Cytokine Responses to Adenovirus and Adenovirus Vectors

Abstract

The expression of cytokines and chemokines in response to adenovirus infection is tightly regulated by the innate immune system. Cytokine-mediated toxicity and cytokine storm are known clinical phenomena observed following naturally disseminated adenovirus infection in immunocompromised hosts as well as when extremely high doses of adenovirus vectors are injected intravenously. This dose-dependent, cytokine-mediated toxicity compromises the safety of adenovirus-based vectors and represents a critical problem, limiting their utility for gene therapy applications and the therapy of disseminated cancer, where intravenous injection of adenovirus vectors may provide therapeutic benefits. The mechanisms triggering severe cytokine response are not sufficiently understood, prompting efforts to further investigate this phenomenon, especially in clinically relevant settings. In this review, we summarize the current knowledge on cytokine and chemokine activation in response to adenovirus- and adenovirus-based vectors and discuss the underlying mechanisms that may trigger acute cytokine storm syndrome. First, we review profiles of cytokines and chemokines that are activated in response to adenovirus infection initiated via different routes. Second, we discuss the molecular mechanisms that lead to cytokine and chemokine transcriptional activation. We further highlight how immune cell types in different organs contribute to synthesis and systemic release of cytokines and chemokines in response to adenovirus sensing. Finally, we review host factors that can limit cytokine and chemokine expression and discuss currently available and potential future interventional approaches that allow for the mitigation of the severity of the cytokine storm syndrome. Effective cytokine-targeted interventional approaches may improve the safety of systemic adenovirus delivery and thus broaden the potential clinical utility of adenovirus-based therapeutic vectors.

Keywords: adenovirus; cytokine storm syndrome; cytokines; inflammation; innate immunity.

Figure 1

Cytokine responses to adenovirus in different biological contexts. The four areas are shaded in different colors, indicating adenovirus infection in various routes. The areas are positioned from left to right according to the virus dose received during infection. Vertically, the table is divided into four time periods from the earliest to the later times post infection. The deepest hues of the gradient colors show the peak times of cytokine response. The triangles indicate the species examined in the studies, and the color of the circles shows which adenovirus species were used. dLN—draining lymph node; BAL—bronchoalveolar lavage; n/a—data are not available; n/d—non detected; #—in this study, the virus was delivered intratracheally. The data for individual cytokines and chemokines, reported in references from [12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115], are shown with superscript numbers.

Figure 2

Molecular mechanisms triggering cytokine activation in response to adenovirus infection. Several main events trigger cytokine and chemokine activation during adenovirus infection. The hubs that play the major roles are shown in red. The orange molecules are associated with IRF3-dependent transcription. The teal color indicates the factors that signal through the NF-κB transcription hub. Integrin β3 activation of IL-1α and IL-1α-dependent augmentation of cytokine production are other main events leading to cytokine expression after adenovirus infection. The data for individual proteins, reported in references from [30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116], are shown with superscript numbers.

Figure 3

Factors enhancing cytokine and chemokine production in response to adenovirus infection. Different factors that bind to adenovirus particles can change the receptor selectivity and target the virus to macrophages and dendritic cells in the absence of the cognate virus receptors. The data for individual signaling molecules as reported in references from [33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118], are shown in parentheses adjacent to indicated proteins.