key: cord-1025205-ttk5tdmr
authors: Chéneau, Coraline; Kremer, Eric J.
title: Adenovirus—Extracellular Protein Interactions and Their Impact on Innate Immune Responses by Human Mononuclear Phagocytes
date: 2020-11-26
journal: Viruses
DOI: 10.3390/v12121351
sha: 5553e374bdec24793cffda30e0f4f93c12289fa8
doc_id: 1025205
cord_uid: ttk5tdmr

The aim of this review is to highlight how, in a syngeneic system, human mononuclear phagocytes respond to environments containing human adenovirus (HAdV) and soluble extracellular proteins that influence their innate immune response. Soluble extracellular proteins, including immunoglobulins, blood clotting factors, proteins of the complement system, and/or antimicrobial peptides (AMPs) can exert direct effects by binding to a virus capsid that modifies interactions with pattern recognition receptors and downstream signaling. In addition, the presence, generation, or secretion of extracellular proteins can indirectly influence the response to HAdVs via the activation and recruitment of cells at the site of infection.

the efficient cytosolic neutralization of mAb-bound HAdV-C5 in vitro [31] and in vivo (in mice) [32] . Again, in a cellular model, Ewan et al. showed that the more TRIM21 is expressed, the more the virus is neutralized [33] . Eichholz et al. then extended these observations to show that HAdV-ICs induce absent in melanoma 2 (AIM2) engagement and pyroptotic DC death. Pyroptosis, an inflammatory cell death that occurs in some mononuclear phagocytes following activation of inflammasome formation, leads to the release of pro-inflammatory cytokines such as TNF, IL-6 and IL-1β [24] . Under natural HAdV infection conditions, this may be a pro-host response. However, in the context of using a HAdV-C5 vector as a vaccine against HIV infections [34, 35] , pyroptosis may have set up a dynamic situation where HAdV-specific T cells were induced to proliferate, home to mucosal sites, and become prime targets for HIV infection [36, 37] .

Although the analyses are low in power and irreproducible due to sample availability, antibody-dependent enhanced infection of mononuclear phagocytes might have been involved in the death of a patient going under HAdV-C5-mediated gene therapy for ornithine transcarbamylase deficiency in the 1990's [38] . These data challenge the safety of HAdV-based therapy in patients with preexisting anti-HAdV immunity [12] . The impact of anti-HAdV Abs also took another twist when Tran et al. [27] showed that the environment created by DCs undergoing HAdV-IC-induced pyroptosis induces bystander DCs to become tolerogenic. These antigen-loaded tolerogenic DCs can drive naïve T cells to mature into HAdV-specific T REGs [27] . What role HAdV-specific T REGs play in HAdV infection and disease is an open question because their effect can be extremely plastic. We have hypothesized that they contribute to persistent HAdV infections and the reduction of possible immune-mediated tissue damage. Another possibility is that harboring a robust anti-HAdV response may generate cross-reactive B-cell responses to more virulent pathogens [39] .

The complement system is a network of more than 50 soluble and cell-bound molecules, produced by essentially all cells in mammals, that contribute to innate and adaptive immunity [40] . This self-amplifying cascade of messenger and effector molecules detects breaches in tissue homeostasis and pathogens. There are three canonical complement pathways: classical (predominantly Ig-mediated); alternative (interaction of complement proteins with microbial components); and mannose-binding lectin [41] . A noncanonical pathway consists of an Ig-dependent, component 3 (C3)-independent mechanism [42] . Typical complement-induced responses are self-limiting, but uncontrolled amplification contributes to disseminated intravascular coagulation, sepsis, and adult respiratory distress syndrome [43] .

