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Lassa virus activates myeloid dendritic cells but suppresses their ability to stimulate T cells.

ABSTRACT: Lassa virus (LASV) is responsible for a viral hemorrhagic fever in humans and the death of 3,000 to 5,000 people every year. The immune response to LASV is poorly understood, but type I interferon (IFN-I) and T-cell responses appear to be critical for the host. We studied the response of myeloid dendritic cells (mDC) to LASV, as mDCs are involved in both IFN-I production and T-cell activation. We compared the response of primary human mDCs to LASV and Mopeia virus (MOPV), which is similar to LASV, but non-pathogenic. We showed that mDCs produced substantial amounts of IFN-I in response to both LASV and MOPV. However, only MOPV-infected mDCs were able to activate T cells. More surprisingly, coculture with T cells completely inhibited the activation of LASV-infected mDCs. These differences between LASV and MOPV were mostly due to the LASV nucleoprotein, which has major immunosuppressive properties, but the glycoprotein was also involved. Overall, these results suggest that mDCs may be important for the global response to LASV and play a role in the outcome of Lassa fever.

SUBMITTER: Schaeffer J

PROVIDER: S-EPMC6258464 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Lassa virus activates myeloid dendritic cells but suppresses their ability to stimulate T cells.

Schaeffer Justine J Carnec Xavier X Reynard Stéphanie S Mateo Mathieu M Picard Caroline C Pietrosemoli Natalia N Dillies Marie-Agnès MA Baize Sylvain S

PLoS pathogens 20181112 11

Lassa virus (LASV) is responsible for a viral hemorrhagic fever in humans and the death of 3,000 to 5,000 people every year. The immune response to LASV is poorly understood, but type I interferon (IFN-I) and T-cell responses appear to be critical for the host. We studied the response of myeloid dendritic cells (mDC) to LASV, as mDCs are involved in both IFN-I production and T-cell activation. We compared the response of primary human mDCs to LASV and Mopeia virus (MOPV), which is similar to LAS ...[more]

PMID: 30419076

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Project description:Herpes simplex virus type 1 (HSV-1) has the ability to delay its clearance from the eye during ocular infection. Here, we show that ocular infection of mice with HSV-1 suppressed expression of the costimulatory molecule CD80 but not CD86 in the cornea. The presence of neutralizing anti-HSV-1 antibodies did not alleviate this suppression. At the cellular level, HSV-1 consistently downregulated the expression of CD80 by dendritic cells (DCs) but not by other antigen-presenting cells. Furthermore, flow cytometric analysis of HSV-1-infected corneal cells during a 7-day period reduced CD80 expression in DCs but not in B cells, macrophages, or monocytes. This suppression was associated with the presence of virus. Similar results were obtained using infected or transfected spleen cells or bone marrow-derived DCs. A combination of roscovitine treatment, transfection with immediate early genes (IE), and infection with a recombinant HSV-1 lacking the ICP22 gene shows the importance of ICP22 in downregulation of the CD80 promoter but not the CD86 promoter in vitro and in vivo At the mechanistic level, we show that the HSV-1 immediate early gene ICP22 binds the CD80 promoter and that this interaction is required for HSV-1-mediated suppression of CD80 expression. Conversely, forced expression of CD80 by ocular infection of mice with a recombinant HSV-1 exacerbated corneal scarring in infected mice. Taken together, these studies identify ICP22-mediated suppression of CD80 expression in dendritic cells as central to delayed clearance of the virus and limitation of the cytopathological response to primary infection in the eye.IMPORTANCE HSV-1-induced eye disease is a major public health problem. Eye disease is associated closely with immune responses to the virus and is exacerbated by delayed clearance of the primary infection. The immune system relies on antigen-presenting cells of the innate immune system to activate the T cell response. We found that HSV-1 utilizes a robust and finely targeted mechanism of local immune evasion. It downregulates the expression of the costimulatory molecule CD80 but not CD86 on resident dendritic cells irrespective of the presence of anti-HSV-1 antibodies. The effect is mediated by direct binding of HSV-1 ICP22, the product of an immediate early gene of HSV-1, to the promoter of CD80. This immune evasion mechanism dampens the host immune response and, thus, reduces eye disease in ocularly infected mice. Therefore, ICP22 may be a novel inhibitor of CD80 that could be used to modulate the immune response.

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Lassa virus activates myeloid dendritic cells but suppresses their ability to stimulate T cells.

Publications

Lassa virus activates myeloid dendritic cells but suppresses their ability to stimulate T cells.

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