Downregulation of Cell Surface Major Histocompatibility Complex Class I Expression Is Mediated by the Left-End Transcription Unit of Fowl Adenovirus 9.

Bryan D Griffin,Éva Nagy,Juan Carlos Corredor,Yanlong Pei

doi:10.3390/v13112211

Abstract

Major histocompatibility complex class I (MHC-I) molecules play a critical role in the host’s antiviral response by presenting virus-derived antigenic peptides to cytotoxic T lymphocytes (CTLs), enabling the clearance of virus-infected cells. Human adenoviruses evade CTL-mediated cell lysis, in part, by interfering directly with the MHC-I antigen presentation pathway through the expression of E3-19K, which binds both MHC-I and the transporter associated with antigen processing protein and sequestering MHC-I within the endoplasmic reticulum. Fowl adenoviruses have no homologues of E3-19K. Here, we show that representative virus isolates of the species Fowl aviadenovirus C, Fowl aviadenovirus D, and Fowl aviadenovirus E downregulate the cell surface expression of MHC-I in chicken hepatoma cells, resulting in 71%, 11%, and 14% of the baseline expression level, respectively, at 12 h post-infection. Furthermore, this work reports that FAdV-9 downregulates cell surface MHC-I through a minimum of two separate mechanisms—a lysosomal-independent mechanism that requires the presence of the fowl adenovirus early 1 (FE1) transcription unit located within the left terminal genomic region between nts 1 and 6131 and a lysosomal-dependent mechanism that does not require the presence of FE1. These results establish a new functional role for the FE1 transcription unit in immune evasion. These studies provide important new information about the immune evasion of FAdVs and will enhance our understanding of the pathogenesis of inclusion body hepatitis and advance the progress made in next-generation FAdV-based vectors.

Highlights

Viruses have evolved diverse strategies to counter the host’s antiviral defenses by targeting components of both the innate and adaptive immune responses [1]
The mean fluorescence intensity (FITC) of unpermeabilized, mock-infected CH-SAH or LMH cells saturated with mouse anti-Major histocompatibility complex class I (MHC-I) monoclonal antibody (MAb) and fluorescein isothiocyanate (FITC)-conjugated anti-mouse antibodies was found to be greater than 20 fluorescence units, indicating a moderate level of cell surface MHC-I
Infection with fowl adenoviruses (FAdVs)-8a or FAdV-9 resulted in an 86% and 89% reduction in MHC-I on the cell surface, respectively, compared to the levels in mock-infected cells

Summary

Introduction

Viruses have evolved diverse strategies to counter the host’s antiviral defenses by targeting components of both the innate and adaptive immune responses [1]. While human adenovirus (HAdV) early genes such as E1A, E1B, E3, and E4 are well known for their roles in counteracting the host’s antiviral defenses through a variety of mechanisms, homologs to these genes are lacking in fowl adenoviruses (FAdVs) that infect avian species [2,3]. Some FAdVs, notably FAdV-2, FAdV-8a and -8b, FAdV-11, and some strains of FAdV-4, are associated with economically important poultry diseases such as inclusion body hepatitis (IBH) [6] and hepatitis hydropericardium syndrome (HHS) [7]. Some FAdV strains, such as FAdV-9 strain A-2A, cause mild or no disease and are routinely isolated from healthy flocks [5]

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Results

Conclusion