The mucosal epithelium of the respiratory tract in muco‐purulent bronchitis caused by<i>Hæmophilus influenzæ</i>

Hers, J.; Mulder, J.

doi:10.1002/path.1700660114

Cited by 76 publications

(38 citation statements)

References 6 publications

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“…Although it is classically considered an extracellular, opportunistic pathogen, there is increasing evidence of intracellular and intercellular niches for NTHI in vitro (36). Further, the presence of NTHI within adenoids and bronchial epithelium suggests that an invasive phenotype may coincide with the chronic nature associated with NTHI-mediated diseases (68)(69)(70)(71)(72). Invasion of epithelial cells could provide NTHI with an environment rich in nutrients and a refuge from immune pressures.…”

Section: Resultsmentioning

confidence: 99%

The Haemophilus influenzae Sap Transporter Mediates Bacterium-Epithelial Cell Homeostasis

et al. 2013

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Nontypeable Haemophilus influenzae (NTHI) is a commensal inhabitant of the human nasopharynx and a causative agent of otitis media and other diseases of the upper and lower human airway. During colonization within the host, NTHI must acquire essential nutrients and evade immune attack. We previously demonstrated that the NTHI Sap transporter, an inner membrane protein complex, mediates resistance to antimicrobial peptides and is required for heme homeostasis. We hypothesized that Sap transporter functions are critical for NTHI interaction with the host epithelium and establishment of colonization. Thus, we cocultured the parent or the sapA mutant on polarized epithelial cells grown at an air-liquid interface, as a physiological model of NTHI colonization, to determine the contribution of the Sap transporter to bacterium-host cell interactions. Although SapAdeficient NTHI was less adherent to epithelial cells, we observed a significant increase in invasive bacteria compared to the parent strain. Upon internalization, the sapA mutant appeared free in the cytoplasm, whereas the parent strain was primarily found in endosomes, indicating differential subcellular trafficking. Additionally, we observed reduced inflammatory cytokine production by the epithelium in response to the sapA mutant strain compared to the parental strain. Furthermore, chinchilla middle ears challenged with the sapA mutant demonstrated a decrease in disease severity compared to ears challenged with the parental strain. Collectively, our data suggest that NTHI senses host environmental cues via Sap transporter function to mediate interaction with host epithelial cells. Epithelial cell invasion and modulation of host inflammatory cytokine responses may promote NTHI colonization and access to essential nutrients.

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Section: Resultsmentioning

confidence: 99%

The Haemophilus influenzae Sap Transporter Mediates Bacterium-Epithelial Cell Homeostasis

et al. 2013

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“…However, for several decades, studies have reported significant numbers of NTHI within and between a variety of human respiratory epithelial and subepithelial cells and macrophages in vitro and ex vivo, including the bronchi of adults with chronic lung disease and the adenoids of children with adenoidal hypertrophy or with a history of chronic otitis media (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27). Few studies have examined the internalization, trafficking, and fate of NTHI in host cells.…”

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confidence: 99%

Internalization and Trafficking of Nontypeable Haemophilus influenzae in Human Respiratory Epithelial Cells and Roles of IgA1 Proteases for Optimal Invasion and Persistence

