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siRNA Electroporation to Modulate Autophagy in Herpes Simplex Virus Type 1-Infected Monocyte-Derived Dendritic Cells
Published on: October 28, 2019
NINJ1 blocks HSV-1 entry into macrophages to impact viral replication and immunity
Ella Hartenian1, Magalie Agustoni1, Petr Broz2
1Department of Immunobiology, University of Lausanne, Lausanne, 1066, Switzerland.
Abstract:
Restriction factors block multiple stages of viral infection. Here we describe how Ninjurin1 (NINJ1) controls HSV-1 infection of macrophages, a key cell type that protects mice against infection. We observe that Ninj1-/- mouse macrophages are more susceptible to HSV-1 infection than WT cells. Given the role of NINJ1 during cell death, we investigate whether its antiviral activity is linked to this function. Surprisingly, we do not observe differences in cell death at early timepoints post HSV-1 infection between genotypes. Instead, we attribute the higher infection rate of Ninj1-/- macrophages to enhanced entry, with more viral particles entering each cell and a greater fraction of infected cells. The increased viral loads in Ninj1-/- cells result in higher ISG and cytokine RNA expression, which we ascribe to both TLR signaling and STING-mediated recognition. Cytokine secretion, however, is severely dampened in infected Ninj1-/- cells, pointing to greater viral replication suppressing the induction of inflammation. In conclusion, NINJ1 acts as a gatekeeper for HSV-1 entry in macrophages, impacting the inflammatory phenotype associated with HSV-1 infection.
Insights
Ninjurin1 (NINJ1) restricts herpes simplex virus type 1 (HSV-1) entry into macrophages. Macrophages lacking NINJ1 show increased viral entry and replication, impacting immune responses and inflammation.
Area of Science:
- Immunology
- Virology
- Cell Biology
Background:
- Restriction factors are crucial in controlling viral infections.
- Macrophages are key immune cells for host defense against viruses like HSV-1.
Purpose of the Study:
- To investigate the role of Ninjurin1 (NINJ1) in controlling HSV-1 infection in macrophages.
- To determine if NINJ1's antiviral function is linked to its role in cell death.
Main Methods:
- Comparison of HSV-1 infection rates in wild-type (WT) and Ninj1 knockout (Ninj1-/-) mouse macrophages.
- Assessment of viral entry, replication, cell death, and immune gene expression (ISG, cytokines).
- Analysis of Toll-like receptor (TLR) and STING-mediated signaling pathways.
Main Results:
- Ninj1-/- macrophages exhibit higher susceptibility to HSV-1 infection compared to WT cells.
- Increased viral entry, not cell death, is responsible for higher infection rates in Ninj1-/- macrophages.
- Elevated viral loads in Ninj1-/- cells lead to increased ISG and cytokine RNA expression but dampened cytokine secretion.
Conclusions:
- NINJ1 functions as a gatekeeper, restricting HSV-1 entry into macrophages.
- NINJ1 influences the inflammatory phenotype of HSV-1 infection by modulating viral entry and replication.
- The findings highlight a novel role for NINJ1 in innate antiviral immunity.
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