RGD capsid modification enhances mucosal protective immunity of a non-human primate adenovirus vector expressing <i>Pseudomonas aeruginosa</i> OprF

Krause, Anja; Whu, W. Z.; Qiu, Jianping; Wafadari, D.; Hackett, Neil R.; Sharma, Anurag; Crystal, Ronald G.; Worgall, Stefan

doi:10.1111/cei.12101

Cited by 19 publications

(21 citation statements)

References 70 publications

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“…However, new strategies to enhance their potency and efficacy are currently being explored. Modification of the fiber through incorporation of an RGD motif in rAd vectors has been shown to elicit strong immune responses to encoded antigens, by expanding the tropism and targeting antigen-presenting cells such as DCs (28,33,46). In this study, we hypothesized that an RGD motif in the fiber of the Ad5.O1C.2B vector would improve the antigenicity and potency of the vaccine.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of a Fiber-Modified Adenovirus Vector Vaccine against Foot-and-Mouth Disease in Cattle

Medina

Montiel

Segundo

et al. 2016

Clin Vaccine Immunol

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Section: Discussionmentioning

confidence: 99%

Evaluation of a Fiber-Modified Adenovirus Vector Vaccine against Foot-and-Mouth Disease in Cattle

Medina

Montiel

Segundo

et al. 2016

Clin Vaccine Immunol

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“…Although several PA vaccines have been trialed including those using OprF, OprI, and flagellin (10)(11)(12)(13)(14)(15)(16)(20)(21)(22)(23)(24)(25), studies such as this one raise an additional possibility of exploiting the potency and flexibility of incorporating a large number of stimulatory T-and B-cell epitopes into epitope string vaccines. In other contexts, such as Plasmodium falciparum vaccination, these can be successfully administered in a "prime-boost" regime through incorporation into an adenoviral vector followed by DNA boost (62).…”

Section: Original Article Discussionmentioning

confidence: 99%

“…Various PA antigens have been considered in mouse, rat, and nonhuman primate, as well as trials in human CF or non-CF vaccinees (10)(11)(12)(13)(14)(15)(16). In a phase III vaccine trial of patients with noncolonized CF, a flagellin vaccine roughly halved the number of PA infections in the recipient cohort (10).…”

mentioning

confidence: 99%

Chronic Infection by Mucoid Pseudomonas aeruginosa Associated with Dysregulation in T-Cell Immunity to Outer Membrane Porin F

Quigley

Reynolds

Goudet

et al. 2015

Am J Respir Crit Care Med

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Rationale: Pseudomonas aeruginosa (PA) is an environmental pathogen that commonly infects individuals with cystic fibrosis (CF) and non-CF bronchiectasis, impacting morbidity and mortality. To understand the pathobiology of interactions between the bacterium and host adaptive immunity and to inform rational vaccine design, it is important to understand the adaptive immune correlates of disease.Objectives: To characterize T-cell immunity to the PA antigen outer membrane porin F (OprF) by analyzing immunodominant epitopes in relation to infection status.Methods: Patients with non-CF bronchiectasis were stratified by frequency of PA isolation. T-cell IFN-g immunity to OprF and its immunodominant epitopes was characterized. Patterns of human leukocyte antigen (HLA) restriction of immunodominant epitopes were defined using HLA class II transgenic mice. Immunity was characterized with respect to cytokine and chemokine secretion, antibody response, and T-cell activation transcripts. Measurements and Main Results:Patients were stratified according to whether PA was never, sometimes (,50%), or frequently (>50%) isolated from sputum. Patients with frequent PA sputumpositive isolates were more likely to be infected by mucoid PA, and they showed a narrow T-cell epitope response and a relative reduction in Th1 polarizing transcription factors but enhanced immunity with respect to antibody production, innate cytokines, and chemokines. Conclusions:We have defined the immunodominant, HLArestricted T-cell epitopes of OprF. Our observation that chronic infection is associated with a response of narrowed specificity, despite strong innate and antibody immunity, may help to explain susceptibility in these individuals and pave the way for better vaccine design to achieve protective immunity.

