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Article Reference Relative contributions of lipooligosaccharide inner and outer core modifications to nontypeable Haemophilus influenzae pathogenesis.
Nontypeable Haemophilus influenzae (NTHi) is a frequent commensal of the human nasopharynx that causes opportunistic infection in immunocompromised individuals. Existing evidence associates lipooligosaccharide (LOS) with disease, but the specific and relative contributions of NTHi LOS modifications to virulence properties of the bacterium have not been comprehensively addressed. Using NTHi strain 375, an isolate for which the detailed LOS structure has been determined, we compared systematically a set of isogenic mutant strains expressing sequentially truncated LOS. The relative contributions of 2-keto-3-deoxyoctulosonic acid, the triheptose inner core, oligosaccharide extensions on heptoses I and III, phosphorylcholine, digalactose, and sialic acid to NTHi resistance to antimicrobial peptides (AMP), self-aggregation, biofilm formation, cultured human respiratory epithelial infection, and murine pulmonary infection were assessed. We show that opsX, lgtF, lpsA, lic1, and lic2A contribute to bacterial resistance to AMP; lic1 is related to NTHi self-aggregation; lgtF, lic1, and siaB are involved in biofilm growth; opsX and lgtF participate in epithelial infection; and opsX, lgtF, and lpsA contribute to lung infection. Depending on the phenotype, the involvement of these LOS modifications occurs at different extents, independently or having an additive effect in combination. We discuss the relative contribution of LOS epitopes to NTHi virulence and frame a range of pathogenic traits in the context of infection.
Article Reference Children with chronic suppurative lung disease have a reduced capacity to synthesize interferon-gamma in vitro in response to non-typeable Haemophilus influenzae.
Chronic suppurative lung disease (CSLD) is characterized by the presence of a chronic wet or productive cough and recurrent lower respiratory infections. The aim of this study was to identify features of innate, cell-mediated and humoral immunity that may increase susceptibility to respiratory infections in children with CSLD. Because non-typeable Haemophilus influenzae (NTHi) is commonly isolated from the airways in CSLD, we examined immune responses to this organism in 80 age-stratified children with CSLD and compared their responses with 51 healthy control children. Cytokines involved in the generation and control of inflammation (IFN-γ, IL-13, IL-5, IL-10 at 72 hours and TNFα, IL-6, IL-10 at 24 hours) were measured in peripheral blood mononuclear cells challenged in vitro with live NTHi. We also measured circulating IgG subclass antibodies (IgG1 and IgG4) to two H. influenzae outer membrane proteins, P4 and P6. The most notable finding was that PBMC from children with CSLD produced significantly less IFN-γ in response to NTHi than healthy control children whereas mitogen-induced IFN-γ production was similar in both groups. Overall there were minor differences in innate and humoral immune responses between CSLD and control children. This study demonstrates that children with chronic suppurative lung disease have an altered systemic cell-mediated immune response to NTHi in vitro. This deficient IFN-γ response may contribute to increased susceptibility to NTHi infections and the pathogenesis of CSLD in children.
Article Reference The ferric uptake regulator and its role in the pathogenesis of nontypeable Haemophilus influenzae.
Nontypeable Haemophilus influenzae (NTHi) is a commensal microorganism of the human nasopharynx, yet is also an opportunistic pathogen of the upper and lower respiratory tracts. Host microenvironments influence gene expression patterns, likely critical for NTHi persistence. The host sequesters iron as a mechanism to control microbial growth, yet iron limitation influences gene expression and subsequent production of proteins involved in iron homeostasis. Careful regulation of iron uptake, via the ferric uptake regulator Fur, is essential in multiple bacteria, including NTHi. We hypothesized therefore that Fur contributes to iron homeostasis in NTHi, is critical for bacterial persistence and likely regulates expression of virulence factors. Toward this end, fur was deleted in the prototypic NTHi clinical isolate, 86-028NP and we assessed gene expression regulated by Fur. As expected, expression of the majority of genes that encode proteins with predicted roles in iron utilization was repressed by Fur. However, 14 Fur-regulated genes encode proteins with no known function, yet may contribute to iron utilization or other biological functions. In a mammalian model of human otitis media, we determined that Fur was critical for bacterial persistence indicating an important role for Fur-mediated iron homeostasis in disease progression. These data provide a profile of genes regulated by Fur in NTHi, and likely identify additional regulatory pathways involved in iron utilization. Identification of such pathways will increase our understanding of how this pathogen can persist within host microenvironments, as a common commensal and importantly, as a pathogen with significant clinical impact.
Article Reference Haemophilus influenzae: recent advances in the understanding of molecular pathogenesis and polymicrobial infections.
Non-typeable Haemophilus influenzae (NTHi) is a human-specific mucosal pathogen and one of the most common causes of bacterial infections in children and patients with chronic obstructive pulmonary disease. It is also frequently found in polymicrobial superinfections. Great strides have recently been made in the understanding of the molecular mechanisms underlying NTHi pathogenesis.
