Highly Pathogenic New World and Old World Human Arenaviruses Induce Distinct Interferon Responses in Human Cells

Huang, Cheng; Kolokoltsova, Olga A.; Yun, Nadezhda E.; Seregin, Alexey; Ronca, Shannon E.; Koma, Takaaki; Paessler, Slobodan

doi:10.1128/jvi.00526-15

Cited by 42 publications

(51 citation statements)

References 54 publications

(61 reference statements)

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“…Densitometry analysis of protein levels obtained in the WB assay was performed by using AlphaEase software (AlphaInnotech). The immunoblotting data for JUNV, MACV, and LASV NP in A549 cells are not shown here but have been reported in our previous study (22). The immunoblotting data for JUNV, MACV, and LASV NP in MoDCs are likewise not shown here but have been reported in the same study (22).…”

Section: Methodssupporting

confidence: 45%

“…Infection with highly pathogenic NW arenaviruses MACV and JUNV, but not OW LASV, led to PKR activation in infected human cells. In our previous studies, we found that the highly pathogenic NW arenaviruses JUNV and MACV, but not the pathogenic OW LASV, induces an IFN response in infected human cells (21,22). The activation of the IFN response is RIG-I dependent in JUNV-infected cells (21).…”

Section: Resultsmentioning

confidence: 92%

“…Human lung epithelial A549 cells (ATCC CCL-185) and HEK293 cells (ATCC CRL-1573) were purchased from the ATCC and maintained in Dulbecco modified Eagle medium (DMEM) containing 10% heatinactivated fetal bovine serum (FBS), 100 U/ml of streptomycin, and 100 U/ml of penicillin. Human primary monocyte-derived dendritic cells (MoDCs) were prepared as described previously (22). Briefly, human blood buffy coats containing peripheral blood mononuclear cells (PBMCs) from three healthy anonymous donors were obtained from the UTMB Blood Center under an institutional review board (IRB) exemption.…”

Section: Methodsmentioning

confidence: 99%

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Highly Pathogenic New World Arenavirus Infection Activates the Pattern Recognition Receptor Protein Kinase R without Attenuating Virus Replication in Human Cells

Huang

Kolokoltsova

Mateer

et al. 2017

J Virol

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The arenavirus family consists of several highly pathogenic viruses, including the Old World (OW) arenavirus Lassa fever virus (LASV) and the New World (NW) Junin virus (JUNV) and Machupo virus (MACV). Host response to infection by these pathogenic arenaviruses is distinct in many aspects. JUNV and MACV infections readily induce an interferon (IFN) response in human cells, while LASV infection usually triggers an undetectable or weak IFN response. JUNV induces an IFN response through RIG-I, suggesting that the host non-self RNA sensor readily detects JUNV viral RNAs (vRNAs) during infection and activates IFN response. Double-stranded-RNA (dsRNA)-activated protein kinase R (PKR) is another host non-self RNA sensor classically known for its vRNA recognition activity. Here we report that infection with NW arenaviruses JUNV and MACV, but not OW LASV, activated PKR, concomitant with elevated phosphorylation of the translation initiation factor α subunit of eukaryotic initiation factor 2 (eIF2α). Host protein synthesis was substantially suppressed in MACV- and JUNV-infected cells but was only marginally reduced in LASV-infected cells. Despite the antiviral activity known for PKR against many other viruses, the replication of JUNV and MACV was not impaired but was slightly augmented in wild-type (wt) cells compared to that in PKR-deficient cells, suggesting that PKR or PKR activation did not negatively affect JUNV and MACV infection. Additionally, we found an enhanced IFN response in JUNV- or MACV-infected PKR-deficient cells, which was inversely correlated with virus replication. The detection of viral RNA by host non-self RNA sensors, including RIG-I and MDA5, is critical to the initiation of the innate immune response to RNA virus infection. Among pathogenic arenaviruses, the OW LASV usually does not elicit an interferon response. However, the NW arenaviruses JUNV and MACV readily trigger an IFN response in a RIG-I-dependent manner. Here, we demonstrate for the first time that pathogenic NW arenaviruses JUNV and MACV, but not the OW arenavirus LASV, activated the dsRNA-dependent PKR, another host non-self RNA sensor, during infection. Interestingly, the replication of JUNV and MACV was not restricted but was rather slightly augmented in the presence of PKR. Our data provide new evidence for a distinct interplay between host non-self RNA sensors and pathogenic arenaviruses, which also provides insights into the pathogenesis of arenaviruses and may facilitate the design of vaccines and treatments against arenavirus-caused diseases.

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Section: Methodssupporting

confidence: 45%

Section: Resultsmentioning

confidence: 92%

Section: Methodsmentioning

confidence: 99%

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Highly Pathogenic New World Arenavirus Infection Activates the Pattern Recognition Receptor Protein Kinase R without Attenuating Virus Replication in Human Cells

Huang

Kolokoltsova

Mateer

et al. 2017

J Virol

Self Cite

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“…LASV infection is associated with a low level of IFN responses (26,27), and type I IFNs have been shown to control LASV, LCMV, and PICV replication (18,(28)(29)(30)(31)(32). However, NW arenaviruses such as MACV and JUNV have been shown to induce high levels of IFNs in A549 cells and human DCs (33,34) but not in human macrophages and monocytes (10). High levels of IFN-␣ have been detected in patient serum and correlate with disease severity for JUNV-caused Argentine hemorrhagic fever (4), though the source cells have not been identified in vivo.…”