The classical and alternative pathways are the most relevant in the context of HAdVs. In the case of the classical pathway, the attachment of Ig to a HAdV capsid induces binding of C1q to initiate the cascade (numerous reviews can be found describing the C1q-C9 cascade and therefore it will not be repeated here [44] ). In pioneering studies, Cichon et al. showed that HAdV-C5-ICs can activate complement [45] . Interestingly, they also were the first to show that high concentrations of HAdV-C5 directly activate a complement pathway, but did not characterize the process. Later, it was shown that HAdV-C5 can induce the alternative complement pathway by binding C3 directly [46] . Lastly, a C1q-dependent mechanism can neutralize HAdV-C5 by covalently linking C4b, which then targets the complex for gC1qBP-mediated uptake where HAdV-C5 is degraded in lysosomes [47] . It is also worth noting that there are exceptions: although human sera can contain Abs that bind canine adenovirus type 2 (CAV-2), the classical and alternative complement pathways are not engaged due to a block upstream of the C3 convertase and interplay between the C1q-C1r2-C1s2 complex and C1q inhibitor and CAV-2 [48] .

As the focus of this review is to link HAdVs, extracellular proteins, and human phagocytes, we have focused on the cellular events downstream of complement activation. All HAdV-associated complement pathways result in the generation of the anaphylatoxins C3a and C5a. Via their cognate receptors C3aR, and C5aR1, and C5aR2, C3a, and C5a exert regulatory effects on the humoral and cellular arms of innate immunity [49] . For example, C3b induces IL-1 and TNF release [50] and activation of phagocytes [51] . Yet, unexpectedly, using an in vitro model system, Zaiss et al. concluded that complement did not affect HAdV-C5 entry or activation of human macrophages [25] . While possible in mice, it is unknown if HAdV-C5 uptake by human neutrophil is affected by the presence of complement or Abs. Notably, HAdV-C5 and neutrophil interactions were significantly reduced when they were incubated in IgG-depleted or serum containing complement [52] .

C5a is a potent inflammatory peptide with a broad spectrum of functions including acting as a chemoattractant for neutrophils, monocytes, and macrophages [53] . In humans, C5aR1 is on the surface of most DC subsets, including monocyte-derived DCs, dermal DCs, and Langerhans cells [54] . The direct effects of C5aR1 engagement leads to the activation of pattern-recognition receptors and FcγRs. Examples of this cross-talk include C3a/C3aR-mediated activation of the inflammasome in human macrophages, monocytes and DCs [55, 56] , and C5a-mediated suppression of Toll-like receptor (TLR)-induced IL-12 production from macrophages [57] , as well as C5a-mediated activation of phagocytes through IC engagement of the inhibitory IgG-binding FcγRIIb with Dectin-1 [58] . C3a and C5a are also involved in the development of Th2 and Th17 immunity through the tweaking of DC activation [59] , and the induction of regulatory T cells (T REGs ) [60] . Whether complement-linked induction of T REGs synergizes with the HAdV-IC induced tolerogenic DC and T REGs [27] is unknown and worthy of more investigation.

On the flip side, thrombocytopenia and anemia can be associated with some severe cases of adenoviremia. Why is this relevant to complement activation? In a GPIb-and C3-dependent manner, platelets can deliver pathogens to tissue resident DCs and increase the pathogen directed immune response [61] . As mentioned above, the direct binding of C3 to some HAdV capsids could influence the anti-HAdV response when they are found in the systemic circulation (whether due to wild-type infections or delivery for gene therapy). In addition to platelets, some adenovirus types that bind CAR induce hemagglutination of human erythrocytes [62] . Therefore, immune adherence may also contribute to the complement-associated response to HAdVs [63] as C3-HAdV complexes could be delivered to the complement receptor 1 (CR1) clustered on the surface of human erythrocytes [64] . It is worth noting that C5a can also activate the coagulation pathway [65] , which brings immunoglobulins, complement, and coagulation factors into the global discussion of an anti-HAdV immune response.

AMPs are effector molecules of the innate immune system and can act as an endogenous antimicrobial against a broad array of infectious agents [66] [67] [68] [69] . More than 1300 AMPs have been identified and many are produced by epithelial cells of skin, oral mucosa, and gastrointestinal tract, and by myeloid cells, including neutrophils, which are among the first leukocytes to infiltrate infected and vector-injected tissues [36] . The ubiquitous expression and rapid production of AMPs allow them to act as first line responders to pathogens [69, 70] . In addition to responses to pathogens, AMPs can recruit and modulate the activities of neutrophils, monocytes, macrophages, DCs and T cells. AMPs can induce the expression of cytokines, neutralize endotoxin and induce angiogenesis [66] [67] [68] . Minor variations in the primary sequence of an AMP can induce major changes in their activity and, therefore, syngeneic systems are the gold standard to understand clinically relevant scenarios [68] . Notably, pockets of negatively charged areas in the hexon hypervariable regions of many HAdV types [71] [72] [73] [74] [75] favor binding of positively charged AMPs.

