Adaptation of wild-type measles virus to cotton rat lung cells: E89K mutation in matrix protein contributes to its fitness

Dong, Jing; Saito, Akatsuki; Mine, Yuta; Sakuraba, Yuta; Nibe, Kazumi; Goto, Yoshitaka; Komase, Katsuhiro; Nakayama, Tetsuo; Miyata, Hironori; Iwata, Hiroyuki; Haga, Takeshi

doi:10.1007/s11262-009-0408-4

Cited by 9 publications

(9 citation statements)

References 34 publications

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“…MVi/Tokyo.JPN/37.99(Y) and MVi/Tokyo.JPN/37.99(Y)C7 are genotype D3, the former is a wild-type isolate, the latter is its cell culture passaged derivative [39]. Both have identical insertions in the M 3′ UTR and identical deletions that replace 27 amino acids at the carboxyl-terminus of the F1 protein with a different sequence of 11 amino acids.…”

Section: Discussionmentioning

confidence: 99%

Wild-Type Measles Viruses with Non-Standard Genome Lengths

et al. 2014

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The length of the single stranded, negative sense RNA genome of measles virus (MeV) is highly conserved at 15,894 nucleotides (nt). MeVs can be grouped into 24 genotypes based on the highly variable 450 nucleotides coding for the carboxyl-terminus of the nucleocapsid protein (N-450). Here, we report the genomic sequences of 2 wild-type viral isolates of genotype D4 with genome lengths of 15,900 nt. Both genomes had a 7 nt insertion in the 3′ untranslated region (UTR) of the matrix (M) gene and a 1 nt deletion in the 5′ UTR of the fusion (F) gene. The net gain of 6 nt complies with the rule-of-six required for replication competency of the genomes of morbilliviruses. The insertions and deletion (indels) were confirmed in a patient sample that was the source of one of the viral isolates. The positions of the indels were identical in both viral isolates, even though epidemiological data and the 3 nt differences in N-450 between the two genomes suggested that the viruses represented separate chains of transmission. Identical indels were found in the M-F intergenic regions of 14 additional genotype D4 viral isolates that were imported into the US during 2007–2010. Viral isolates with and without indels produced plaques of similar size and replicated efficiently in A549/hSLAM and Vero/hSLAM cells. This is the first report of wild-type MeVs with genome lengths other than 15,894 nt and demonstrates that the length of the M-F UTR of wild-type MeVs is flexible.

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Section: Discussionmentioning

confidence: 99%

Wild-Type Measles Viruses with Non-Standard Genome Lengths

et al. 2014

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“…For example, the adaptation of the measles virus to cotton rats was accompanied by a single mutation in the matrix protein, and the adaptation of chimpanzee immune deficiency virus to human lymphoid tissue also was dependent on a point mutation in the gag matrix protein (35,36). The mechanisms of how the mutated matrix proteins mediated the effect on replicative fitness in a new host remain largely unknown.…”

Section: Discussionmentioning

confidence: 99%

A Single Amino Acid Change in the Marburg Virus Matrix Protein VP40 Provides a Replicative Advantage in a Species-Specific Manner