Article Reference Haemophilus influenzae and the lung (Haemophilus and the lung).
Haemophilus influenzae is present as a commensal organism in the nasopharynx of most healthy adults from where it can spread to cause both systemic and respiratory tract infection. This bacterium is divided into typeable forms (such as type b) or nontypeable forms based on the presence or absence of a tough polysaccharide capsule. Respiratory disease is predominantly caused by the nontypeable forms (NTHi). Haemophilus influenzae has evolved a number of strategies to evade the host defense including the ability to invade into local tissue. Pathogenic properties of this bacterium as well as defects in host defense may result in the spread of this bacterium from the upper airway to the bronchi of the lung. This can result in airway inflammation and colonization particularly in chronic obstructive pulmonary disease. Treatment of respiratory tract infection with Haemophilus influenzae is often only partially successful with ongoing infection and inflammation. Improvement in patient outcome will be dependent on a better understanding of the pathogenesis and host immune response to this bacterium.
Article Reference Incorporation of phosphorylcholine into the lipooligosaccharide of nontypeable Haemophilus influenzae does not correlate with the level of biofilm formation in vitro.
Nontypeable Haemophilus influenzae (NTHi) is an opportunistic pathogen that causes otitis media in children and community-acquired pneumonia or exacerbations of chronic obstructive pulmonary disease in adults. A large variety of studies suggest that biofilm formation by NTHi may be an important step in the pathogenesis of this bacterium. The objective of this report was to determine the relationship between the presence of phosphorylcholine in the lipooligosaccharide of NTHi and the level of biofilm formation. The study was performed on 111 NTHi clinical isolates collected from oropharyngeal samples of healthy children, middle ear fluid of children with otitis media, and sputum samples of patients with chronic obstructive pulmonary disease or community-acquired pneumonia. NTHi clinical isolates presented a large variation in the level of biofilm formation in a static assay and phosphorylcholine content. Isolates collected from the oropharynx and middle ear fluid of children tended to have more phosphorylcholine and made denser biofilms than isolates collected from sputum samples of patients with chronic obstructive pulmonary disease or community-acquired pneumonia. No correlation was observed between biofilm formation and the presence of phosphorylcholine in the lipooligosaccharide for either planktonic or biofilm growth. This lack of correlation was confirmed by abrogating phosphorylcholine incorporation into lipooligosaccharide through licA gene deletion, which had strain-specific effects on biofilm formation. Altogether, we present strong evidence to conclude that there is no correlation between biofilm formation in a static assay and the presence of phosphorylcholine in lipooligosaccharide in a large collection of clinical NTHi isolates collected from different groups of patients.
Article Reference Cellular interaction of nontypeable Haemophilus influenzae triggers cytotoxicity of infected type II alveolar cells via apoptosis.
Nontypeable Haemophilus influenzae (NTHi) is an important cause of lower respiratory tract infections, resulting in exacerbations of chronic obstructive pulmonary disease (COPD). Despite its pathogenic potential, little is known regarding the role of intracellular NTHi in pathogenesis of pulmonary infection. Kinetics of NTHi internalization was studied using gentamicin protection assays. NTHi strains isolated from COPD patients efficiently adhere to and invade type II alveolar (A549) cells. During early stages, that is, 6 h postinfection, we noted a substantial increase in NTHi invasion with no evidence of intracellular replication. Electron microscopy revealed that the majority of internalized NTHi resided within membrane bound acidic endocytic vacuoles. However, at later stages, that is, 8 h postinfection, significant reduction in viable intracellular NTHi was observed and vacuoles were found to be empty with NTHi escape into the cytosol. By 12 h, cytopathic changes of cells were evident with massive vacuolization of cytoplasm, intense chromatin condensation, and intact plasma membrane. Furthermore, analysis of apoptotic markers confirmed that infected A549 cells underwent apoptosis at later stages. In addition, inhibition of internalization of NTHi by cytochalasin D prevented apoptosis of cells. Collectively, these findings suggest that internalization of NTHi and its escape from vacuolar compartments triggers cytotoxicity of alveolar cells via apoptosis during the infection process.
Article Reference Relative contribution of lipooligosaccharide inner and outer core modifications to nontypable Haemophilus influenzae pathogenesis.