Among the AMPs is a subset dubbed "alarmins", which include defensins, lactoferrin (Lf), and LL-37. Defensins are~30 amino acid cationic peptides with a conserved framework of six disulfide-linked cysteines. Two α-defensins, human neutrophil peptides 1 and 2 (HNP-1 and -2) stimulate monocyte, DC and T cell recruitment [76] [77] [78] [79] . The four human β-defensins (hBD1-4) stimulate recruitment of monocytes, DCs, T cells and mast cells [80] [81] [82] . Both αand β-defensins also have selective actions: α-defensins induce the recruitment of human CD8 + and CD4 + /CD45RA + naïve T cells, whereas β-defensins induce recruitment of immature DCs and CD4 + /CD45RO + memory T cells [79] . Furthermore, during interaction with TLR-1 and -2 on monocytes and DCs, hBD3 can induce upregulation of costimulatory molecules CD80, CD86 and CD40 [83] .

Lf, an atypically large alarmin (80 kDa), is a multifunctional member of the transferrin family that sequesters iron and is found in various secretory fluids, such as milk, saliva, tears, and nasal secretions. Lactoferrin induces DC maturation via DC-SIGN or targeting TLR-2 and -4 and drives Th1 responses [84] [85] [86] [87] . Lf also induces DC maturation. Lactoferricin, a biologically active N-terminal fragment of 49 aa, also exhibits immunomodulatory effects, such as stimulation of monocyte differentiation and release of pro-inflammatory cytokines [88] .

LL-37 is a 37 amino acid cationic peptide found in lysosomes of macrophages, polymorphonuclear leukocytes, and keratinocytes. LL-37 serves a critical role against infections by its chemotactic activity [89] , influencing phagocytosis [90] , TLR activation [91] [92] [93] , DC differentiation, and induced T-cell polarization [94] .

Alarmins influence HAdV infections and immunogenicity via mechanisms that vary in each model system. HNP-1 and human defensin 5 (HD5) impair HAdV-C5, -D12 and -B35 infection of epithelial cells by stabilizing an intrinsically disordered region of the vertex and thus prevent initial stages of viral disassembly post-entry [95] [96] [97] [98] . By contrast, based on protein separation using bronchoalveolar lavage, Skrygan et al. concluded that defensins are not important anti-HAdV-C5 factors during infection of lung epithelium [99] . Recently, Tartaglia et al. showed that HD5 regulates immunogenicity by increasing HAdV-D26 and HAdV-D48 infections in mice (but not HAdV-C5 and HAdV-B35) [100] . It is relevant to note that HD1, 3, and 4 are elevated in nasal aspirates from children with HAdV infections [101] . While the authors assumed that increased levels of defensins should be pro-host, this assumption is challenging to demonstrate in a clinical setting. While not directly related to human phagocytes, tumor-derived HD5 affected oncolytic HAdV-B3 replication during cancer therapy [102] . Interestingly, HD5 inhibition was circumvented by the capacity of HAdV-B3 to produce virus-like particles made up of penton-dodecahedra that sequester and neutralize HD5.

Arnberg and colleagues demonstrated that lactoferrin binds to the negatively-charged hexon hypervariable regions of HAdV-C5, -A31 and -B35 [75] , thereby acting as a bridge to increase infection in human epithelial-like cells [103] . Notably, enhanced infection is independent of CAR [104] , the primary cellular attachment molecule for HAdV-C5 and -A31 [105] . Lf also mediates increased HAdV-C5 transduction in human monocytes, pDCs, cDCs, and Langerhans cells possibly via the engagement of DC-SIGN [86] and other factors. Interestingly, human Lf has no effect on HAdV-C2 infection of the above phagocytes while bovine Lf increased HAdV transduction [106] .

