Immunity to Respiratory Viruses (Annual Review of Immunology Book 27)

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  1. Journal Rankings on Immunology
  2. Phagocytes: Macrophages and Neutrophils
  3. Natural Killer Cells
  4. Regulatory cytokine function in the respiratory tract

The strong interaction between sulfur and gold drives the sulfur atom to fill the free orbitals of a gold atom, creating a coordinate covalent bond [ , ]. Such approach has been extensively applied to associate nucleic acids [ - ] and antigens [ , ] with gold nanoparticles. Amine groups, on the other hand, are present on all protein and peptide antigens, which can be linked to nanocarriers via amide bond formation, typically through carbodiimide crosslinker chemistry. Bioconjugations with amine-containing antigens are commonly performed using 1-ethyl 3- dimethylamino propyl carbodi-imide EDC and N-hydroxysuccinimide NHS.

The NHS esters then covalently conjugate to primary amines to form an intermediate compound that is subsequently hydrolysed to the desired conjugate [ ]. Polydopamine functionalization is another conjugation approach that is increasingly applied to associate proteins and peptides with nanoparticles. In alkaline pH, dopamine undergoes oxidative self-polymerization to form a layer of polydopamine that can coat almost any type of material [ - ].

Journal Rankings on Immunology

This mussel-like adhesive layer enables a secondary reaction with biomolecules containing thiol or amine groups [ , ]. The technique has been demonstrated on both organic and inorganic nanoparticles [ , ]. Dopamine-incorporated polymers have also been employed to adsorb proteins for macrophage-targeted delivery [ ]. The versatile technique can be applied to conjugate multiple cargoes for vaccine applications [ ]. Electrostatic attraction between oppositely charged antigens and nanoparticles have been exploited to prepare nanoparticle vaccines.

In general, cationic nanocarriers are prepared for the association of anionic protein antigens. In the case of liposomes, cationic lipid DOTAP is frequently applied to render the nanocarrier positively charged. Strategies have also been employed to prepare antigens with added anionic moieties via recombinant protein engineering. The vaccine formulation elevated antigen-specific cellular responses and inhibited tumor growth in a mouse model [ , ].

In another work based on PRINT Particle Replication in Non-wetting Templates technology, electrostatic interaction was exploited to generate nanoparticle vaccines of cylindrical shape. Cationic particles were prepared by blending positively charged polymers with PLGA prior to the imprint lithography process.

Upon mixing with anionic hemagglutinin proteins of influenza viruses, a high level of antigen binding to the particle surface was achieved [ ]. Immunization with the nanoparticle vaccine elicited a more potent anti-influenza antibody response compared to a commercial vaccine based on inactivated subunit influenza viruses.

Unlike other spherical nanoparticle vaccines, the platform offers the ability to mimic the filamentous shape that can be found among many virus species. Synthetic nanoparticles have high surface energies owing to their large radii of curvature. As a result, adsorption of protein can occur spontaneously owing to a combination of weak interaction forces, leading to the formation of protein corona formation [ ].

This phenomenon was demonstrated to facilitate the assembly of synthetic virus-like nanoparticles [ ]. Upon mixing gold nanoparticles with viral antigens, rapid protein adsorption took place on the nanoparticle surface. This adsorption led to colloidal stabilization of gold nanoparticles, preventing their aggregation in biological buffers. Biochemical analysis showed the facile assembly method surrounded each nanoparticle with approximately coronavirus spike proteins, inducing enhanced anti-viral immune responses.

The adsorption approach has been used extensively to associated antigens with nanocarriers, including nanoparticles made of gold [ ], calcium phosphate [ , ], aluminium hydroxide [ ], carbon [ , ], silica [ , ], and organic polymers [ , ]. The range of adsorbed biomolecules vary from DNA [ , , ], adjuvant [ ], small peptides, and protein antigens [ , , , ]. It is important to note that formation of protein corona is a dynamic process that can be strongly influenced by both nanomaterials and antigen of interest [ ].

Studies have also shown that antigens can undergo conformational changes upon nanoparticle adsorption [ ], which could have both positive and negative effects on the resulting vaccine formulations. Coating nanoparticles with cellular membranes is an emerging functionalization approach that can pave ways to novel vaccine formulations with virus-mimetic features. It has been shown that following dispersion of cell membrane vesicles with nanoparticles, highly controlled membrane coating can be achieved, yielding unilamellar membrane cloaked nanoparticles retaining membrane proteins in their right-side-out orientation [ - ].

