Potent Inhibition of Junín Virus Infection by Interferon in Murine Cells

Huang, Cheng; Walker, Aida G.; Grant, Ashley; Kolokoltsova, Olga A.; Yun, Nadezhda E.; Seregin, Alexey; Paessler, Slobodan

doi:10.1371/journal.pntd.0002933

Cited by 17 publications

(13 citation statements)

References 33 publications

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“…In some cases, it is also possible that IFNs and cytokines might actually help the host to control or limit NW JUNV or MACV infection, which might explain how certain patients recovered from infections. In agreement with this, we find that IFNs are critical to control JUNV and MACV infections in murine systems (22,23,55,56). It is also worth noting that in the case of LASV infection in an NHP model, an early peak of type I IFN production correlated with animal survival, whereas fatal infection was characterized by a lack of early type I IFN production (57).…”

Section: Discussionsupporting

confidence: 86%

“…Recombinant JUNV (Romero strain), MACV (Carvallo strain), and LASV (Josiah strain) were prepared as described previously (22,23). Briefly, virus stocks were propagated at a multiplicity of infection (MOI) of 0.001 on Vero cells (American Tissue Culture Collection, Manassas, VA).…”

Section: Viruses and Cellsmentioning

confidence: 99%

“…A Western blotting (WB) assay was performed as described previously (22). Protein lysates were prepared in 2ϫ Laemmli SDS-PAGE sample buffer from virus-infected cells.…”

Section: Wb Assay and Antibodiesmentioning

confidence: 99%

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

Huang

Kolokoltsova

Yun

et al. 2015

J Virol

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The arenavirus family includes several important pathogens that cause severe and sometimes fatal diseases in humans. The highly pathogenic Old World (OW) arenavirus Lassa fever virus (LASV) is the causative agent of Lassa fever (LF) disease in humans. LASV infections in severe cases are generally immunosuppressive without stimulating interferon (IFN) induction, a proinflammatory response, or T cell activation. However, the host innate immune responses to highly pathogenic New World (NW) arenaviruses are not well understood. We have previously shown that the highly pathogenic NW arenavirus, Junin virus (JUNV), induced an IFN response in human A549 cells. Here, we report that Machupo virus (MACV), another highly pathogenic NW arenavirus, also induces an IFN response. Importantly, both pathogenic NW arenaviruses, in contrast to the OW highly pathogenic arenavirus LASV, readily elicited an IFN response in human primary dendritic cells and A549 cells. Coinfection experiments revealed that LASV could potently inhibit MACV-activated IFN responses even at 6 h after MACV infection, while the replication levels of MACV and LASV were not affected by virus coinfection. Our results clearly demonstrated that although all viruses studied herein are highly pathogenic to humans, the host IFN responses toward infections with the NW arenaviruses JUNV and MACV are quite different from responses to infections with the OW arenavirus LASV, a discovery that needs to be further investigated in relevant animal models. This finding might help us better understand various interplays between the host immune system and highly pathogenic arenaviruses as well as distinct mechanisms underlying viral pathogenesis.

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Section: Discussionsupporting

confidence: 86%

Section: Viruses and Cellsmentioning

confidence: 99%

See 1 more Smart Citation

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

Huang

Kolokoltsova

Yun

et al. 2015

J Virol

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“…Viruses and cells. Recombinant JUNV (Romero strain), MACV (Carvallo strain), and LASV (Josiah strain) stock viruses were prepared and propagated by infecting Vero cells (American Tissue Culture Collection [ATCC], Manassas, VA) at an MOI of 0.001 (51,52). Supernatants were harvested at day 4 postinfection and clarified by centrifugation and filtration through filters (0.45-m pore size) to remove cell debris.…”

Section: Methodsmentioning

confidence: 99%

“…WB assay and antibodies. A Western blotting (WB) assay was performed as described previously (51). Cell protein lysates were prepared with 2ϫ Laemmli SDS-PAGE sample buffer containing protease inhibitor cocktail for mammalian cells and phosphatase inhibitor cocktails.…”

Section: Methodsmentioning

confidence: 99%

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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The interplay between viperin antiviral activity, lipid droplets and Junín mammarenavirus multiplication

et al. 2018

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Junín arenavirus infections are associated with high levels of interferons in both severe and fatal cases. Upon Junín virus (JUNV) infection a cell signaling cascade initiates, that ultimately attempts to limit viral replication and prevent infection progression through the expression of host antiviral proteins. The interferon stimulated gene (ISG) viperin has drawn our attention as it has been highlighted as an important antiviral protein against several viral infections. The studies of the mechanistic actions of viperin have described important functional domains relating its antiviral and immune-modulating actions through cellular lipid structures. In line with this, through silencing and overexpression approaches, we have identified viperin as an antiviral ISG against JUNV. In addition, we found that lipid droplet structures are modulated during JUNV infection, suggesting its relevance for proper virus multiplication. Furthermore, our confocal microscopy images, bioinformatics and functional results also revealed viperin-JUNV protein interactions that might be participating in this antiviral pathway at lipid droplet level. Altogether, these results will help to better understand the factors mediating innate immunity in arenavirus infection and may lead to the development of pharmacological agents that can boost their effectiveness thereby leading to new treatments for this viral disease.

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Potent Inhibition of Junín Virus Infection by Interferon in Murine Cells

Cited by 17 publications

References 33 publications

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

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

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

The interplay between viperin antiviral activity, lipid droplets and Junín mammarenavirus multiplication

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