Finally, Uchio et al. found LL-37 also inhibits propagation of HAdV-B3, -D8, -D19a, and -D37, but not -E4 (which is likely of simian origin and now endemic in some military training camps) infection of A549 cells [107] . By contrast, Gordon et al. found that LL-37 inhibits the propagation of HAdV-D19 (but no significant inhibition on HAdV-B3, -C5, or -D8) [108] . These differences may be due to the experimental design with respect to the sequential versus simultaneous addition of virus and LL-37, and the dose of LL-37.

The coagulation system is a multiprotein cascade that is involved in blood clot formation [109] . Secreted in the systemic circulation as inactive zymogens, the vitamin K-dependent coagulation factors VII, IX and X all share a common structural N terminal γ-carboxyl glutamic acid domain and a C terminal serine protease domain. It is the N terminus that binds with nanomolar affinity to some of the hexon hypervariable regions [110] . Based on HAdV pathogenicity, it is difficult to explain what selective advantage binding to vitamin K-dependent coagulation factors adds. Numerous studies and reviews address the impact of vitamin K-dependent coagulation factors on HAdV-mediated gene transfer in mice [111] [112] [113] [114] , with the global conclusion that vitamin K-dependent coagulation factors act as bridges between the negatively-charged capsid and negatively-charged heparan sulfate proteoglycans. The use of coagulation factors by HAdV may be important for liver tropism following intravenous injection of HAdV-C5 vectors, and during naturally occurring infections. Indeed HAdV-C5 and -A31 require FIX or FX to infect human corneal epithelial (HCE) cells and human lung carcinoma (A549) cells [115] . It is noteworthy that Eichholz et al. found that human FX coupled to HAdV-C5 did not induce greater uptake by, or maturation of, human DCs [116] . Therefore, the mechanism by which some coagulations factors modify the tropism and response to some HAdVs and their vectors needs greater species-specific analyses. That being said, Alba et al. quantified HAdV-C5 and FX-binding-ablated HAdV-C5-mediated gene transfer in a non-human primate and found that HAdV-C5 vectors efficiently mediated gene transfer to the liver, whereas FX-binding-ablated vectors primarily targeted the spleen. Therefore, some data generated using mice may be consistent with the mechanism underlying hepatocyte transduction in humans [117] .

Whenever possible, we focused on how HAdVs and extracellular proteins impact the innate immune response in human phagocytes. A caveat though is that the use of replication-defective HAdV vectors precludes the analyses of the impact of extracellular proteins on events downstream of entry into the nucleus. When necessary we have introduced data generated in other systems (e.g., rodents) to provide background. For example, HAdVs alone readily induce the maturation of murine DCs, but poorly induce human DC maturation [13, 118] . We know that coagulation factor-specific interactions influence HAdV innate immune responses differentially in mouse and in human phagocytes. Murine FX-armored HAdVs stimulated murine macrophages in vitro and in vivo, whereas human FX-HAdV complexes had no effect on human DCs in vitro [116, 119] . While bovine Lf increases HAdV-C2 infection of human DCs, human Lf has no effect [106] . Nonetheless, data from rodents can generate avenues to explore in humans. For example, Gounder et al. found that murine α-defensins protect mice from oral infection by mouse adenovirus 1 (MAdV-1). Yet, in spite of the sensitivity of MAdV-1 infection to α-defensin neutralization in cell culture, α-defensin production by Paneth cell had no effect on the kinetics and magnitude of MAdV-1 dissemination to the brain. This may have been due to a delay in the production of neutralizing Abs. Thus, in mice, α-defensins play a role in antiviral immunity that is distinct from their antiviral activity observed in cell culture [120] .

