Abstract
Despite decades of clinical and preclinical investigations, we still poorly grasp our innate immune response to human adenoviruses (HAdVs) and their vectors. In this study, we explored the impact of lactoferrin on three HAdV types that are being used as vectors for vaccines. Lactoferrin is a secreted globular glycoprotein that influences direct and indirect innate immune response against a range of pathogens following a breach in tissue homeostasis. The mechanism by which lactoferrin complexes increases HAdV uptake and induce maturation of human phagocytes is unknown. We show that lactoferrin redirects HAdV types from species B, C, and D to Toll-like receptor 4 (TLR4) cell surface complexes. TLR4-mediated internalization of the HAdV-lactoferrin complex induced an NLRP3-associated response that consisted of cytokine release and transient disruption of plasma membrane integrity, without causing cell death. These data impact our understanding of HAdV immunogenicity and may provide ways to increase the efficacy of HAdV-based vectors/vaccines.
Highlights
The gaps in our understanding of our innate immune response to human adenovirus (HAdV)based vaccines are significant
We quantified the affinity of human lactoferrin to each capsid by surface plasmon resonance (SPR)
The HAdVs were immobilized on a CM5 sensor chip and escalating doses of lactoferrin were injected over the sensor surfaces
Summary
The gaps in our understanding of our innate immune response to human adenovirus (HAdV)based vaccines are significant. Following vaccine injection, how do the rapid recruitment of myeloid cells, release of danger-associated molecular patterns (DAMPs), and presence of host defense proteins/peptides (HDPs), influence the response to vector-encoded transgenes? We addressed the impact of an HDP on three HAdV-based vaccine vectors. Many HDPs are HAdV-Lactoferrin Induced Phagocyte Maturation produced by neutrophils and epithelial cells of the skin, oral mucosa, and gastrointestinal tract. The alarmins (e.g. lactoferrin, a-defensin, and cathelicidin LL-37) are a subset of HDPs that modulate innate and adaptive immune responses by directly engaging several pathways including pattern recognition receptor (PRR) signalling in antigen-presenting cells (APCs) [1, 2]. Lactoferrin can induce dendritic cell (DC) maturation and, in the context of infections, drive Th1 responses [5,6,7]
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