Koehler

Kolesnikova

Welzel

et al. 2016

J Virol

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Marburg virus (MARV) induces severe hemorrhagic fever in humans and nonhuman primates but only transient nonlethal disease in rodents. However, sequential passages of MARV in rodents boosts infection leading to lethal disease. Guinea pig-adapted MARV contains one mutation in the viral matrix protein VP40 at position 184 (VP40 D184N ). The contribution of the D184N mutation to the efficacy of replication in a new host is unknown. In the present study, we demonstrated that recombinant MARV containing the D184N mutation in VP40 [rMARV VP40(D184N) ] grew to higher titers than wild-type recombinant MARV (rMARV WT ) in guinea pig cells. Moreover, rMARV VP40(D184N) displayed higher infectivity in guinea pig cells. Comparative analysis of VP40 functions indicated that neither the interferon (IFN)-antagonistic function nor the membrane binding capabilities of VP40 were affected by the D184N mutation. However, the production of VP40-induced virus-like particles (VLPs) and the recruitment of other viral proteins to the budding site was improved by the D184N mutation in guinea pig cells, which resulted in the higher infectivity of VP40 D184N -induced infectious VLPs (iVLPs) compared to that of VP40-induced iVLPs. In addition, the function of VP40 in suppressing viral RNA synthesis was influenced by the D184N mutation specifically in guinea pig cells, thus allowing greater rates of transcription and replication. Our results showed that the improved viral fitness of rMARV VP40(D184N) in guinea pig cells was due to the better viral assembly function of VP40 D184N and its lower inhibitory effect on viral transcription and replication rather than modulation of the VP40-mediated suppression of IFN signaling. IMPORTANCEThe increased virulence achieved by virus passaging in a new host was accompanied by mutations in the viral genome. Analyzing how these mutations affect the functions of viral proteins and the ability of the virus to grow within new host cells helps in the understanding of the molecular mechanisms increasing virulence. Using a reverse genetics approach, we demonstrated that a single mutation in MARV VP40 detected in a guinea pig-adapted MARV provided a replicative advantage of rMARV VP40(D184N) in guinea pig cells. Our studies show that this replicative advantage of rMARV VP40 D184N was based on the improved functions of VP40 in iVLP assembly and in the regulation of transcription and replication rather than on the ability of VP40 to combat the host innate immunity. F iloviruses, including Ebolaviruses (EBOV) and Marburg virus (MARV), are enveloped, nonsegmented, negative-strand RNA viruses (1). These viruses are known to cause severe fevers in humans and nonhuman primates, with case fatality rates of up to 90% (2). Although several antivirals and vaccines currently are being tested in clinical studies, none of them are licensed for human use. Therefore, work with filoviruses is restricted to biosafety level 4 (BSL-4) facilities. The recent EBOV outbreak in Guinea, Sierra Leone, and Liberia demonstrated the ...

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“…Adapted virus MV99YC7, which adapted well to CRL cells after serial passages, possesses a mutation in the M gene causing E89K substitution and one silent mutation in the L gene, as compared to the parental virus MV99Y [10]. Human PBMC were isolated from healthy adults using Ficoll-Paque PREMIUM (GE Healthcare Bio-science, Piscataway, NJ).…”

Section: Methodsmentioning

confidence: 99%

“…It also can affect efficient growth and cell-cell fusion [8, 9]. A previous study revealed that the E89K substitution mutation in M protein plays a key role in wild-type MeV adaptation in the cotton rat and cotton rat lung (CRL) cells [10]. …”

Section: Introductionmentioning

confidence: 99%

The E89K Mutation in the Matrix Protein of the Measles Virus Affects In Vitro Cell Death and Virus Replication Efficiency in Human PBMC

Dong

Zhu²,

Saito³

et al. 2012

TOVJ

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Matrix protein is known to have an important role in the process of virus assembly and virion release during measles virus replication. In the present in vitro study, a single mutation of E89K in the matrix protein was shown to affect cell death and virus replication efficiency in human PBMC. One strain with this mutation caused less cell death than the parental virus, and possessed high virus replication efficiency. Moreover, by Annexin V-FITC staining, polycaspase FLICA staining, and double labeling with poly-caspase FLICA and the Hoechst stain, the cell death seen was shown to be apoptosis.

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Adaptation of wild-type measles virus to cotton rat lung cells: E89K mutation in matrix protein contributes to its fitness

Cited by 9 publications

References 34 publications

Wild-Type Measles Viruses with Non-Standard Genome Lengths

Wild-Type Measles Viruses with Non-Standard Genome Lengths

A Single Amino Acid Change in the Marburg Virus Matrix Protein VP40 Provides a Replicative Advantage in a Species-Specific Manner

The E89K Mutation in the Matrix Protein of the Measles Virus Affects In Vitro Cell Death and Virus Replication Efficiency in Human PBMC

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