Protection against Streptococcus pneumoniae lung infection after nasopharyngeal colonization requires both humoral and cellular immune responses

Robert, Wilson; Cohen, Jonathan; José, Ricardo J.; Vogel, Corné P. de; Baxendale, Helen; Brown, Jeremy

doi:10.1038/mi.2014.95

Cited by 126 publications

(157 citation statements)

References 48 publications

(66 reference statements)

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“…Macrophage phagocytosis of S. pneumoniae is enhanced by antibody (12). However, in mouse models, antibody to S. pneumoniae acquired by previous nasopharyngeal colonization had little effect on S. pneumoniae clearance from the lung at very early time points (13,14).In contrast to the extensive data on the role of AMs, there are few data on the relative importance of non-AM-dependent lung immunity against S. pneumoniae. Both smoking and viral respira- Citation Camberlein E, Cohen JM, José R, Hyams CJ, Callard R, Chimalapati S, Yuste J, Edwards LA, Marshall H, van Rooijen N, Noursadeghi M, Brown JS.…”

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confidence: 83%

Importance of Bacterial Replication and Alveolar Macrophage-Independent Clearance Mechanisms during Early Lung Infection with Streptococcus pneumoniae

Camberlein¹,

Cohen²,

José³

et al. 2015

Infect Immun

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f Although the importance of alveolar macrophages for host immunity during early Streptococcus pneumoniae lung infection is well established, the contribution and relative importance of other innate immunity mechanisms and of bacterial factors are less clear. We have used a murine model of S. pneumoniae early lung infection with wild-type, unencapsulated, and para-amino benzoic acid auxotroph mutant TIGR4 strains to assess the effects of inoculum size, bacterial replication, capsule, and alveolar macrophage-dependent and -independent clearance mechanisms on bacterial persistence within the lungs. Alveolar macrophage-dependent and -independent (calculated indirectly) clearance half-lives and bacterial replication doubling times were estimated using a mathematical model. In this model, after infection with a high-dose inoculum of encapsulated S. pneumoniae, alveolar macrophage-independent clearance mechanisms were dominant, with a clearance half-life of 24 min compared to 135 min for alveolar macrophage-dependent clearance. In addition, after a high-dose inoculum, successful lung infection required rapid bacterial replication, with an estimated S. pneumoniae doubling time of 16 min. The capsule had wide effects on early lung clearance mechanisms, with reduced half-lives of 14 min for alveolar macrophage-independent and 31 min for alveolar macrophage-dependent clearance of unencapsulated bacteria. In contrast, with a lower-dose inoculum, the bacterial doubling time increased to 56 min and the S. pneumoniae alveolar macrophage-dependent clearance half-life improved to 42 min and was largely unaffected by the capsule. These data demonstrate the large effects of bacterial factors (inoculum size, the capsule, and rapid replication) and alveolar macrophage-independent clearance mechanisms during early lung infection with S. pneumoniae. Microaspiration of potentially pathogenic bacteria colonizing the nasopharynx is the probable cause of most cases of bacterial pneumonia. Whether microaspiration results in pneumonia will depend on the numbers of bacteria reaching the lung, their virulence, and the host's ability to clear the invading bacteria. Defining the efficacy of different lung immune mechanisms and the bacterial characteristics for successful infection will be essential for understanding the epidemiology of pneumonia and for the design of effective preventative strategies. Initial lung immune defenses include the resident alveolar macrophages (AMs) (1-3), physical removal of microbes by mucociliary clearance, and mucosal antibacterial peptides (e.g., defensins) and proteins (e.g., lysozyme and lactoferrin) (4, 5). The importance of AMs for preventing lung infections due to Streptococcus pneumoniae, the commonest cause of bacterial pneumonia, is well established (2, 6-9). The published data indicate that AM recognition and AM phagocytosis of S. pneumoniae are essential for controlling bacterial numbers during the first few hours of lung infection. Impairment of AMmediated bacterial clearance during early infection, ...

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confidence: 83%

Importance of Bacterial Replication and Alveolar Macrophage-Independent Clearance Mechanisms during Early Lung Infection with Streptococcus pneumoniae

Camberlein¹,

Cohen²,

José³

et al. 2015

Infect Immun

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“…[15][16][17][18][19][20][21] These observations suggest that novel vaccine strategies could harness the immunizing effects of nasopharyngeal colonization to prevent serious infections, and this is the subject addressed in this review with a particular focus on the potential of nasopharyngeal colonization for the prevention of S. pneumoniae and N. meningitidis infections, which are used as case studies that illustrate the benefits and potential drawbacks of this approach.…”

