Mini-Symposium: Recurrent Lower Respiratory Tract Infections
Regulation of bacterial trafficking in the nasopharynx

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Summary

Bacterial ‘colonisation’ of the nasopharynx by potential bacterial pathogens is frequent in early childhood and is frequent as part of a dynamic process in which the microbiota of the oral and nasopharynx are established. New understanding recognizes this process is evolving and that competition and likely regulation occurs among potential pathogens as well as between pathogens and commensals. Such events elicit host responses that either results in clearance or persistence within the nasal and oral pharynx. Environmental factors such as recent antibiotic usage, smoking and vaccines all impact on the success of specific bacterial species in this competition. Understanding the significant bacterial interactions as well as how bacteria work in concert to regulate density, expression of virulence factors and capacity to produce disease are likely to provide new approaches to disease prevention.

Introduction

Bacterial colonization of the nasopharynx (np) has long been recognized as a critical event in disease pathogenesis for both invasive diseases as well as respiratory tract infections. The predominant focus until recently has been on individual pathogens and the pathogenesis of disease following np acquisition. As examples, Faden and colleagues observed that early colonization of the np in infants with Streptococcus pneumoniae (SP) or nontypable Haemophilus influenza (NTHi) was an important risk feature for early onset of middle ear disease1 and Leach and colleagues reported that early colonization with NTHi and SP results in a 30 fold increase in risk for AOM in Aboriginal infants compared with colonization with Moraxella cataharralis alone.2 Revai and colleagues identified a significantly greater odds ratio for development of AOM during a viral upper respiratory tract infection for children colonized with an otopathogen compared with those who were not.3 Furthermore, in invasive diseases due to Neisseria meningitidis, Haemophilus influenzae type B and Streptococcus pneumoniae, the specific pathogen is almost always present in the nasopharynx and in fact, sterilization of the nasopharynx to prevent further transmission has been incorporated into secondary prevention strategies for both meningococcal and HiB disease.

The focus for disease prevention has been on risk factors for colonization with potential pathogens, such as age, gender, breast feeding, day care attendance, and exposure to smoke or the impact of selective pressure from antimicrobial treatment or conjugate vaccines on colonization with pathogenic strains as epidemiologic clues to identify strategies to prevent colonization and thereby prevent disease.4, 5 More recently, investigators have begun to view bacterial colonization with potential pathogens within the context of a microbial community and to explore the dynamics of colonization and the influences that result in persistence or clearance, disease or ‘asymptomatic’ carriage.6 This review will explore and highlight our expanding understanding of the process of colonization and potential mechanisms that regulate the pathogen-commensul state with a focus on SP and NTHi. We will also speculate on how the results from ‘in vitro’ and animal studies are relevant to clinical and epidemiologic observations primarily about otitis media, but potentially applicable to all bacterial respiratory tract infection.

Section snippets

Natural History of Colonization with Respiratory Pathogens in Children

Prospective studies in the first year of life in US infants report that initial colonization occurs during the first month and increases rapidly over the first six months.1 Moraxella catarrhalis is both the earliest and the most prevalent among the respiratory pathogens during this period, achieving colonization rates of 55% in infants at six months and 72% by 12 months of age. SP and NTHi are found in 38% and 19% respectively at 6 months of life. Similar findings are reported in Aboriginal

Colonization with respiratory pathogens elicits an inflammatory response

Weiser and colleagues demonstrated that inoculation of SP into the nasopharynx in a mouse model results in signaling events that initiate an inflammatory response as well as promoting the opening of epithelial barriers at cellular junctions permitting cytokines and neutrophils to enter the lumen.16 Within 24 hours, a mild rhinitis is present characterized histologically by the presence of neutrophils. Weiser describes the process as similar to the inflammatory response seen in the lungs during

Colonization with respiratory pathogens elicits an immune response

Colonization with SP elicits local immune responses such that on rechallenge, an enhanced neutrophilic invasion that rapidly reduces the bacterial density within the np is observed.16 The response appears related to either cellular or humoral defenses. These immune responses may partially explain the recognized age related decline in pneumococcal disease in children as nearly all children have been previously ‘colonized’ by age 3 [Wroe P personal communication] Colonization is also recognized

Turnover of SP and NTHi strains within the np is common

Recent descriptions of competition between bacterial pathogens of the same species have demonstrated that pneumococci posses weapons such as bacteriocins that target other pneumococci.18 In contrast, studies by Levin and colleagues demonstrate that nasal challenge in neonatal rats with an established resident strain permits a second strain to co-colonize when the resident and challenge strains are SP or NTHi, but not when the resident and challenge strains are Staphylococcus aureas (SA).19 The

Competition among bacterial pathogens enhances the np inflammatory response

Competition between different species has also revealed that co-inoculation or sequential challenge results in increased inflammation and clearance or co-existence as the outcome appears to be strain specific.19, 20 In general, competition between SP and NTHi is immune mediated and associated with increased neutrophilic infiltration compared to colonization with either species alone. The observation that children colonized with more than one potential pathogen are more likely to develop AOM

Do commensals ‘regulate’ bacterial virulence?

The evidence that interactions within the nasopharyngeal microbial community influence the outcome of colonization and its potential clinical relevance has been presented above. Future strategies for controlling the inflammatory response may lead to new approaches for preventing respiratory tract colonization from progressing to disease. The influence of microbial communities as a modifier for the development of disease following colonization remains poorly understood. Potentially the microbial

What are the potential implications of viewing bacterial virulence within the context of a microbial community?

The primary focus of antibiotic selection and vaccine impact has been on the role of such strategies on resistance of and/or colonization with respiratory tract pathogens. However, if as a growing body of evidence suggests, microbial communities regulate colonization and/or progression from colonization to disease, then a broader view of antimicrobial selection and vaccine impact will be necessary. Antibiotic exposure results in clearance of susceptible pneumococci and accumulation of resistant

Educational Aims

  • To understand the dynamic nature of bacterial trafficking through the nasopharynx and upper airways

  • To recognize the importance of this process in the development of both acute and chronic diseases of the respiratory system including the middle ear

  • To understand that ‘colonisation’ is a dynamic event generating inflammatory and immunological responses which may produce upper airways symptoms including coryza

  • To understand the complex interaction of host and environmental factors that influence the

Acknowledgements

This work was supported, in part, by the National Institute of Allergy and Infectious Diseases at the National Institutes of Health [R01 AI068043 to MMP].

Melinda Pettigrew PhD for discussions about role of commensuls in regulation of colonization and virulence.

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