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“…Understanding the molecular mechanism of C3 binding to bacterial surfaces offers a potential means for preventing and/or treating diseases caused by these Gram-negative pathogens. Moreover, since C3b binding to proteins greatly facilitates antigen presentation by antigen-presenting cells (50), C3b binding to OprF may be one mechanism whereby OprF serves as a potent vaccine (36,51).…”

Section: Figmentioning

confidence: 99%

Identification of OprF as a Complement Component C3 Binding Acceptor Molecule on the Surface of Pseudomonas aeruginosa

et al. 2015

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Pseudomonas aeruginosa is a versatile opportunistic pathogen that can cause devastating persistent infections. Complement is a highly conserved pathway of the innate immune system, and its role in the first line of defense against pathogens is widely appreciated. One of the earliest events in the complement cascade is the conversion of C3 to C3a and C3b, the latter typically binds to one or more acceptor molecules on the pathogen surface. We previously demonstrated that complement C3b binding acceptors exist on the P. aeruginosa surface. In the current study, we utilized either C3 polyclonal or C3b monoclonal antibodies in a farWestern technique followed by mass spectroscopy to identify the C3b acceptor molecule(s) on the P. aeruginosa surface. Our data provide evidence that OprF (an outer membrane porin, highly conserved in the Pseudomonadaceae) binds C3b. An oprFdeficient P. aeruginosa strain exhibits reduced C3 deposition compared to the wild type. We observed reduced internalization of oprF-deficient bacteria by neutrophils after opsonization compared with wild-type P. aeruginosa. Heterologous expression of OprF significantly enhanced C3b binding and increased serum-mediated bactericidal effects in complement-susceptible Escherichia coli. Furthermore, the predicted secondary structure of the C-terminal, surface-exposed region of OprF has high structural identity to the OmpA domain of several other Gram-negative bacteria, one of which is known to bind C3b. Therefore, these findings provide new insights into the biology of complement interactions with P. aeruginosa and other Gram-negative bacteria. Pseudomonas aeruginosa is an opportunistic nosocomial human pathogen that causes a wide range of clinical symptoms and infections in immunocompromised patients. This bacterium is often the causative agent of acute and chronic infections of the airway, sepsis, burn wounds, and skin infections. Excessive infiltration of neutrophils at the site of infection and the presence of complement have been observed in inflamed tissue and blood (1, 2). Serum sensitivity is directly dependent upon recognition of the bacterial surface by antibodies and complement (3). Prior studies also suggested that complement binds to the P. aeruginosa surface and enhances phagocytosis by acting as an opsonin (4). In this study, we sought to understand the consequences of complement interaction with P. aeruginosa. C3 is the central component of the complement system, playing a crucial role in the three major complement component activation processes. C3b, a product of C3 activation, binds covalently to bacterial surfaces through either a reactive intramolecular ester or an amide bond (5). C3b also participates in the formation of C5 convertase that cleaves C5 and initiates the sequential deposition of the remaining complement components to form the C5b-9 membrane attack complex (MAC), which may result in direct killing of microorganisms (6).The human complement system plays an important role in the clearance of early pulmonary P. aeruginosa inf...

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RGD capsid modification enhances mucosal protective immunity of a non-human primate adenovirus vector expressing Pseudomonas aeruginosa OprF

Cited by 19 publications

References 70 publications

Evaluation of a Fiber-Modified Adenovirus Vector Vaccine against Foot-and-Mouth Disease in Cattle

Evaluation of a Fiber-Modified Adenovirus Vector Vaccine against Foot-and-Mouth Disease in Cattle

Chronic Infection by Mucoid Pseudomonas aeruginosa Associated with Dysregulation in T-Cell Immunity to Outer Membrane Porin F

Identification of OprF as a Complement Component C3 Binding Acceptor Molecule on the Surface of Pseudomonas aeruginosa

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