2014

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Nontypeable Haemophilus influenzae (NTHI) is a leading cause of opportunistic infections of the respiratory tract in children and adults. Although considered an extracellular pathogen, NTHI has been observed repeatedly within and between cells of the human respiratory tract, and these observations have been correlated to symptomatic infection. These findings are intriguing in light of the knowledge that NTHI persists in the respiratory tract despite antibiotic therapy and the development of bactericidal antibodies. We hypothesized that intracellular NTHI avoids, escapes, or neutralizes the endolysosomal pathway and persists within human respiratory epithelial cells and that human IgA1 proteases are required for optimal internalization and persistence of NTHI. Virtually all strains encode a human IgA1 protease gene, igaA, and we previously characterized a novel human IgA1 protease gene, igaB, that is associated with disease-causing strains and is homologous to the IgA1 protease that is unique to pathogenic Neisseria spp. Here, we show that NTHI invades human bronchial epithelial cells in vitro in a lipid raft-independent manner, is subsequently trafficked via the endolysosomal pathway, and is killed in lysosomes after variable durations of persistence. IgaA is required for optimal invasion. IgaB appears to play little or no role in adherence or invasion but is required for optimal intracellular persistence of NTHI. IgaB cleaves lysosome-associated membrane protein 1 (LAMP1) at pHs characteristic of the plasma membrane, early endosome, late endosome, and lysosome. However, neither IgA1 protease inhibits acidification of intracellular vesicles containing NTHI. NTHI IgA1 proteases play important but different roles in NTHI invasion and trafficking in respiratory epithelial cells. Nontypeable Haemophilus influenzae (NTHI) is a Gram-negative, human-exclusive commensal bacterium of the nasopharynx and is a leading cause of opportunistic infections in the upper and lower respiratory tracts, including otitis media, sinusitis, conjunctivitis, community-acquired pneumonia, and exacerbations of chronic obstructive pulmonary disease (COPD) and of cystic fibrosis (1, 2).When a new strain of NTHI is acquired, the outcome depends on a variety of dynamic host and bacterial factors. Colonization and the transition from commensal to opportunistic pathogen require NTHI to resist host innate immune defenses, including nutrient sequestration, mucociliary clearance, antimicrobial peptides, secretory IgA1, and phagocytosis by immune cells or by epithelial cells. Bacterial counterresistance mechanisms under investigation include adhesins, antimicrobial peptide degradation, IgA1 protease, biofilm production, modification of surface-exposed lipooligosaccharide moieties, production of outer membrane vesicles (OMVs), and others (3-12). Understanding these factors will help identify targets for therapeutic intervention, as NTHI infections induce acquired immunity consisting largely of strain-specific bactericidal antibodies that afford littl...

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“…Patients with chronic bronchitis, bronchiectasis, and cystic fibrosis are particularly predisposed to infection with nontypable H. influenzae (14,17). Direct contact between H. influenzae and airway epithelial cells has been demonstrated during airway infection, and attachment to epithelial cells is mediated by specific bacterial surface molecules (3,18). Although epithelial cell receptors for these bacterial adhesive proteins have been more difficult to identify, the use of surface molecules on epithelial cells to detect and respond to infection by H. influenzae seems likely.…”

mentioning

confidence: 99%

Haemophilus influenzaeStimulates ICAM-1 Expression on Respiratory Epithelial Cells

Frick¹,

Joseph²,

Pang³

et al. 2000

The Journal of Immunology

119

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Epithelial cells interact directly with bacteria in the environment and play a critical role in airway defense against microbial pathogens. In this study, we examined the response of respiratory epithelial cells to infection with nontypable Haemophilus influenzae. Using an in vitro cell culture model, we found that epithelial cell monolayers released significant quantities of IL-8 and expressed increased levels of ICAM-1 mRNA and surface protein in response to H. influenzae. In contrast, levels of IL-1β, TNF-α, and MHC class I were not significantly affected, suggesting preferential activation of a specific subset of epithelial genes directed toward defense against bacteria. Induction of ICAM-1 required direct bacterial interaction with the epithelial cell surface and was not reproduced by purified H. influenzae lipooligosaccharide. Consistent with a functional role for this response, induction of ICAM-1 by H. influenzae mediated increased neutrophil adherence to the epithelial cell surface. Furthermore, in an in vivo murine model of airway infection with H. influenzae, increased epithelial cell ICAM-1 expression coincided with increased chemokine levels and neutrophil recruitment in the airway. These results indicate that ICAM-1 expression on human respiratory epithelial cells is induced by epithelial cell interaction with H. influenzae and suggest that an ICAM-1-dependent mechanism can mediate neutrophil adherence to these cells independent of inflammatory mediator release by other cell types. Direct induction of specific epithelial cell genes (such as ICAM-1 and IL-8) by bacterial infection may allow for rapid and efficient innate defense in the airway.

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The mucosal epithelium of the respiratory tract in muco‐purulent bronchitis caused byHæmophilus influenzæ

Cited by 76 publications

References 6 publications

The Haemophilus influenzae Sap Transporter Mediates Bacterium-Epithelial Cell Homeostasis

The Haemophilus influenzae Sap Transporter Mediates Bacterium-Epithelial Cell Homeostasis

Internalization and Trafficking of Nontypeable Haemophilus influenzae in Human Respiratory Epithelial Cells and Roles of IgA1 Proteases for Optimal Invasion and Persistence

Haemophilus influenzaeStimulates ICAM-1 Expression on Respiratory Epithelial Cells

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