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

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.

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Variability among Macaca fascicularis in the innate immune response to Toll‐like receptor 4 (TLR4) agonists

The FASEB Journal ◽

10.1096/fasebj.22.1_supplement.899.5 ◽

2008 ◽

Vol 22 (S1) ◽

Author(s):

Charles Wayne Frevert ◽

Renee Hukkanen ◽

Steve Mongovin ◽

Kay Larsen ◽

Mike Agy ◽

...

Keyword(s):

Immune Response ◽

Innate Immune Response ◽

Macaca Fascicularis ◽

Innate Immune ◽

Toll Like Receptor ◽

Toll Like Receptor 4

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Toll-like receptor-4 expressed on gastric pit cells may initiate innate immune response of gastric mucosa against Helicobactor pylori infection

Gastroenterology ◽

10.1016/s0016-5085(08)80293-4 ◽

2001 ◽

Vol 120 (5) ◽

pp. A59

Author(s):

Kazuhito Rokutan ◽

Shigetada Teshima ◽

Tsukasa Kawahara ◽

Tomoko Kawai ◽

Takeshi Nikawa ◽

...

Keyword(s):

Immune Response ◽

Gastric Mucosa ◽

Innate Immune Response ◽

Innate Immune ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Helicobactor Pylori ◽

Pit Cells

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Energetics of Endotoxin Recognition in the Toll-Like Receptor 4 Innate Immune Response

Scientific Reports ◽

10.1038/srep17997 ◽

2015 ◽

Vol 5 (1) ◽

Cited By ~ 19

Author(s):

Teresa Paramo ◽

Susana M. Tomasio ◽

Kate L. Irvine ◽

Clare E. Bryant ◽

Peter J. Bond

Keyword(s):

Immune Response ◽

Innate Immune Response ◽

Innate Immune ◽

Toll Like Receptor ◽

Toll Like Receptor 4

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Therapeutic approach to regulate innate immune response by Toll-like receptor 4 antagonist E5564 in rats with D-galactosamine-induced acute severe liver injury

Journal of Gastroenterology and Hepatology ◽

10.1111/j.1440-1746.2008.05770.x ◽

2009 ◽

Vol 24 (6) ◽

pp. 1089-1094 ◽

Cited By ~ 20

Author(s):

Toshiyuki Kitazawa ◽

Tatsuhiro Tsujimoto ◽

Hideto Kawaratani ◽

Hiroshi Fukui

Keyword(s):

Immune Response ◽

Liver Injury ◽

Innate Immune Response ◽

Therapeutic Approach ◽

Innate Immune ◽

Toll Like Receptor ◽

Severe Liver ◽

Toll Like Receptor 4

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Identification of PGN_1123 as the Gene Encoding Lipid A Deacylase, an Enzyme Required for Toll-Like Receptor 4 Evasion, inPorphyromonas gingivalis

Journal of Bacteriology ◽

10.1128/jb.00683-18 ◽

2019 ◽

Vol 201 (11) ◽

Cited By ~ 3

Author(s):

Sumita Jain ◽

Ana M. Chang ◽

Manjot Singh ◽

Jeffrey S. McLean ◽

Stephen R. Coats ◽

...

Keyword(s):

Immune Response ◽

Porphyromonas Gingivalis ◽

Innate Immune Response ◽

Lipid A ◽

Innate Immune ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Gene Encoding ◽

Content Type ◽

Chronic Inflammatory Condition

ABSTRACTRemoval of one acyl chain from bacterial lipid A by deacylase activity is a mechanism used by many pathogenic bacteria to evade the host's Toll-like receptor 4 (TLR4)-mediated innate immune response. InPorphyromonas gingivalis, a periodontal pathogen, lipid A deacylase activity converts a majority of the initially synthesized penta-acylated lipid A, a TLR4 agonist, to tetra-acylated structures, which effectively evade TLR4 sensing by being either inert or antagonistic at TLR4. In this paper, we report successful identification of the gene that encodes theP. gingivalislipid A deacylase enzyme. This gene, PGN_1123 inP. gingivalis33277, is highly conserved withinP. gingivalis, and putative orthologs are phylogenetically restricted to theBacteroidetesphylum. Lipid A of ΔPGN_1123 mutants is penta-acylated and devoid of tetra-acylated structures, and the mutant strain provokes a strong TLR4-mediated proinflammatory response, in contrast to the negligible response elicited by wild-typeP. gingivalis. Heterologous expression of PGN_1123 inBacteroides thetaiotaomicronpromoted lipid A deacylation, confirming that PGN_1123 encodes the lipid A deacylase enzyme.IMPORTANCEPeriodontitis, commonly referred to as gum disease, is a chronic inflammatory condition that affects a large proportion of the population.Porphyromonas gingivalisis a bacterium closely associated with periodontitis, although how and if it is a cause for the disease are not known. It has a formidable capacity to dampen the host's innate immune response, enabling its persistence in diseased sites and triggering microbial dysbiosis in animal models of infection.P. gingivalisis particularly adept at evading the host's TLR4-mediated innate immune response by modifying the structure of lipid A, the TLR4 ligand. In this paper, we report identification of the gene encoding lipid A deacylase, a key enzyme that modifies lipid A to TLR4-evasive structures.

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