CD46-Utilizing Adenoviruses Inhibit C/EBPβ-Dependent Expression of Proinflammatory Cytokines

Abstract

The majority of adenovirus serotypes utilize the coxsackievirus-adenovirus receptor (CAR) for virus-host cell attachment, but subgroup B and subgroup D (adenovirus type 37 [Ad37]) viruses recognize CD46. CD46 is a ubiquitously expressed receptor that serves as a cofactor for the inactivation of the complement components C3b and C4b, and it also serves as a receptor for diverse microbial pathogens. A reported consequence of CD46 engagement is a reduced capability of human immune cells to express interleukin-12 (IL-12), a cytokine involved in both the innate and adaptive immune responses. Studies were thus undertaken to determine whether CD46-utilizing Ads alter the expression of proinflammatory cytokines. Subgroup B (Ad16 and -35) and Ad37, but not Ad2 or -5, significantly reduced IL-12 production by human peripheral blood mononuclear cells stimulated with gamma interferon (IFN-␥) and lipopolysaccharide. IL-12 mRNA (p35 and p40 subunits) levels as well as other cytokine mRNA levels (IL-1␣ and -␤, IL-1Ra, and IL-6) were decreased upon interaction with CD46-utilizing Ads. Analysis of transcription factor activity required for cytokine expression indicated that CD46-utilizing Ads preferentially inhibited IFN-␥-induced C/EBP␤ protein expression, consequently reducing its ability to form DNA complexes. Interference with IFN-␥ signaling events by CD46-utilizing Ads, but not CAR-utilizing Ads, reveals a potentially critical difference in the host immune response against distinct Ad vectors, a situation that has implications for gene delivery and vaccine development.Accumulating knowledge has revealed that virus association with cell receptors may have important consequences beyond simple host cell recognition. For example, human adenovirus (Ad)-receptor interactions trigger multiple signaling pathways, some of which promote cell entry (32-34), while others may provoke acute inflammatory responses (8,18,36,41,(57)(58)(59). Many of the 51 known Ad serotypes classified into subgroups A to F cause acute upper respiratory tract, gastrointestinal, and ocular diseases. Cell tropism is a major factor that influences the pathological consequences of Ad infection. Ad cell entry is initiated by binding of the virus fiber protein to a specific host receptor and is followed by the association of the penton base capsid protein with ␣ v integrins leading to virus internalization (42). While most Ad serotypes use coxsackievirus-adenovirus receptor (CAR) as their primary attachment receptor (6, 60), subgroup B and at least one subgroup D virus use an alternative receptor, CD46 (13,52,55,64).CD46, also known as membrane cofactor protein, is a member of the family of complement regulatory proteins that bind the complement proteins C3b and C4b, serving as a cofactor for their inactivation by a serum protease (53). In addition to certain Ad serotypes, CD46 is a receptor for multiple microbial pathogens, including a gram-negative bacterium, Neisseria sp. (25), the Edmonston strain of measles virus (MV) (12, 40), and human herpesvirus 6 (HHV6...

Metabolically Favorable Remodeling of Human Adipose Tissue by Human Adenovirus Type 36

“…Ad-36 reduced MCP-1 expression in explants, but Ad-19 increases MCP-1 expression (62) and Ad-7 increases interleukin-8 production (63). On the other hand, adenovirus types 16, 35, and 37 reduce proinflammatory cytokine expressions (64). Interestingly, Ad-37 is reported to increase adiposity in animals (33).…”

Modulation of viability and maturation of human monocyte‐derived dendritic cells by oncolytic adenoviruses

“…46 For PBMCs and plasmacytoid DCs different responses to CAR-binding and CD46-binding adenoviruses have been reported. 54,55 Clearly, differences between adenovirus serotypes with respect to how they affect DCs and more generally strategies for directed modulation of DC functions by adenovirus capsid modification need further investigation.…”

Preferential Activation of Toll-Like Receptor Nine by CD46-Utilizing Adenoviruses

“…Adenovirus vectors were propagated in 293 cells as previously described (22). Ad5.F16 empty capsids (EC), produced during normal viral propagation, were readily purified from mature particles on CsCl gradients due to an approximate 1.5-cm distance separating the two viral species.…”

“…Our previous studies showed that infection of human PBMC by the CD46-utilizing Ads Ad37, Ad16, and Ad35 leads to an impairment in cytokine production (22). CD46 Ads, but not the CAR-utilizing Ad5, interfere with gamma interferon signaling events in monocytes that are necessary for expression of the C/EBP␤ transcription factor, which in turn is required for subsequent proinflammatory cytokine gene transcription.…”