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Lactoferrin Retargets Human Adenoviruses to TLR4 to Induce an Abortive NLRP3-Associated Pyroptotic Response in Human

Coraline Chéneau1, Karsten Eichholz1, Tuan Hiep Tran1

  • 1Institut de Génétique Moléculaire de Montpellier, Université de Montpellier, CNRS, Montpellier, France.

Frontiers in Immunology
|June 7, 2021
PubMed

Insights

Lactoferrin enhances human adenovirus (HAdV) uptake by immune cells via Toll-like receptor 4 (TLR4). This interaction triggers an NLRP3-associated response, boosting innate immunity without causing cell death, potentially improving HAdV vector vaccines.

Area of Science:

  • Immunology
  • Virology
  • Molecular Biology

Background:

  • Innate immune responses to human adenoviruses (HAdVs) and their vectors are not fully understood.
  • HAdVs are frequently used as vaccine vectors, necessitating a deeper comprehension of their immunogenicity.

Purpose of the Study:

  • To investigate the effect of lactoferrin on HAdV uptake and innate immune response.
  • To elucidate the mechanism by which lactoferrin influences HAdV-mediated immune activation.

Main Methods:

  • Studied the interaction of lactoferrin with HAdV types B, C, and D.
  • Utilized Toll-like receptor 4 (TLR4) and NLRP3 inflammasome assays.
  • Assessed phagocyte maturation and cytokine release.

Main Results:

  • Lactoferrin complexes redirected HAdVs to TLR4 on the cell surface.
  • TLR4-mediated internalization of HAdV-lactoferrin complexes induced an NLRP3-associated response.
  • Observed cytokine release and transient plasma membrane disruption without cell death.

Conclusions:

  • Lactoferrin modulates HAdV uptake and innate immune activation through TLR4 and NLRP3.
  • This mechanism enhances HAdV immunogenicity without compromising cell viability.
  • Findings may inform strategies to improve the efficacy of HAdV-based vaccine vectors.
Keywords:
IL-1βLactoferrinTLR4 (Toll-like receptor 4)adenovirusdendritic cell (DC)

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