Streptococcus Pneumoniae

Molecular Mechanisms of Host-Pathogen Interactions

Jeremy Brown, Sven Hammerschmidt, Carlos Orihuela

• Publisher: Academic Press
• Year: 2015
• Print ISBN: 9780124105300
• eBook ISBN: 9780124114531
• Topic: Ciencias biológicas
• Subtopic: Microbiología

Streptococcus Pneumoniae: Molecular Mechanisms of Host-Pathogen Interactions provides a comprehensive overview of our existing knowledge on Streptococcus pneumoniae antibiotic resistance, dissemination, and pathogenesis, including immunology. It presents a state-of-the-art overview of the implications of existing data, along with the areas of research that are important for future insights into the molecular mechanisms of pneumococcal infections and how to combat these infections. Users will find a timely update on the topic, as the dramatic increase in antibiotic resistance pneumoniae cases and limitations of the currently available pneumoniae vaccines are creating new concerns on these gram-positive bacteria that are endowed with a high virulence potential, and are the most common etiologic agent of respiratory and life-threatening invasive diseases. - Provides an updated overview of our existing knowledge on Streptococcus pneumoniae antibiotic resistance, dissemination, and pathogenesis, including immunology - Helps strengthen interdisciplinary networking and the focus of scientific resources by targeting epidemiology, vaccines, genetics, antibiotic resistance, clonal dissemination, Streptococcus pneumoniae biology, functional genomics, inflammasome, biomarkers, and more - Multi-authored by leaders in the field who present a state-of-the-art overview of what the implications are of existing data, and the areas of research that are important for future insights into the molecular mechanisms of pneumococcal infections - Supports combinatory networking in order to find new solutions in clinical therapies - Reflects the most topical pneumococcal research trends

Section D

Pneumococcal Interactions with the Host

Outline

Chapter 15 Nasopharyngeal Colonization with Streptococcus pneumoniae

Chapter 16 Pneumococcal Biofilms and Bacterial Persistence During Otitis Media Infections

Chapter 17 Pneumococcal Pili and Adhesins

Chapter 18 Exploitation of Host Signal Transduction Pathways Induced by Streptococcus pneumoniae

Chapter 19 Mechanisms of Predisposition to Pneumonia

Chapter 20 Mechanisms Causing the Inflammatory Response to Streptococcus pneumoniae

Chapter 21 Streptococcus pneumoniae Interactions with Macrophages and Mechanisms of Immune Evasion

Chapter 22 Cell-Mediated Immunity to the Pneumococcus

Chapter 23 Pneumococcal Invasion

Chapter 15

Nasopharyngeal Colonization with Streptococcus pneumoniae

Kirsty R. Short^1,2 and Dimitri A. Diavatopoulos^3,4, ¹Department of Viroscience, Erasmus Medical Center, Rotterdam, The Netherlands, ²School of Biomedical Sciences, University of Queensland, Brisbane, Australia, ³Laboratory of Pediatric Infectious Diseases, Department of Pediatrics, Radboud University Medical Center, Nijmegen, The Netherlands, ⁴Laboratory of Medical Immunology, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands

The ability to colonize the human upper respiratory tract and transmit to a new host are perhaps the strongest selective pressures driving the evolution of Streptococcus pneumoniae. Indeed, many of the mechanisms that have been widely studied in the context of pneumococcal disease play an essential role in the establishment and maintenance of pneumococcal colonization. In this chapter we discuss the various challenges the pneumococcus faces in order to successfully colonize the nasopharynx, the dynamics of S. pneumoniae colonization, and the factors that, in some individuals, contribute to increased pneumococcal colonization and transmission.

Keywords

Streptococcus pneumoniae colonization; carriage; transmission; viral co-infection

Introduction

To survive in the human population, Streptococcus pneumoniae has evolved to colonize the mucosal surfaces of the upper respiratory tract. From there, the pneumococcus can then successfully spread to other susceptible hosts. The success of the pneumococcus in surviving and persisting in the human population is clearly demonstrated by the approximately 1.9–5.8 billion people estimated to be colonized with S. pneumoniae at any given time (inferred from [1,2]). Despite the fact that the pneumococcus is notorious for its ability to cause severe invasive disease, the majority of colonized individuals will not develop clinical symptoms. This strongly suggests that colonization actually represents the primary selective force for pneumococcal evolution and implies that many of the host–pathogen interactions observed during pneumococcal disease must be viewed within the context of asymptomatic colonization. In this chapter we will discuss the dynamics and mechanisms of pneumococcal colonization of the upper respiratory tract and subsequent transmission to a new host. Although we will also briefly touch upon how pneumococcal colonization perturbs mucosal homeostasis and how this affects immune signaling, disease development, and bacterial clearance, these aspects are primarily discussed in other chapters.

Natural Barriers to Pneumococcal Colonization

Pneumococcal transmission occurs via contact with the respiratory secretions of colonized individuals [3]. It is not clear whether pneumococcal transmission occurs directly via the inhalation of bacteria, or indirectly via contact with contaminated surfaces. Indeed, while S. pneumoniae does not remain viable for an extended period of time on contaminated hands, contact with objects carrying pneumococci in the form of desiccation-resistant biofilms may still play a role in pneumococcal transmission [4–6]. Following initial entry into the airways, S. pneumoniae must overcome several hurdles before it can establish stable mucosal colonization in the upper respiratory tract. These hurdles, and the mechanisms by which the pneumococcus overcomes them, are discussed in detail below.