The law of parsimony suggests synergistic interactions between Abs, coagulation factors, complement and AMPs in most pathological or vaccine-associated paradigms. Yet, some AMPs can inhibit the complement pathway. Lf, by blocking the formation of C3 convertase [121] , and HNP-1, by blocking the C1q hemolytic activity [122] , can inhibit the classical complement pathway. Xu et al. demonstrated that FX shields HAdV-C5 and blocks HAdV-dependent complement activation [123] . In each scenario, two parameters are crucial: site and timeline of infection. If HAdVs enter via intranasal, oral, gastrointestinal, ocular, intravenous, intradermal, or muscular tissues, the first cells to be infected, and then those recruited, will differ. For example, some phagocytes (e.g., alveolar macrophages) are recruited to specific organs and not all extracellular proteins will be all present or secreted at the same level.

The timeline of infection and extracellular protein secretion are also crucial parameters. Depending on the extracellular protein first secreted, it could change HAdV interactions with its target cell. For example, if an AMP binds first, does that interaction prevent Ab binding? Do Abs outcompete AMPs because of affinity or avidity? Are there situations where they act synergistically? Unsurprisingly, assays addressing these complex interactions are challenging because of the direct effect of some extracellular proteins on phagocyte homeostasis and recruitment. Yet, these issues are critically important to understand in the scenario where AdV-based vaccines are used [12] . It is possible that some extracellular proteins could be used as adjuvants to increase vaccine efficacy. If an AMP is used as an adjuvant, could the complex increase HAdV uptake by phagocytes? or uptake by other tissue resident cells? There exist multiple modifications of HAdV capsid sequences (or coating the capsid with protective polymers) that reduce binding of extracellular proteins [124] [125] [126] [127] . Testing these HAdV vectors as vaccines could provide valuable information on the complex interactions that alarmins could play. We know very little about what happens in the 48 h post-vaccine injection (predominantly in muscle for vaccines): what cells are recruited and in what ratio? What do they secrete in a host with or without preexisting humoral and cellular immunity? How does this combination of cells and extracellular proteins modify the innate and adaptive immune response? Clearly multiple extracellular proteins are found in the same microenvironment and therefore addressing their impact on HAdV uptake in binary analyses poorly considers HAdV or phagocyte interactions. Add on top tissue undergoing an inflammatory reaction where the extracellular matrix, which is composed of proteins, proteoglycans, and glycoproteins each with varying physical and biochemical properties, is degraded and releases peptides. Matrix metalloproteinases, ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs), and serine proteinases (plasmin and cathepsin G) are the most common extracellular matrix degrading enzymes [128] . Very little is known about how extracellular matrix degradation modifies HAdV tropism and immunogenicity. Data that may shed light onto this process might be gleaned from oncolytic vectors that express enzymes that degrade the extracellular matrix [129] .

Author Contributions: C.C. and E.J.K. wrote the manuscript and have read and agreed to the published version of the manuscript. Both authors have read and agreed to the published version of the manuscript.

Funding: This work benefited from support by the LabEx "EpiGenMed", an "Investissements d'avenir" program, Université de Montpellier, the Innovative Medicine Initiative EboVac2 (#115861), The Fondation Pierre Fabre, the Agence Nationale de la Recherche (NORAD-19-CE37-0008-04, Goal-14-CE13-0014-03), ERA-Net (E-Rare) Joint Transnational Call (ANR-17-RAR3-0001-01), and l'Institut de Génétique Moléculaire de Montpellier. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

The authors declare no conflict of interest.

Encyclopedia of Virology

Human and Animal Viruses

Adenoviruses across the animal kingdom: A walk in the zoo

Adenovirus-mediated gene delivery: Potential applications for gene and cell-based therapies in the new era of personalized medicine

Adenovirus Infections in Immunocompetent and Immunocompromised Patients

Intestinal Adenovirus Shedding Before Allogeneic Stem Cell Transplantation Is a Risk Factor for Invasive Infection Post-transplant

Live Oral Adenovirus Type 4 and Type 7 Vaccine Induces Durable Antibody Response

Safety and High Level Efficacy of the Combination Malaria Vaccine Regimen of RTS,S/AS01B With Chimpanzee Adenovirus 63 and Modified Vaccinia Ankara Vectored Vaccines Expressing ME-TRAP

Biodistribution and Toxicological Safety of Adenovirus Type 5 and Type 35 Vectored Vaccines Against Human Immunodeficiency Virus-1 (HIV-1), Ebola, or Marburg Are Similar Despite Differing Adenovirus Serotype Vector, Manufacturer's Construct, or Gene Inserts

Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: A preliminary report of a phase 1/2, single-blind, randomised controlled trial

Single-shot Ad26 vaccine protects against SARS-CoV-2 in rhesus macaques

Ebola vaccine trials: Progress in vaccine safety and immunogenicity

Pros and Cons of Adenovirus-Based SARS-CoV-2 Vaccines

Activation of a dendritic cell-T cell axis by Ad5 immune complexes creates an improved environment for replication of HIV in T cells

Adenovirus membrane penetration activates the NLRP3 inflammasome

Development of Novel Adenoviral Vectors to Overcome Challenges Observed With HAdV-5-based Constructs

Therapeutic plasma proteins-Application of proteomics in process optimization, validation, and analysis of the final product

Plasma Protein Fractions in Healthy Blood Donors Quantitated by an Automated Multicapillary Electrophoresis System

Antimicrobial Peptides: An Introduction. In Antimicrobial Peptides

Immune Complex-Loaded Dendritic Cells Are Superior to Soluble Immune Complexes as Antitumor Vaccine

Cytokines in adenoviral disease in children: Association of interleukin-6, interleukin-8, and tumor necrosis factor alpha levels with clinical outcome

Participation of immune complexes in adenovirus infection

Zika virus infection enhances future risk of severe dengue disease

Protective and enhancing interactions among dengue viruses 1-4 and Zika virus

Immune-Complexed Adenovirus Induce AIM2-Mediated Pyroptosis in Human Dendritic Cells

Antiviral Antibodies Target Adenovirus to Phagolysosomes and Amplify the Innate Immune Response

Adenovirus-Antibody Complexes Contributed to Lethal Systemic Inflammation in a

Humoral immune response to adenovirus induce tolerogenic bystander dendritic cells that promote generation of regulatory T cells

High efficiency transduction of dendritic cells by adenoviral vectors targeted to DC-SIGN

Cross-Presentation in Mouse and Human Dendritic Cells

Antibodies mediate intracellular immunity through tripartite motif-containing 21 (TRIM21)

Coordinated Neutralization and Immune Activation by the Cytosolic Antibody Receptor TRIM21

TRIM21 mediates antibody inhibition of adenovirus-based gene delivery and vaccination

Regulation of Virus Neutralization and the Persistent Fraction by TRIM21

HIV-1 vaccine-induced immunity in the test-of-concept Step Study: A case-cohort analysis

Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): A double-blind, randomised, placebo-controlled, test-of-concept trial

Vaccine adjuvants alum and MF59 induce rapid recruitment of neutrophils and monocytes that participate in antigen transport to draining lymph nodes

Adenovirus vector vaccination induces expansion of memory CD4 T cells with a mucosal homing phenotype that are readily susceptible to HIV-1

Did Dendritic Cell Activation, Induced by Adenovirus-Antibody Complexes, Play a Role in the Death of Jesse Gelsinger?

Monocytes are more susceptible in vitro in rhesus macaques of Chinese origin to recombinant serotype 5 adenovirus with higher preexisting vector specific neutralizing antibody titer

Complement: A key system for immune surveillance and homeostasis

Natural antibodies and complement link innate and acquired immunity

Generation of C5a in the absence of C3: A new complement activation pathway

Complement: A unique innate immune sensor for danger signals

Role of C5A in Inflammatory Responses

Complement activation by recombinant adenoviruses

Recombinant Adenovirus Vectors Activate the Alternative Complement Pathway, Leading to the Binding of Human Complement Protein C3 Independent of Anti-Ad Antibodies

Complement C4 Prevents Viral Infection through Capsid Inactivation

Interactions Between Human Plasma Components and A Xenogenic Adenovirus Vector: Reduced Immunogenicity During Gene Transfer

Old dogs-new tricks: Immunoregulatory properties of C3 and C5 cleavage fragments

In vitro and in vivo dependency of chemokine generation on C5a and TNF-alpha

The role of complement in inflammation and phagocytosis

Neutrophils Interact with Adenovirus Vectors via Fc Receptors and Complement Receptor 1