These nanoparticles are structurally analogous to enveloped viruses consisting of cell-derived lipid membranes stabilized via viral capsids or matrix proteins [ ]. The membrane coating approach has been adapted for vaccine preparations against cancer and bacteria [ , - ].

Phagocytes: Macrophages and Neutrophils

Enhanced dendritic cell activation and presentation of a melanoma-associated tumor antigen gp was demonstrated by Fang et al. The enhanced immune response to the membrane antigen was attributed to increased cellular delivery and colocalization with immunological adjuvant facilitated by the nanoparticles. Gao et al. The OMV-coated nanoparticles significantly increased antigen delivery to lymph nodes and elevated production of cytokines associated with bacterial containment [ ]. The membrane cloaking approach offers a titillating strategy towards future vaccine designs as the method enables coupling of membrane-anchored antigens in their native conformation with immunogenic nanocarriers.

Advances in nanotechnology and its adoption in vaccinology have helped push the boundaries of non-live, subunit vaccines, resulting in many exciting demonstrations of effective immune potentiation by nanoformulations. Not only can nanoparticle vaccines enhance humoral responses against target antigens, they have been shown to promote cell-based immunity as well as immunological memory. These are hallmarks of good vaccine formulations that are often inherent to live attenuated viruses.

An increasing number of studies have shed light on the mechanisms behind the benefits of nanoparticle vaccines, including lymph node targeting, multivalent antigen display, and coordinated delivery of antigens and adjuvants. These features can find their mechanistic analogues in the immunological processing of viruses. Given the frequent semblance between nanoparticle vaccines and viruses regarding their size, morphology, antigen display, and adjuvanticity effect, nanoparticles present a compelling platform in bridging the gap between live and non-live vaccines.

Emerging techniques in nanoparticle functionalization also pave ways to novel formulation designs that promise controlled immune modulation. Going forward, understanding of virology may assist scientists and engineering in preparing emerging nanoformulations with advanced virus-like features. Such vaccine nanotechnology is envisioned to improve vaccine safety, potency, and availability, offering compelling platforms towards addressing the many public health threats yet to have effective prophylaxis and treatment options.

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Natural Killer Cells

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Immunity against viruses

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Regulatory cytokine function in the respiratory tract

Mol Ther. What controls the melting properties of DNA-linked gold nanoparticle assemblies? J Am Chem Soc. A DNA-based method for rationally assembling nanoparticles into macroscopic materials. Oligonucleotide-modified gold nanoparticles for intracellular gene regulation. Mol Pharmaceut. M2e-immobilized gold nanoparticles as influenza A vaccine: Role of soluble M2e and longevity of protection. Gold nanoparticle-M2e conjugate coformulated with CpG induces protective immunity against influenza A virus. Bioconjugate Chemistry. Lysine-tagged peptide coupling onto polylactide nanoparticles coated with activated ester-based amphiphilic copolymer: a route to highly peptide-functionalized biodegradable carriers.

Colloids and surfaces B, Biointerfaces. Toll-like receptor-2 agonist functionalized biopolymer for mucosal vaccination. In the absence of any viral infection, transfer of specific CD8 T-cells was sufficient to trigger an inflammatory cascade producing the appearance of an interstitial pneumonia From these studies it is apparent that there is incredibly robust and long-lasting CD8 immunity following viral infection, with cytotoxic precursor cells detectable at more than fold increased levels for life The ability of CD8 cells to clear a pulmonary viral infection is not simply related either to the number of cells or to their cytolytic capacity as Tc1 cells are able to isolate and clear influenza infections far more rapidly than equally cytolytic Tc2 cells This is likely to reflect the fact that these subpopulations are able to migrate to the lung with different efficiencies and also have different capacities to attract other antiviral populations.

When considering the differing contributions of these T lymphocyte subpopulations to protection and inflammation in the context of BAL measurements, it is worth noting that comparative analysis of T lymphocytes from parenchyma, airways or mediastinal lymph nodes shows distinct populations In view of the many experimental systems in which there is a distinct impact from T lymphocytes making particular Th1 or Th2 cytokines, there have been many attempts to investigate the effect of specific cytokines on clearance of infection.

In mice expressing transgenic IL-4 in the lung, there is delayed clearance of virus, although this in turn leads to an enhanced neutralising antibody response This re-inforces the general principle that there are many parallel mechanisms for clearing infection from the lung, although these may be associated with different inflammatory consequences. A case in point is experimental infection with RSV, in which immunisation-induced Th2 eosinophilia can be reversed by treatment with the Th1-skewing cytokine, IL However, despite reversing the eosinophilia, the clinical outcome is relatively unchanged The critical importance of understanding these sometimes subtle differences in protective cytokine responses is demonstrated by experiences with RSV vaccine design.

