The lack of maturation of Ebola virus-infected dendritic cells results from the cooperative effect of at least two viral domains

Ndongala M.Lubaki, Philipp Ilinykh, Colette Pietzsch, Bersabeh Tigabu, Alexander Freiberg, Richard A. Koup, Alexander Bukreyeva

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Abstract

Ebola virus (EBOV) infections are characterized by deficient T lymphocyte responses, T lymphocyte apoptosis, and lymphopenia in the absence of direct infection of T lymphocytes. In contrast, dendritic cells (DC) are infected but fail to mature appropriately, thereby impairing the T cell response. We investigated the contributions of EBOV proteins in modulating DC maturation by generating recombinant viruses expressing enhanced green fluorescent protein and carrying mutations affecting several potentially immunomodulating domains. They included envelope glycoprotein (GP) domains, as well as innate response antagonist domains (IRADs) previously identified in the VP24 and VP35 proteins. GP expressed by an unrelated vector, but not the wild-type EBOV, was found to strongly induce DC maturation, and infections with recombinant EBOV carrying mutations disabling GP functional domains did not restore DC maturation. In contrast, each of the viruses carrying mutations disabling any IRAD in VP35 induced a dramatic upregulation of DC maturation markers. This was dependent on infection, but not interaction with GP. Disabling of IRADs also resulted in up to a several hundredfold increase in secretion of cytokines and chemokines. Furthermore, these mutations induced formation of homotypic DC clusters, which represent close correlates of their maturation and presumably facilitate transfer of antigen from migratory DC to lymph node DC. Thus, an individual IRAD is insufficient to suppress DC maturation; rather, the suppression of DC maturation and the " immune paralysis" observed during EBOV infections results from a cooperative effect of two or more individual IRADs.

Original languageEnglish (US)
Pages (from-to)7471-7485
Number of pages15
JournalJournal of Virology
Volume87
Issue number13
DOIs
StatePublished - Jul 2013

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Ebolavirus
dendritic cells
Dendritic Cells
cooperatives
antagonists
glycoproteins
Glycoproteins
Ebola Hemorrhagic Fever
T-lymphocytes
T-Lymphocytes
Mutation
infection
mutation
Infection
Viruses
viruses
Lymphopenia
paralysis
chemokines
green fluorescent protein

ASJC Scopus subject areas

  • Immunology
  • Virology

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The lack of maturation of Ebola virus-infected dendritic cells results from the cooperative effect of at least two viral domains. / M.Lubaki, Ndongala; Ilinykh, Philipp; Pietzsch, Colette; Tigabu, Bersabeh; Freiberg, Alexander; Koup, Richard A.; Bukreyeva, Alexander.

In: Journal of Virology, Vol. 87, No. 13, 07.2013, p. 7471-7485.

Research output: Contribution to journalArticle

M.Lubaki, Ndongala ; Ilinykh, Philipp ; Pietzsch, Colette ; Tigabu, Bersabeh ; Freiberg, Alexander ; Koup, Richard A. ; Bukreyeva, Alexander. / The lack of maturation of Ebola virus-infected dendritic cells results from the cooperative effect of at least two viral domains. In: Journal of Virology. 2013 ; Vol. 87, No. 13. pp. 7471-7485.
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