Mucus Barrier

Within the upper respiratory tract, the nasopharynx is the primary niche of pneumococcal colonization [7,8]. The nasopharynx is lined with the same ciliated pseudostratified columnar epithelium present in the nasal cavity. These ciliated epithelial cells are covered by a 0.5–10 µm thick mucus layer. This mucus layer is produced by surface goblet cells which are dispersed throughout the epithelial layer, as well as by goblet cells present in clefts that extend down into the underlying basement membrane and lamina propria. This mucus layer represents a major barrier to successful pneumococcal colonization. Specifically, the mucus layer consists of an upper viscous gel that contains antimicrobial compounds, traps larger particles including bacteria, and transports these, through ciliary beating, toward the pharynx for removal via the oral-fecal route [9]. The mucosal fluid also contains various polymer-like mucin glycoproteins, with both shared and unique features (reviewed in [10]). Many of these mucins are extensively covered with negatively charged N-acetylneuraminic acid (sialic acid) [11,12], which can bind to positively charged particles (e.g., bacteria) with high avidity, preventing these particles from crossing the mucus barrier, and thus facilitating their removal via mucociliary clearance. To overcome these adhesive restrictions, the pneumococcus expresses one of more than 90 polysaccharide capsules, a layer of polysaccharide molecules which is primarily covalently attached to the peptidoglycan cell wall. Whereas the pneumococcal capsule is well known for its role in providing protection to complement and phagocytic clearance during invasive pneumococcal disease, its contribution toward colonization has remained unclear for a long time. In light of the central role of colonization in the pneumococcal life cycle, it is likely that the role of capsule extends beyond resistance to complement and phagocytic killing. Pneumococcal capsules are immunologically highly distinct. However, they share one unique feature: None of them are positively charged. Indeed, with the exception of serotypes 7F, 7A, 15, 33F, 37, and 1, which have a net neutral charge, the other polysaccharide capsules are negatively charged due the presence of uronic acid, phosphate, and pyruvate [13]. A study by Weiser and colleagues identified an important role of the capsule during colonization; they found that the capsule mediates translocation of the pneumococci across the negatively charged mucus layer [14]. This facilitated subsequent pneumococcal adherence to epithelial cells and establishment of colonization. Subsequent work by Li et al. showed that the capsular serotype is also the most important factor in determining the bacterial surface charge and that this is strongly correlated to serotype distribution in carriage [15]. To aid in this process, S. pneumoniae expresses several exoglycosidases (e.g., NanA, NanB, and NanC), which cleave sialic acid residues [16] and thus further negate the adhesive properties of the mucins.

Although expression of the polysaccharide capsule is important for evading the adhesive effects of the mucus layer, the presence of capsule inhibits adherence to epithelial cells [17]. Indeed, it has long been known that “transparent” phenotypes adhere better to epithelial cells than “opaque” phenotypes, which produce one- to sixfold more capsule than transparent colonies [18]. Strikingly, and through a mechanism which has not yet been fully elucidated, Hammerschmidt et al. showed that pneumococci in close proximity to epithelial cells shed their capsule [19], which likely allows increased access of surface-exposed pneumococcal adhesins to host receptors on epithelial cells, and adherence to and invasion of epithelial cells.

During transport across the mucus layer, cilia beating by epithelial cells is inhibited by the pneumococcal pore-forming toxin pneumolysin (Ply) [20], suggesting an essential role for this virulence factor in colonization. It was therefore surprising that deletion of Ply did not attenuate pneumococcal colonization of mice in a study by Rubins et al. [21]. However, a subsequent study by Kadioglu et al. showed that Ply-deficient strains were indeed less able to colonize the nasopharynx, but also found that this effect was dependent not only on the capsule type but also on the genetic background [22]. Perhaps this should not come as a surprise, considering the above-described importance of the capsule in the evasion of mucus entrapment, as well as other factors that might be encoded on the genome.

Antimicrobial Compounds

The peptidoglycan cell wall and its covalently bound teichoic acids and polysaccharide capsule further promote pneumococcal survival by conferring resistance to the many antimicrobial compounds present in normal mucus [23]. One of the principal antimicrobial compounds is lysozyme, which is present in very high concentrations in airway mucus [24]. Human lysozyme is a muramidase which enzymatically targets the bond between N-acetyl glucosamine and N-acetyl muramic acid residues on peptidoglycan, resulting in cell wall degradation. Lysozyme can also directly kill both Gram positive and Gram negative bacteria via its cationic antimicrobial peptide motif, which has been shown to occur independent of its muramidase activity [25]. To evade enzymatic cell wall degradation by lysozyme, S. pneumoniae produces two enzymes: the peptidoglycan N-acetylglucosamine deacetylase PgdA [26] and the O-acetyltransferase Adr [27]. A study by Davis et al. found that these enzymes act in synergy in modifying the targeting moieties on the pneumococcal peptidoglycan, rendering its peptidoglycan less recognizable by mucosal lysozyme. While this was associated with a decrease in fitness, the net effects of peptidoglycan modification provided a strong in vivo survival advantage to S. pneumoniae in the context of high concentrations of lysozyme M [28]. Weiser and colleagues also elegantly showed that cleavage of pneumococcal peptidoglycan in the presence of active Ply induces intracellular immune signaling via the cytosolic innate immune receptor nucleotide-binding oligomerization domain-containing prot...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• List of Contributors
• Preface
• Section A: Streptococcus pneumoniae Epidemiology and Vaccines
• Section B: Genetics and Functional Genomics of Streptococcus pneumoniae
• Section C: Streptococcus pneumoniae Biology
• Section D: Pneumococcal Interactions with the Host
• Index