IL-4 Down-Regulates Anaphylatoxin Receptors in Monocytes and Dendritic Cells and Impairs Anaphylatoxin-Induced Migration In Vivo

The new face of anaphylatoxins in immune regulation

C3a modulates IL-1β secretion in human monocytes by regulating ATP efflux and subsequent NLRP3 inflammasome activation

Complement-mediated "bystander" damage initiates host NLRP3 inflammasome activation

C5a Negatively Regulates Toll-like Receptor 4-Induced Immune Responses

Anti-inflammatory activity of IgG1 mediated by Fc galactosylation and association of FcγRIIB and dectin-1

A regulatory role for the C5a anaphylatoxin in type 2 immunity in asthma

Absence of signaling into CD4+ cells via C3aR and C5aR enables autoinductive TGF-β1 signaling and induction of Foxp3+ regulatory T cells

A platelet-mediated system for shuttling blood-borne bacteria to CD8α+ dendritic cells depends on glycoprotein GPIb and complement C3

The Cell Adhesion Molecule "CAR" and Sialic Acid on Human Erythrocytes Influence Adenovirus In Vivo Biodistribution

Immune Adherence Revisited: Novel Players in an Old Game

Direct evidence for the clustered nature of complement receptors type 1 on the erythrocyte membrane

Sepsis, apoptosis and complement

Antimicrobial peptides: General overview and clinical implications in human health and disease

AMPed up immunity: How antimicrobial peptides have multiple roles in immune defense

The expanding scope of antimicrobial peptide structures and their modes of action

The next generation of antimicrobial peptides (AMPs) as molecular therapeutic tools for the treatment of diseases with social and economic impacts

Cutaneous Injury Induces the Release of Cathelicidin Anti-Microbial Peptides Active Against Group A Streptococcus

Revised Crystal Structure of Human Adenovirus Reveals the Limits on Protein IX Quasi-Equivalence and on Analyzing Large Macromolecular Complexes

Structure of human adenovirus

Crystal Structure of Human Adenovirus at 3.5 A Resolution

Identification of coagulation factor (F)X binding sites on the adenovirus serotype 5 hexon: Effect of mutagenesis on FX interactions and gene transfer

Lactoferrin-Hexon Interactions Mediate CAR-Independent Adenovirus Infection of Human Respiratory Cells

Human defensins activate monocyte-derived dendritic cells, promote the production of proinflammatory cytokines, and up-regulate the surface expression of CD91

Monocyte-chemotactic activity of defensins from human neutrophils

Identification of Defensin-1, Defensin-2, and CAP37/Azurocidin as T-cell Chemoattractant Proteins Released from Interleukin-8-stimulated Neutrophils

Human neutrophil defensins selectively chemoattract naive T and immature dendritic cells

Defensins: Linking Innate and Adaptive Immunity Through Dendritic and T Cell CCR6

Epithelial cell-derived human β-defensin-2 acts as a chemotaxin for mast cells through a pertussis toxin-sensitive and phospholipase C-dependent pathway

Human β-defensin 4: A novel inducible peptide with a specific salt-sensitive spectrum of antimicrobial activity

Human -defensin-3 activates professional antigen-presenting cells via Toll-like receptors 1 and 2

Lactoferrin, a major defense protein of innate immunity, is a novel maturation factor for human dendritic cells

Lactoferrin Acts as an Alarmin to Promote the Recruitment and Activation of APCs and Antigen-Specific Immune Responses

Adenovirus serotype 5 infects human dendritic cells via a coxsackievirus-adenovirus receptor-independent receptor pathway mediated by lactoferrin and DC-SIGN

Recombinant human lactoferrin induces human and mouse dendritic cell maturation via Toll-like receptors 2 and 4

The Human Lactoferrin-Derived Peptide hLF1-11 Exerts Immunomodulatory Effects by Specific Inhibition of Myeloperoxidase Activity

Ll-37, the Neutrophil Granule-And Epithelial Cell-Derived Cathelicidin, Utilizes Formyl Peptide Receptor-Like 1 (Fprl1) as a Receptor to Chemoattract Human Peripheral Blood Neutrophils, Monocytes, and T Cells

