arenavirus pathogens cause a wide spectrum of diseases in humans ranging from central nervous disease to lethal hemorrhagic fevers with little treatment options. The reason why some arenaviruses can cause severe human diseases while others cannot is unknown. We find that the Z proteins of all known pathogenic arenaviruses, Lymphocytic choriomeningitis virus (LCMV), Lassa, Junin, Machupo, Sabia, Guanarito, Chapare, Dandenong, and Lujo viruses, can inhibit RIG-i and MDA5, in sharp contrast to those of 14 other non-pathogenic arenaviruses. Inhibition of the RIG-i-like receptors (RLRs) by pathogenic Z proteins is mediated by the protein-protein interactions of Z and RLRs, which leads to the disruption of the interactions between RLRs and mitochondrial antiviral signaling (MAVS). The Z-RLR interactive interface are located within the N-terminal domain (NTD) of the Z protein and the N-terminal CARD domains of RLRs. Swapping of the LCMV Z NTD into the non-pathogenic Pichinde virus (PICV) genome does not affect virus growth in Vero cells, but significantly inhibits the type I IFN responses and increases viral replication in human primary macrophages. In summary, our results show for the first time an innate immune suppressive mechanism shared by the diverse pathogenic arenaviruses and thus shed important light on the pathogenic mechanism of human arenavirus pathogens. We show that all known human pathogenic arenaviruses share a common innate immune suppression mechanism that is based on the viral Z protein-mediated RLR inhibition. Our study sheds important insights into the potential mechanism of arenavirus pathogenesis, provides a convenient way to evaluate the pathogenic potential of known and emerging arenaviruses, and reveals a novel target for the development of broad-spectrum therapies to treat this group of diverse pathogens. More broadly, our study provides a better understanding of the mechanisms of viral immune suppression and host-pathogen interactions. Copyright © 2014, American Society for Microbiology. All Rights Reserved.
    Journal of Virology 12/2014; 89(5). DOI:10.1128/JVI.03349-14 · 4.65 Impact Factor
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    ABSTRACT: Arenaviruses include multiple human pathogens ranging from the low-risk lymphocytic choriomeningitis virus (LCMV) to highly virulent hemorrhagic fever (HF) causing viruses such as Lassa (LASV), Junin (JUNV), Machupo (MACV), Lujo (LUJV), Sabia (SABV), Guanarito (GTOV), and Chapare (CHPV), for which there are limited preventative and therapeutic measures. Why some arenaviruses can cause virulent human infections while others cannot, even though they are isolated from the same rodent hosts, is an enigma. Recent studies have revealed several potential pathogenic mechanisms of arenaviruses, including factors that increase viral replication capacity and suppress host innate immunity, which leads to high viremia and generalized immune suppression as the hallmarks of severe and lethal arenaviral HF diseases. This review summarizes current knowledge of the roles of each of the four viral proteins and some known cellular factors in the pathogenesis of arenaviral HF as well as of some human primary cell-culture and animal models that lend themselves to studying arenavirus-induced HF disease pathogenesis. Knowledge gained from these studies can be applied towards the development of novel therapeutics and vaccines against these deadly human pathogens.
    06/2015; 4(2):283-306. DOI:10.3390/pathogens4020283

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