Section: World (Nw) Pathogens (Junv Machupo Virus [Macv] Guanarito mentioning

confidence: 99%

Differential Inhibition of Macrophage Activation by Lymphocytic Choriomeningitis Virus and Pichinde Virus Is Mediated by the Z Protein N-Terminal Domain

Xing

Chai

et al. 2015

J Virol

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Several arenavirus pathogens, such as Lassa and Junin viruses, inhibit macrophage activation, the molecular mechanism of which is unclear. We show that lymphocytic choriomeningitis virus (LCMV) can also inhibit macrophage activation, in contrast to Pichinde and Tacaribe viruses, which are not known to naturally cause human diseases. Using a recombinant Pichinde virus system, we show that the LCMV Z N-terminal domain (NTD) mediates the inhibition of macrophage activation and immune functions.A renaviruses include several hemorrhagic fever (HF)-causing agents, such as Lassa fever virus (LASV) and Junin virus (JUNV), with limited preventative or therapeutic measures (1, 2). Arenavirus pathogenesis is associated with high viremia and generalized immune suppression, the mechanism of which is poorly understood (3, 4). Macrophages and dendritic cells (DCs) are the early target cells of arenavirus infections. Activated macrophages and DCs play important roles in both innate and adaptive immunity (5, 6). Several studies have shown that LASV and JUNV, but not their nonpathogenic counterparts Mopeia virus (MOPV) and Tacaribe virus (TCRV), can inhibit human macrophage activation (7-10), the molecular mechanism of which is unknown. As all arenaviruses encode a conserved nucleoprotein (NP) RNase with activity to block the interferon (IFN) induction (11-18), it seems unlikely that NP mediates the differential inhibition of macrophages by various arenaviruses. We have recently found that the Z proteins from known arenavirus pathogens, including HF-causing LASV and JUNV as well as lymphocytic choriomeningitis virus (LCMV), that can cause neurologic diseases (19), but not those from others, such as TCRV and Pichinde virus (PICV), which have not been associated with significant human diseases (20, 21), can inhibit RIG-i/MDA5 and block the RIG-i-like-receptor (RLR)-dependent IFN production in macrophages and that the differential RLR inhibition is determined by the N-terminal domain (NTD) (22).To determine whether this newly discovered Z NTD-mediated RLR inhibition contributes to the differential inhibition of human macrophages by distinct arenaviruses, we analyzed the macrophage activation upon infection with LCMV, TCRV, PICV (both the P2 and the P18 strains), or a recombinant PICV encoding a chimeric Z protein with the 31-residue NTD from LCMV (rP18-ZN LCMV ) (22). Human monocyte-derived macrophages (hMDMs) were obtained as described previously (22) and treated with lipopolysaccharide (LPS) for 6 h or infected with the aforementioned arenaviruses at a multiplicity of infection (MOI) of 2 for 1 and 3 days. The infection rate was nearly 100% for each virus as demonstrated by the intracellular immunofluorescence staining of viral NP with anti-NP antibody (Fig. 1A). Macrophage activation was first assessed by flow cytometric analysis of the surface expression of CD80 and CD86, the two established macrophage activation markers and costimulatory molecules.LPS, a known strong inducer of macrophage activation, caused substantial increase...

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“…MAVS activation leads to downstream signaling cascades that induce the activation and nuclear translocation of interferon regulatory factors 3 (IRF3) and 7 (IRF7) as well as nuclear factor kappa B (NF-κB), which ultimately upregulate gene expression of IFN and pro-inflammatory cytokines. While studies have shown that transfected LASV RNA can activate the IFN-β promoter in a RIG-I-dependent manner [58], IFN-β expression is not upregulated in the context of LASV infection [59], indicating that LASV efficiently evades or inhibits the IFN response in the context of virus infection. In contrast, IFN and interferon-stimulated genes (ISGs) are upregulated in both JUNV and MACV infection [59,60].…”

Section: Arenavirus Interactions With Pattern Recognition Receptorsmentioning

confidence: 95%

Differential Immune Responses to Hemorrhagic Fever-Causing Arenaviruses

2019

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The family Arenaviridae contains several pathogens of major clinical importance. The Old World (OW) arenavirus Lassa virus is endemic in West Africa and is estimated to cause up to 300,000 infections each year. The New World (NW) arenaviruses Junín and Machupo periodically cause hemorrhagic fever outbreaks in South America. While these arenaviruses are highly pathogenic in humans, recent evidence indicates that pathogenic OW and NW arenaviruses interact with the host immune system differently, which may have differential impacts on viral pathogenesis. Severe Lassa fever cases are characterized by profound immunosuppression. In contrast, pathogenic NW arenavirus infections are accompanied by elevated levels of Type I interferon and pro-inflammatory cytokines. This review aims to summarize recent findings about interactions of these pathogenic arenaviruses with the innate immune machinery and the subsequent effects on adaptive immunity, which may inform the development of vaccines and therapeutics against arenavirus infections.

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Highly Pathogenic New World and Old World Human Arenaviruses Induce Distinct Interferon Responses in Human Cells

Cited by 42 publications

References 54 publications

Highly Pathogenic New World Arenavirus Infection Activates the Pattern Recognition Receptor Protein Kinase R without Attenuating Virus Replication in Human Cells

Highly Pathogenic New World Arenavirus Infection Activates the Pattern Recognition Receptor Protein Kinase R without Attenuating Virus Replication in Human Cells

Differential Inhibition of Macrophage Activation by Lymphocytic Choriomeningitis Virus and Pichinde Virus Is Mediated by the Z Protein N-Terminal Domain

Differential Immune Responses to Hemorrhagic Fever-Causing Arenaviruses

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