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An attenuated Machupo virus with a disrupted L-segment intergenic region protects guinea pigs against lethal
Joseph W Golden1, Brett Beitzel2, Jason T Ladner2
1Department of Molecular Virology, Virology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD, 21702, United States. joseph.w.golden.ctr@mail.mil.
Abstract:
Machupo virus (MACV) is a New World (NW) arenavirus and causative agent of Bolivian hemorrhagic fever (HF). Here, we identified a variant of MACV strain Carvallo termed Car91 that was attenuated in guinea pigs. Infection of guinea pigs with an earlier passage of Carvallo, termed Car68, resulted in a lethal disease with a 63% mortality rate. Sequencing analysis revealed that compared to Car68, Car91 had a 35 nucleotide (nt) deletion and a point mutation within the L-segment intergenic region (IGR), and three silent changes in the polymerase gene that did not impact amino acid coding. No changes were found on the S-segment. Because it was apathogenic, we determined if Car91 could protect guinea pigs against Guanarito virus (GTOV), a distantly related NW arenavirus. While naïve animals succumbed to GTOV infection, 88% of the Car91-exposed guinea pigs were protected. These findings indicate that attenuated MACV vaccines can provide heterologous protection against NW arenaviruses. The disruption in the L-segment IGR, including a single point mutant and 35 nt partial deletion, were the only major variance detected between virulent and avirulent isolates, implicating its role in attenuation. Overall, our data support the development of live-attenuated arenaviruses as broadly protective pan-arenavirus vaccines.
Insights
An attenuated Machupo virus (MACV) strain, Car91, protected guinea pigs against lethal Guanarito virus (GTOV) infection. This suggests live-attenuated arenavirus vaccines offer broad protection against New World arenaviruses.
Area of Science:
- Virology
- Immunology
- Vaccinology
Background:
- Machupo virus (MACV) causes severe Bolivian hemorrhagic fever.
- New World (NW) arenaviruses pose significant public health threats.
- Development of effective arenavirus vaccines is crucial.
Purpose of the Study:
- To investigate the attenuation of a MACV variant (Car91).
- To evaluate the protective potential of Car91 against a heterologous NW arenavirus.
- To identify genetic determinants of arenavirus attenuation.
Main Methods:
- Comparative sequencing of virulent (Car68) and attenuated (Car91) MACV strains.
- Infection of guinea pigs with MACV strains to assess virulence.
- Challenge studies using Guanarito virus (GTOV) in Car91-vaccinated guinea pigs.
Main Results:
- MACV strain Car91 exhibited significant attenuation in guinea pigs compared to Car68.
- Car91 displayed a 35 nt deletion and a point mutation in the L-segment IGR.
- Car91-exposed guinea pigs showed 88% protection against lethal GTOV challenge.
Conclusions:
- Genetic alterations in the L-segment IGR are associated with MACV attenuation.
- Attenuated MACV provides heterologous protection against related NW arenaviruses.
- Live-attenuated arenaviruses show promise as broad-spectrum pan-arenavirus vaccines.
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