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.
"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"
[Show abstract][Hide abstract] 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 · 3.99 Impact Factor
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Arenavirus pathogens cause a wide spectrum of diseases in humans ranging from central nervous system disease to lethal hemorrhagic fevers with few 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) and Lassa, Junin, Machupo, Sabia, Guanarito, Chapare, Dandenong, and Lujo viruses, can inhibit retinoic acid-inducible gene 1 (RIG-i) and Melanoma Differentiation-Associated protein 5 (MDA5), in sharp contrast to those of 14 other nonpathogenic 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 lead to the disruption of the interactions between RLRs and mitochondrial antiviral signaling (MAVS). The Z-RLR interactive interfaces 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 nonpathogenic Pichinde virus (PICV) genome does not affect virus growth in Vero cells but significantly inhibits the type I interferon (IFN) responses and increases viral replication in human primary macrophages. In summary, our results show for the first time an innate immune-system-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 an innate immune suppression mechanism that is based on viral Z protein-mediated RLR inhibition. Our report offers important insights into the potential mechanism of arenavirus pathogenesis, provides a convenient way to evaluate the pathogenic potential of known and/or emerging arenaviruses, and reveals a novel target for the development of broad-spectrum therapies to treat this group of diverse pathogens. More broadly, our report provides a better understanding of the mechanisms of viral immune suppression and host-pathogen interactions.
Journal of Virology 12/2014; 89(5). DOI:10.1128/JVI.03349-14 · 4.44 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Viral hemorrhagic fevers (VHFs) encompass a group of diseases with cardinal symptoms of fever, hemorrhage, and shock. The liver is a critical mediator of VHF disease pathogenesis and high levels of ALT/AST transaminases in plasma correlate with poor prognosis. In fact, Lassa Fever (LF), the most prevalent VHF in Africa, was initially clinically described as hepatitis. Previous studies in non-human primate (NHP) models also correlated LF pathogenesis with a robust proliferative response in the liver. The purpose of the current study was to gain insight into the mechanism of liver injury and to determine the potential role of proliferation in LF pathogenesis. C57Bl/6J mice were infected with either the pathogenic (for NHPs) strain of lymphocytic choriomeningitis virus (LCMV, the prototypic arenavirus), LCMV-WE, or with the non-pathogenic strain, LCMV-ARM. As expected, LCMV-WE, but not ARM, caused a hepatitis-like infection. LCMV-WE also induced a robust increase in the number of actively cycling hepatocytes. Despite this increase in proliferation, there was no significant difference in liver size between LCMV-WE and LCMV-ARM, suggesting that cell cycle was incomplete. Indeed, cells appeared arrested in the G1 phase and LCMV-WE infection increased the number of hepatocytes that were simultaneously stained for proliferation and apoptosis. LCMV-WE infection also induced expression of a non-conventional virus receptor, AXL-1, from the TAM (TYRO3/AXL/MERTK) family of receptor tyrosine kinases and this expression correlated with proliferation. Taken together, these results shed new light on the mechanism of liver involvement in VHF pathogenesis. Specifically, it is hypothesized that the induction of hepatocyte proliferation contributes to expansion of the infection to parenchymal cells. Elevated levels of plasma transaminases are likely explained, at least in part, by abortive cell cycle arrest induced by the infection. These results may lead to the development of new therapies to prevent VHF progression.
PLoS ONE 03/2015; 10(3):e0122839. DOI:10.1371/journal.pone.0122839 · 3.23 Impact Factor
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