Section: Nasopharyngeal Commensal Speciesmentioning

confidence: 99%

“…15,16,18,19 Importantly, intranasal administration of the 6B strain without successful colonization also augmented local mucosal serological responses, 82 showing that exposure of the nasopharynx to the organism can stimulate an immunological response even if colonization was not detected.…”

mentioning

confidence: 99%

“…In addition to Th17-cell responses, the antibody response to colonization is also important for protection against S. pneumoniae lung infection in a mouse model. 19 In the human experimental challenge model, colonization augmented S. pneumoniae-specific IL-17-secreting CD4+ T-cells in the human lung, 20 suggesting that there may also be a role for colonization-induced Th17 cells in limiting lung infection in humans.…”

mentioning

confidence: 99%

“…21 In these challenge studies, colonization resulted in cellular and humoral immune responses to S pneumoniae. Data from mouse colonization models indicate that nasopharyngeal colonization leads to Th17-cell responses 16,18,19 that enhance phagocyte recruitment to the nasopharynx, 18,78 and are critical for both the initial clearance of the colonizing strain and subsequent protection against recolonization. The impact of these phagocytic responses is enhanced by the effects of specific antibody via opsonization and agglutination of S. pneumoniae.…”

mentioning

confidence: 99%

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The new first-line defense: the potential of nasopharyngeal colonization in vaccine strategies

Chan¹,

Cohen²,

Brown³

2016

VDT

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Abstract:Pathogens that can colonize the upper respiratory tract include Streptococcus pneumoniae, Hemophilus influenzae, Neisseria meningitidis, Moraxella catarrhalis, and Staphylococcus aureus. While these pathogens commonly asymptomatically colonize the nasopharynx of healthy adults, disease progression may occur in some individuals. In addition to these respiratory pathogens, there are a large number of commensal species also found in the upper respiratory tract which only very rarely cause disease, creating a complex community of bacterial species in the nasopharynx. This review addresses the novel, potential strategies that utilize the interactions between both homologous and heterologous species in the nasopharynx to vaccinate individuals against pathogenic bacteria. These strategies include the mechanisms employed by colonizing bacteria to regulate the presence of other species in the nasopharynx and the effect that colonization of the nasopharynx has on the host immune response. Interventional strategies investigated so far include the introduction of nonpathogenic bacteria to the nasopharynx to immunize against a closely related species, controlled colonization using both wild-type and attenuated species, and the use of other nonpathogenic colonizers to express antigens from potential pathogens. All these approaches harness the ability of the colonization to induce a mucosal immune response that can protect against future infection. In this review, S. pneumoniae and N. meningitidis colonization are used as case studies for this approach as the immunological effects of colonization have been widely studied in animal and human models. Colonization-based strategies have great potential, and, in particular, the attenuated strain approach has produced some encouraging data in animal models. However, the strategy for attenuating virulence must be stringent and caused by highly stable mutations that are unlikely to revert. In addition, the consequences of artificial administration of genetically modified bacteria to the nasopharynx on the usual host microbiome are unknown and would need to be monitored carefully.

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Pneumococcal lipoproteins involved in bacterial fitness, virulence, and immune evasion

et al. 2016

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Edited by Wilhelm JustStreptococcus pneumoniae (pneumococcus) has evolved sophisticated strategies to survive in several niches within the human body either as a harmless commensal or as a serious pathogen causing a variety of diseases. The dynamic interaction between pneumococci and resident host cells during colonization of the upper respiratory tract and at the site of infection is critical for bacterial survival and the development of disease. Pneumococcal lipoproteins are peripherally anchored membrane proteins and have pivotal roles in bacterial fitness including envelope stability, cell division, nutrient acquisition, signal transduction, transport (as substrate-binding proteins of ABC transporter systems), resistance to oxidative stress and antibiotics, and protein folding. In addition, lipoproteins are directly involved in virulence-associated processes such as adhesion, colonization, and persistence through immune evasion. Conversely, lipoproteins are also targets for the host response both as ligands for toll-like receptors and as targets for acquired antibodies. This review summarizes the multifaceted roles of selected pneumococcal lipoproteins and how this knowledge can be exploited to combat pneumococcal infections.

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Protection against Streptococcus pneumoniae lung infection after nasopharyngeal colonization requires both humoral and cellular immune responses

Cited by 126 publications

References 48 publications

Importance of Bacterial Replication and Alveolar Macrophage-Independent Clearance Mechanisms during Early Lung Infection with Streptococcus pneumoniae

Importance of Bacterial Replication and Alveolar Macrophage-Independent Clearance Mechanisms during Early Lung Infection with Streptococcus pneumoniae

The new first-line defense: the potential of nasopharyngeal colonization in vaccine strategies

Pneumococcal lipoproteins involved in bacterial fitness, virulence, and immune evasion

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