A Substitution in the Transmembrane Region of the Glycoprotein Leads to an Unstable Attenuation of Machupo Virus

Patterson, Michael J.; Koma, Takaaki; Seregin, Alexey; Huang, Cheng; Miller, Milagros; Smith, Jennifer K.; Yun, Nadezhda E.; Smith, Jeanon N.; Paessler, Slobodan

doi:10.1128/jvi.01007-14

Cited by 18 publications

(17 citation statements)

References 33 publications

(42 reference statements)

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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: 83%

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: 83%

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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“…This is in line with the findings of previous studies performed by others and us, in which GPC was identified to be the major viral factor for the attenuation of the vaccine strain of JUNV (14,16,22). Consistent with our previous report, rMACV infection was lethal to IFN-␣␤/␥ R Ϫ/Ϫ mice (15,18). In contrast, the virological and pathological results clearly demonstrated that rMACV/Cd#1-GPC was avirulent in the IFN-␣␤/␥ R Ϫ/Ϫ mouse model, similar to the findings for the live-attenuated Cd#1 vaccine strain of JUNV.…”

Section: Figsupporting

confidence: 82%

“…However, the F438I mutation was unstable in vivo. MACV isolates reverting to the wild-type sequence (F438) were identified in mice that succumbed to MACV F438I infection (15). The importance of the F427I mutation in JUNV attenuation was also demonstrated in guinea pigs infected with JUNV.…”

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confidence: 88%

“…To determine viral growth kinetics, Vero cells and A549 cells were infected at a multiplicity of infection (MOI) of 0.01, and the supernatant was collected from 0 to 96 h postinfection (hpi). To identify whether rMACV/Cd#1-GPC is genetically stable in vitro, we serially passaged the virus in Vero cells in duplicate as previously described (15). The serial passage was performed at an estimated MOI of 0.01 on the basis of the results in Fig.…”

Section: Cells and Virusesmentioning

confidence: 99%

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Machupo Virus Expressing GPC of the Candid#1 Vaccine Strain of Junin Virus Is Highly Attenuated and Immunogenic

Koma

Patterson

Huang

et al. 2016

J Virol

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Machupo virus (MACV) is the causative agent of Bolivian hemorrhagic fever. Our previous study demonstrated that a MACV strain with a single amino acid substitution (F438I) in the transmembrane domain of glycoprotein is attenuated but genetically unstable in mice. MACV is closely related to Junin virus (JUNV), the causative agent of Argentine hemorrhagic fever. Others and our group have identified the glycoprotein to be the major viral factor determining JUNV attenuation. In this study, we tested the compatibility of the glycoprotein of the Candid#1 live-attenuated vaccine strain of JUNV in MACV replication and its ability to attenuate MACV in vivo. Recombinant MACV with the Candid#1 glycoprotein (rMACV/Cd#1-GPC) exhibited growth properties similar to those of Candid#1 and was genetically stable in vitro. In a mouse model of lethal infection, rMACV/Cd#1-GPC was fully attenuated, more immunogenic than Candid#1, and fully protective against MACV infection. Therefore, the MACV strain expressing the glycoprotein of Candid#1 is safe, genetically stable, and highly protective against MACV infection in a mouse model. IMPORTANCECurrently, there are no FDA-approved vaccines and/or treatments for Bolivian hemorrhagic fever, which is a fatal human disease caused by MACV. The development of antiviral strategies to combat viral hemorrhagic fevers, including Bolivian hemorrhagic fever, is one of the top priorities of the Implementation Plan of the U.S. Department of Health and Human Services Public Health Emergency Medical Countermeasures Enterprise. Here, we demonstrate for the first time that MACV expressing glycoprotein of Candid#1 is a safe, genetically stable, highly immunogenic, and protective vaccine candidate against Bolivian hemorrhagic fever.

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“…Most recently, this model was used to demonstrate that a single point mutation in the transmembrane region of the GP2 glycoprotein is involved in the attenuation of JUNV strain Candid#1, the current vaccine used in Argentina for prevention of AHF [ 121 ]. These findings were recently repeated with MACV, and the same mutation leads to viral attenuation in the mouse model [ 146 ]. Thus, while not useful for pathogenesis or MCM development, immune intact neonatal mice can provide valuable insight in the factors contributing to the attenuation of NW arenaviruses.…”

Section: Arenavirus Animal Modelsmentioning

confidence: 86%

Animal Models for the Study of Rodent-Borne Hemorrhagic Fever Viruses: Arenaviruses and Hantaviruses

Golden

Hammerbeck

Mucker

et al. 2015

BioMed Research International

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Human pathogenic hantaviruses and arenaviruses are maintained in nature by persistent infection of rodent carrier populations. Several members of these virus groups can cause significant disease in humans that is generically termed viral hemorrhagic fever (HF) and is characterized as a febrile illness with an increased propensity to cause acute inflammation. Human interaction with rodent carrier populations leads to infection. Arenaviruses are also viewed as potential biological weapons threat agents. There is an increased interest in studying these viruses in animal models to gain a deeper understating not only of viral pathogenesis, but also for the evaluation of medical countermeasures (MCM) to mitigate disease threats. In this review, we examine current knowledge regarding animal models employed in the study of these viruses. We include analysis of infection models in natural reservoirs and also discuss the impact of strain heterogeneity on the susceptibility of animals to infection. This information should provide a comprehensive reference for those interested in the study of arenaviruses and hantaviruses not only for MCM development but also in the study of viral pathogenesis and the biology of these viruses in their natural reservoirs.

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A Substitution in the Transmembrane Region of the Glycoprotein Leads to an Unstable Attenuation of Machupo Virus

Cited by 18 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

Machupo Virus Expressing GPC of the Candid#1 Vaccine Strain of Junin Virus Is Highly Attenuated and Immunogenic

Animal Models for the Study of Rodent-Borne Hemorrhagic Fever Viruses: Arenaviruses and Hantaviruses

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