The cationic peptide LL-37 binds Mac-1 (CD11b/CD18) with a low dissociation rate and promotes phagocytosis

The anti-microbial peptide LL-37 inhibits the activation of dendritic cells by TLR ligands

LL-37 promotes rapid sensing of CpG oligodeoxynucleotides by B lymphocytes and plasmacytoid dendritic cells

Cytosolic sensing of extracellular self-DNA transported into monocytes by the antimicrobial peptide LL37

The cationic antimicrobial peptide LL-37 modulates dendritic cell differentiation and dendritic cell-induced T cell polarization

Mechanism of adenovirus neutralization by Human alpha-defensins

An intrinsically disordered region of the adenovirus capsid is implicated in neutralization by human alpha defensin 5

Direct evidence from single-cell analysis that human α-defensins block adenovirus uncoating to neutralize infection

Insight into the mechanisms of adenovirus capsid disassembly from studies of defensin neutralization

Inhibition of adenovirus infection by the bronchoalveolar lavage supernatant in vitro

Alpha-defensin 5 differentially modulates adenovirus vaccine vectors from different serotypes in vivo

Human Neutrophil Defensin-1, -3, and -4 Are Elevated in Nasal Aspirates from Children with Naturally Occurring Adenovirus Infection

Studies on the Interaction of Tumor-Derived HD5 Alpha Defensins with Adenoviruses and Implications for Oncolytic Adenovirus Therapy

Adenoviruses use lactoferrin as a bridge for CAR-independent binding to and infection of epithelial cells

Membrane Dynamics and Signaling of the Coxsackievirus and Adenovirus Receptor

Adenovirus receptors: Implications for targeting of viral vectors

CD209/DC-SIGN mediates efficient infection of monocyte-derived dendritic cells by clinical adenovirus 2C isolates in the presence of bovine lactoferrin

Anti-adenoviral effects of human cationic antimicrobial protein-18/LL-37, an antimicrobial peptide, by quantitative polymerase chain reaction

Human cathelicidin (LL-37), a multifunctional peptide, is expressed by ocular surface epithelia and has potent antibacterial and antiviral activity

Overview of the coagulation system

Adenovirus serotype 5 hexon is critical for virus infection of hepatocytes in vivo

Multiple vitamin K-dependent coagulation zymogens promote adenovirus-mediated gene delivery to hepatocytes

The importance of coagulation factors binding to adenovirus: Historical perspectives and implications for gene delivery

Interaction of adenovirus with antibodies, complement, and coagulation factors

Coagulation Factors IX and X Enhance Binding and Infection of Adenovirus Types 5 and 31 in Human Epithelial Cells

Human Coagulation Factor X-Adenovirus Type 5 Complexes Poorly Stimulate an Innate Immune Response in Human Mononuclear Phagocytes

Coagulation factor X mediates adenovirus type 5 liver gene transfer in non-human primates (Microcebus murinus)

Murine dendritic cells infected with adenovirus vectors show signs of activation

Coagulation Factor X Activates Innate Immunity to Human Species C Adenovirus

Defensins Potentiate a Neutralizing Antibody Response to Enteric Viral Infection

Modulation of classical C3 convertase of complement by tear lactoferrin

Inhibition of Activation of the Classical Pathway of Complement by Human Neutrophil Defensins

Coagulation factor X shields adenovirus type 5 from attack by natural antibodies and complement

Substitution of blood coagulation factor X-binding to Ad5 by position-specific PEGylation: Preventing vector clearance and preserving infectivity

Achieving systemic delivery of oncolytic viruses

Capsid Engineering of Adenovirus Vectors: Overcoming Early Vector-Host Interactions for Therapy

Redirecting adenovirus tropism by genetic, chemical, and mechanical modification of the adenovirus surface for cancer gene therapy

Proteinases involved in matrix turnover during cartilage and bone breakdown

Macrophage metalloelastase (MME) as adjuvant for intra-tumoral injection of oncolytic adenovirus and its influence on metastases development