RSV vaccine trials in the s led to enhanced morbidity and mortality on exposure to live virus in those vaccinated compared with controls. This was associated with peribronchiolar infiltration and excess eosinophils in the lungs and blood 34 — Mortality is thus likely to have been associated with priming for a pathogenic, excessive Th2 response. It has recently been possible to dissect out the viral proteins responsible for damaging eosinophilia and create vaccines for use in mouse models which are capable of inducing protection without the associated pathological consequences The latter knockouts are extremely susceptible to mycobacterial and nocardia infections.

Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide. Sign In or Create an Account. Sign In. Advanced Search. Article Navigation. Close mobile search navigation Article Navigation. Volume Article Contents. Innate immunity.

Specific immunity. Key points for clinical practice. Pulmonary defences to acute respiratory infection Rosemary J Boyton. Oxford Academic. Google Scholar. Peter J Openshaw.

Cite Citation. Permissions Icon Permissions. Abstract Of all sites in the body, the lung is perhaps challenged by the greatest onslaught of microbial pathogens, many of which would cause lethal infections if unopposed. View large Download slide. The innate response of the respiratory epithelium. Immunol Rev. Pier GB.

Role of the cystic fibrosis transmembrane conductance regulator in innate immunity to Pseudomonas aeruginosa infections. CpG motifs in bacterial DNA cause inflammation in the lower respiratory tract. J Clin Invest. Bacterial killing is enhanced by expression of lysozyme in the lungs of transgenic mice.


J Immunol. A possible role for lysozyme in determining acute exacerbations of chronic bronchitis. Clin Exp Immunol. Klebanoff S, Waltersdorph N. Pro-oxidant activity of transferrin and lactoferrin. J Exp Med. Innate immunity and pulmonary host defence. Lower respiratory tract lactoferrin and lysozyme arise in the airways and are elevated in association with chronic bronchitis. J Lab Clin Med. Cystic fibrosis airway epithelia fail to kill bacteria because of abnormal airway surface fluid. Localization of lung surfactant protein D on mucosal surfaces in human tissues.

Collectins and pulmonary innate immunity. Surfactant protein A deficient mice are susceptible to group B streptococcal infection. Surfactant protein-A-deficient mice are susceptible to Pseudomonas aeruginosa infection. Salvi S, Holgate ST. Could the airway epithelium play an important role in mucosal immunoglobulin A production?

Clin Exp Allergy. J Virol. Type I IFN modulates innate and specific antiviral immunity. Haemophilus influenzae stimulates ICAM-1 expression on respiratory epithelial cells. Hussell T, Openshaw PJ. J Gen Virol. Role of interleukin in primary influenza virus infection. Antibodies to the IL receptor beta 2 chain mark human Th1 but not Th2 cells in vitro and in vivo.

Curr Opin Immunol. Migration kinetics and final destination of type I and type 2 CD8 effector cells predict protection against pulmonary virus infection. Baumgarth N, Kelso A. Functionally distinct T cells in three compartments of the respiratory tract after influenza virus infection.

Eur J Immunol. Local IL-4 expression in the lung reduces pulmonary influenza-virus-specific secondary cytotoxic responses. IL treatment attenuates T helper cell type 2 and B cell responses but does not improve vaccine-enhanced lung illness. Expression of the nitric oxide synthase 2 gene is not essential for early control of mycobacterium tuberculosis in the murine lung.

Infect Immun. Protective role of gamma interferon during recall response to influenza virus. Endogenous interleukin is involved in resistance of mice to Mycobacterium avium complex infection. An epidemiologic study of altered reactivity to respiratory syncytial RS virus infection in children previously vaccinated with inactivated RS virus vaccine. Am J Epidemiol. Field evaluation of a respiratory syncytial virus vaccine and trivalent parainfluenza virus vaccine in a pediatric population.

Respiratory syncytial virus disease in infants despite prior administration of antigenic inactivated vaccine. Respiratory virus immunization. A field trial of two inactivated respiratory virus vaccine: an aqueous trivalent parainfluenza virus vaccine and an alum-precipitated respiratory syncytial virus vaccine. Eliminating a region of respiratory syncytial virus attachment protein allows induction of protective immunity with vaccine enhanced lung eosinophilia. Gamma delta T cells are critical for survival and early pro-inflammatory cytokine gene expression during murine Klebsiella pneumonia.

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