The Role of Human BetaDefensin2 in Emphasis Typ

Authors: Daniel Dalcin Marina Ulanova

Publish Date: 2013/10/19

Volume: 2, Issue: 2, Pages: 159-166

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Abstract

Cystic fibrosis CF is the most common genetic disease affecting the Caucasian population Chronic Pseudomonas aeruginosa pulmonary infection is the major cause of morbidity and mortality in CF patients Human betadefensin2 hBD2 is an inducible pulmonary antimicrobial peptide that exerts bacteriostatic activity in a concentrationdependent manner The decreased expression and compromised function of hBD2 contributes to the pathogenesis of P aeruginosa infection in the CF lung The purpose of this review is to outline the significance of hBD2 in P aeruginosa chronic pulmonary infection in CF patientsThe average human inhales ~10000 L of air every day Respiration is a portal of entry for not only atmospheric gases but also for harmful particulate pervasive in the environment The pulmonary epithelium is therefore continually exposed to microorganisms but remains sterile under normal physiologic conditions This remarkable phenomenon is a testament to the innate immune defenses that provide a silent mode of broad immune protection The importance of the innate immune system in protecting the lungs from infection is clearly illustrated in the pathologic condition that arises in cystic fibrosis CF mucoviscidosis which severely damages the pulmonary innate immune defenses 1Cystic fibrosis is the most common lethal genetic disorder affecting the Caucasian population with an incidence of 1 in 2500 births 2 CF is caused by an autosomal recessive mutation in the cystic fibrosis transmembrane conductance regulator CFTR gene within chromosome seven 3 This mutation results in the functional defect in the cyclic adenosine monophosphate stimulated pulmonary chloride pump causing abnormal ion transport in epithelial cells 4 5 CF is therefore a disease of ion transport across the epithelium affecting fluid secretion in exocrine glands and the epithelium of the respiratory reproductive and gastrointestinal tracts 6 Although CF causes a multitude of pathophysiologic effects the most significant effect is the impaired ciliary clearance that results in the accumulation of mucus in the lung creating a haven for bacteria Moreover the dehydrating conditions in the lung caused by the elevated levels of sodium chloride in the airway secretions severely weaken the host pulmonary innate defenses The initial acute pulmonary infection of the CF lung is typically a result of colonization by Haemophilus influenzae and Staphylococcus aureus while the ensuing chronic infection is caused by Pseudomonas aeruginosa 7 8 The chronic infection in the lungs of CF patients caused by P aeruginosa is responsible for the high rate of morbidity and mortality associated with this genetic disease 9Pseudomonas aeruginosa is a ubiquitous antibiotic resistant Gramnegative opportunistic bacterium 10 At 63 million base pairs the PAO1 strain of P aeruginosa has the largest genome sequenced 11 This large genome provides the genetic machinery that enables P aeruginosa to readily undergo significant genetic and phenotypic transformations in response to environmental changes contributing to its versatility and antibiotic resistance potential Although P aeruginosa is pervasive in the environment it only causes infection in immunodeficient hosts eg CF patients patients with acquired immunodeficiency syndrome burn victims etc Among the many clinical manifestations of P aeruginosa infection P aeruginosa’s opportunistic mode of infection is most known in the chronic pulmonary infection that is the hallmark of CF 12 Once acquired P aeruginosa almost always colonizes the lungs of CF patients for life 13The innate immune system provides the first line of defense against microorganisms pervasive in the environment Unlike the adaptive immune system innate immunity is nonspecific lacks memory and is not influenced by previous exposure Antimicrobial peptides AMPs are cationic endogenous antibiotic proteins expressed throughout the epithelium that are effectors of the innate immune system AMPs exert antimicrobial activity in a concentrationdependent manner making their expression a critical factor in host defense 14 The amphiphathic nature of AMPs contributes to their effectiveness at interacting with hydrophobic and anionic components of the bacterial membrane 15 Cathelicidins αdefensins βdefensins and θdefensins are among the major classes of human AMPs 16Betadefensins are at the interface between the adaptive and innate immune systems betadefensins exhibit chemotactic function towards immature dendritic cells memory T cells expressing the chemokine receptor CCR6 neutrophils primed with tumor necrosis factor TNFα and mast cells 17 18 Individual betadefensins have specific antimicrobial activity Among the various types of defensin AMPs only the expression of human betadefensin2 hBD2 and human betadefensin3 hBD3 is increased following stimulation by proinflammatory cytokines all other defensin AMPs are continuously expressed 19 However although the expression of hBD2 and hBD3 can be stimulated by proinflammatory cytokines eg TNFα interleukin IL1β IL17 and IL22 these antimicrobial peptides are still expressed in unstimulated cells in basal amounts 20 21 An additional difference between these two AMPs that are induced by humoral stimulation is that hBD2 primarily targets Gramnegative bacteria such as P aeruginosa while hBD3 exerts broad bacteriostatic activity against both Grampositive and Gramnegative bacteria 22 hBD2 like all defensins is found throughout the epithelium of mammals However hBD2 is most concentrated in the epithelia of the lung tonsils and trachea and therefore plays a critical role in the prevention of pulmonary infection 23 24 The inducible properties of hBD2 suggest it plays a significant role in innate immune defenseHuman betadefensin2 is a cationic 41 amino acid 4 kDa AMP intricately involved in the innate immune response of vertebrates that works synergistically with other antimicrobial molecules such as lactoferrin and lysozyme 24 25 Like other betadefensins hBD2 is a monomeric protein containing six conserved cysteine residues forming three core disulfide bonds 26 The initial contact between hBD2 and invading microorganisms is an electrostatic amphipathic attraction between the cationic AMP and the negatively charged phospholipid groups of the bacterium’s phospholipid bilayer 27 28 Following initial electrostatic attraction hBD2 exerts its antimicrobial effects through insertion within the phospholipid bilayer disrupting the membrane integrity of the invading bacteria resulting in the collapse of membrane potential and death of the invading pathogen 29 Nuclear magnetic resonance NMR analysis of the crystal structures of hBD2 suggests that the formation of a hBD2 octamer is a prerequisite to the binding of the bacteria cell surface and subsequent increases in membrane permeability 30A common theme in pathogen—host interactions is the selection against virulence factors required for the establishment of infection as the stage the infection shifts from acute to chronic Genetic variants are selected that promote longterm survivability and clonal expansion while variants that no longer provide a survival advantage are selected against In the CF lung P aeruginosa undergoes significant genetic and phenotypic transformations in response to changes in the pulmonary milieu P aeruginosa mutates to a mucoid flagelladeficient phenotype over the course of chronic pulmonary infection 31 32 The changes in the expression of P aeruginosa virulence factors affect the expression of hBD2 in the pulmonary epithelium that weakens the innate immune defense of the lung 33

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