Human Metapneumovirus Establishes Persistent Infection in Lung Microvascular Endothelial Cells and Primes a Th2-Skewed Immune Response.

Antonella Bugatti,Silvano Sozzani,Simona Fiorentini,Francesca Caccuri,Serena Messali,Stefania Marsico,Arnaldo Caruso,Cinzia Giagulli,Sara Roversi,Manuela Fogli,Daniela Bosisio

doi:10.3390/microorganisms8060824

Antonella Bugatti, Silvano Sozzani + Show 9 more

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https://doi.org/10.3390/microorganisms8060824

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Journal: Microorganisms	Publication Date: May 30, 2020
Citations: 3	License type: CC BY 4.0

Affiliation: University of Brescia, University of Calabria

Abstract

Human Metapneumovirus (HMPV) is a major cause of lower respiratory tract infections. HMPV infection has been hypothesized to alter dendritic cell (DC) immune response; however, many questions regarding HMPV pathogenesis within the infected lung remain unanswered. Here, we show that HMPV productively infects human lung microvascular endothelial cells (L-HMVECs). The release of infectious virus occurs for up to more than 30 days of culture without producing overt cytopathic effects and medium derived from persistently HMPV-infected L-HMVECs (secretome) induced monocyte-derived DCs to prime naïve CD4 T-cells toward a Th2 phenotype. Moreover, we demonstrated that infected secretomes trigger DCs to up-regulate OX40L expression and OX40L neutralization abolished the pro-Th2 effect that is induced by HMPV-secretome. We clarified secretome from HMPV by size exclusion and ultracentrifugation with the aim to characterize the role of viral particles in the observed pro-Th2 effect. In both cases, the percentage of IL-4-producing cells and expression of OX40L returned at basal levels. Finally, we showed that HMPV, per se, could reproduce the ability of secretome to prime pro-Th2 DCs. These results suggest that HMPV, persistently released by L-HMVECs, might take part in the development of a skewed, pro-Th2 lung microenvironment.

Highlights

Virus infections are the primary cause of respiratory illness in humans and, in particular, RNA viruses, such as respiratory syncytial virus (RSV), Human metapneumovirus (HMPV), parainfluenza, and influenza viruses, are the most common pathogens that are associated with lower respiratory tract infections
We first examined the ability of HMPV to replicate in L-HMVECs in order to assess if microvascular endothelial cells (ECs) can represent a relevant target for HMPV infection
We have demonstrated that primary L-HMVECs support a productive in vitro infection of HMPV, showing no evidence of a cytopathic effect over the first month PI and, interestingly, this persistent state of infection was characterized by a continuous release of viral particles

Summary

Introduction

Virus infections are the primary cause of respiratory illness in humans and, in particular, RNA viruses, such as respiratory syncytial virus (RSV), Human metapneumovirus (HMPV), parainfluenza, and influenza viruses, are the most common pathogens that are associated with lower respiratory tract infections. Studies that were performed in immunized mice have shown that primary HMPV infection elicits weak, innate, and aberrant adaptive immune responses that are characterized by the induction of Th2-type cytokines, at later stages of infection. This event coincides with virus persistence in the lung [8,17]. We have shown that HMPV infection is maintained for as long as more than two years in a subset of epithelial cells by overcoming apoptosis These cells may act as a reservoir of infectious virus that could contribute to in vivo viral persistence [21]

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