Adenovirus-triggered innate signalling pathways

Abstract

Adenoviruses are important infectious agents and also emerging vectors in different biomedical applications. These viruses elicit a strong innate and adaptive immune response, which influences both the course of disease and the success of the applied vectors. Several Toll-like Receptor (TLR)-dependent and -independent mechanisms contribute to these responses. Understanding of the involved viral and cellular factors is crucial for the treatment of various adenovirus diseases and the optimal design of adenovirus vector applications. Here we summarize our current understanding of the complex nature of adenovirus-induced innate immune mechanisms.

Innate Immunity to Adenovirus

“…1B) (Arnberg, 2012;Wolfrum and Greber, 2013). Entry pathways into immune cells, such as macrophages and dendritic cells, may be different and could be modulated by cytokines or antibodies, and availability of low-affinity, high-avidity receptors, such as scavenger receptors (Meier et al, 2005;Fejer et al, 2011;Khare et al, 2012;Mercer and Greber, 2013). Entry of HAdV-C2/ 5 into polarized epithelial cells from the apical side (facing the airways) is enhanced by cytokines and chemokines, including interleukin 8 and tissue necrosis factor alpha (Lutschg et al, 2011).…”

“…Collectively, innate immunity steers the organism to adaptive immunity, which is pathogen specific, and comprises selective antibodies. Both innate and adaptive immunity generally antagonize viral efficacy in gene therapy (reviewed in Janeway and Medzhitov, 2002;Fejer et al, 2011;Russell et al, 2012), although the treatment of aggressive forms of cancer by therapeutic viruses can be enhanced by the inflammatory host response (for reviews, see Wong et al, 2010;Russell et al, 2012). Here we summarize the current knowledge of the mechanisms that lead to inflammation and innate immunity in cells inoculated with HAdV.…”

Pre-existing immunity against Ad vectors

“…[38][39][40][41] Upon activation, the above PRR molecules trigger signaling pathways such as NF-KB, which can induce the production of numerous pro-inflammatory mediators including cytokines (interferon (IFN) a/ b, interleukin (IL)-1a/ b, tumor necrosis factor (TNF)a, and IL-6) and chemokines (IL-8, macrophage inflammatory protein (MIP)-1a/b, IP-10, RANTES, and monocyte chemoattractant protein (MCP)-1). [38][39][40] Among these pro-inflammatory molecules, IL-1 and its receptor IL-1R1, as well as type I IFN, play a central role as they induce positive feed-back loops that in turn, produce additional pro-inflammatory mediators. [42][43][44] The role of innate immunity on antigen expression and vector efficacy after Ad immunization was revealed by comparing different HAd of various immunogenicities.…”

Xenogenic Adenoviral Vectors

“…Furthermore, intravenous inoculations of large doses of AdV vectors can also have life-threatening consequences mediated by strong activation of innate immune reactions. 44 The tremendous potential of AdV vectors is hampered by the immune responses to AdVs. For the success of these vectors, it is critical to understand thoroughly the underlying mechanisms.…”