Nipah Virus Infection of Immature Dendritic Cells Increases Its Transendothelial Migration Across Human Brain Microvascular Endothelial Cells

Abstract

Nipah virus (NiV) can infect multiple organs in humans with the central nervous system (CNS) being the most severely affected. Currently, it is not fully understood how NiV spreads throughout the body. NiV has been shown to infect certain leukocyte populations and we hypothesized that these infected cells could cross the blood-brain barrier (BBB), facilitating NiV entry into the CNS. Here, three leukocyte types, primary immature dendritic cells (iDC), primary monocytes (pMO), and monocytic cell line (THP-1), were evaluated for permissiveness to NiV. We found only iDC and THP-1 were permissive to NiV. Transendothelial migration of mock-infected and NiV-infected leukocytes was then evaluated using an in vitro BBB model established with human brain microvascular endothelial cells (HBMEC). There was approximately a threefold increase in migration of NiV-infected iDC across endothelial monolayer when compared to mock-infected iDC. In contrast, migration rates for pMO and THP-1 did not change upon NiV infection. Across TNF-α-treated endothelial monolayer, there was significant increase of almost twofold in migration of NiV-infected iDC and THP-1 over mock-infected cells. Immunofluorescence analysis showed the migrated NiV-infected leukocytes retained their ability to infect other cells. This study demonstrates for the first time that active NiV infection of iDC and THP-1 increased their transendothelial migration activity across HBMEC and activation of HBMEC by TNF-α further promoted migration. The findings suggest that NiV infection of leukocytes to disseminate the virus via the “Trojan horse” mechanism is a viable route of entry into the CNS.

Neurological pathophysiology of SARS‐CoV‐2 and pandemic potential RNA viruses: a comparative analysis

“…NiV can be detected in bronchiolar epithelial cells in most human cases [131]. There is little literature available regarding NiV entry to the CNS and its proliferation throughout the host, though most studies seem to indicate that specific leukocyte populations allow infected cells to cross the BBB, facilitating NiV entry into the CNS [128]. NiV was found to infect neurons and microglial cells that express CD68 in nonhuman primates [132].…”

Mechanisms of Pathogen Invasion into the Central Nervous System

“…NiV also infects phagocytic cells, predominately immature dendritic cells (iDCs) (Mathieu et al, 2011;Tiong et al, 2018). NiV-infected iDCs migrated across human BMECs an in vitro model of the BBB and delivered virus to other cells (Tiong et al, 2018).…”

“…NiV also infects phagocytic cells, predominately immature dendritic cells (iDCs) (Mathieu et al, 2011;Tiong et al, 2018). NiV-infected iDCs migrated across human BMECs an in vitro model of the BBB and delivered virus to other cells (Tiong et al, 2018). NiV infection of iDCs also enhanced their migratory activity compared to uninfected iDCs, suggesting that NiV infection promotes its neuroinvasion through multiple mechanisms.…”

Zika virus enhances monocyte adhesion and transmigration favoring viral dissemination to neural cells

“…The BBB is an extremely tight endothelium separating bloodstream-circulating virions from the neural target cells. The Trojan Horse strategy, consisting of the infection of circulating leukocytes that carry virus through endothelial monolayers, has been proposed for numerous viruses in various in vitro infection assays 15–19 , but never highlighted in an in vivo context. Monocytes are considered as well-suited viral carriers since they exhibit potent transmigrating abilities over endothelial barriers, including the BBB 20 .…”