Nontypable Haemophilus influenzae (NTHi) is a frequent commensal of the human nasopharynx that causes opportunistic infection in immunocompromised individuals. Existing evidence associates lipooligosaccharide (LOS) with disease, but the specific and relative contribution of NTHi LOS modifications to virulence properties of the bacterium has not been comprehensively addressed. Using NTHi strain 375, an isolate where the detailed LOS structure has been determined, we compared systematically a set of isogenic mutant strains expressing sequentially truncated LOS. The relative contribution of 2-keto-3-deoxyoctulosonic acid, the tri-heptose inner core, oligosaccharide extensions on heptoses I and III, phosphorylcholine, di-galactose and sialic acid to NTHi resistance to antimicrobial peptides (AMP), self-aggregation, biofilm formation, cultured human respiratory epithelial infection, and murine pulmonary infection was assessed. We show that opsX, lgtF, lpsA, lic1 and lic2A contribute to bacterial resistance to AMP; lic1 is related to NTHi self-aggregation; lgtF, lic1 and siaB are involved in biofilm growth; opsX and lgtF participate in epithelial infection; opsX, lgtF and lpsA contribute to lung infection. Depending on the phenotype, the involvement of these LOS modifications occurs at a different extent, independently or having an additive effect in combination. Collectively, we propose the relative contribution of LOS epitopes to NTHi virulence and frame a range of pathogenic traits in the context of infection.
Article Reference Association of serum interleukin-27 with the exacerbation of chronic obstructive pulmonary disease.
We have previously demonstrated that chronic obstructive pulmonary disease (COPD) patients who do not have Siglec-14 are less prone to exacerbation of the disease. Siglec-14 is a myeloid cell protein that recognizes bacteria and triggers inflammatory responses. Therefore, soluble mediators secreted by myeloid cells responding to Siglec-14 engagement could be involved in the pathogenesis of exacerbation and could potentially be utilized as biomarkers of exacerbation. To find out, we sought genes specifically induced in Siglec-14(+) myeloid cells and evaluated their utility as biomarkers of COPD exacerbation. Using DNA microarray, we compared gene expression levels in Siglec-14(+) and control myeloid cell lines stimulated with or without nontypeable Haemophilus influenzae to select genes that were specifically induced in Siglec-14(+) cells. The expressions of several cytokine and chemokine genes were specifically induced in Siglec-14(+) cells. The concentrations of seven gene products were analyzed by multiplex bead array assays in paired COPD patient sera (n = 39) collected during exacerbation and stable disease states. Those gene products that increased during exacerbation were further tested using an independent set (n = 32) of paired patient sera. Serum concentration of interleukin-27 (IL-27) was elevated during exacerbation (discovery set: P = 0.0472; verification set: P = 0.0428; combined: P = 0.0104; one-sided Wilcoxon matched-pairs signed-rank test), particularly in exacerbations accompanied with sputum purulence and in exacerbations lasting more than a week. We concluded that IL-27 might be mechanistically involved in the exacerbation of COPD and could potentially serve as a systemic biomarker of exacerbation.
Article Reference [Regulation of expression, function, and inflammatory responses of innate immune receptor Toll-like receptor-2 (TLR2) during inflammatory responses against infection].
Toll-like receptor-2 (TLR2) is one of the important innate immune receptors that play an important role in recognizing the pathogens and producing inflammatory cytokines. In this review, we focus on the regulatory mechanisms of expression, function and inflammatory responses of TLR2 during pathogenic infection in innate immune cells. We first showed that nontypeable Haemophilus influenzae (NTHi), an important human pathogen that exacerbates otitis media and chronic obstructive pulmonary diseases (COPD), induces inflammatory responses through activation of NF-κB via two distinct signals, NIK-IKKα/β-IκBα and MKK3/6-p38 pathways. Moreover, TLR2 was greatly up-regulated by NTHi through the positive IKK-IκBα-dependent NF-κB pathway and the negative MKK3/6-p38α/β pathway. Importantly, glucocorticoids synergistically enhance NTHi-induced TLR2 up-regulation likely via a negative cross-talk with the inhibitory p38 MAPK. The results provide novel insights into the role of glucocorticoids in regulating host defense and innate immune responses through TLR2 regulation. We next focused on the pathogenesis of cystic fibrosis (CF), a common lethal inherited disorder characterized by recurrent pulmonary infections and obstruction caused by chronic mucus hypersecretion and inflammation. We demonstrated an increased expression of TLR2, due to an enhanced DNA de-methylation and Sp1-dependent transcriptional activation in CF epithelial cells. Furthermore, a Th17 cytokine IL-17A synergistically increased TLR2 signal through an enhancement of p38 phosphorylation. These studies suggest the importance of TLR2 and IL-17 signals in the pathogenesis of CF. Finally, by focusing on neutrophils and CF airway epithelial cells, we identified curcumin as a potent inhibitor of TLR2-mediated inflammatory responses.
Article Reference Nontypeable Haemophilus influenzae genetic islands associated with chronic pulmonary infection.
Haemophilus influenzae (Hi) colonizes the human respiratory tract and is an important pathogen associated with chronic obstructive pulmonary disease (COPD). Bacterial factors that interact with the human host may be important in the pathogenesis of COPD. These factors, however, have not been well defined. The overall goal of this study was to identify bacterial genetic elements with increased prevalence among H. influenzae strains isolated from patients with COPD compared to those isolated from the pharynges of healthy individuals.
Article Reference Respiratory syncytial virus promotes Moraxella catarrhalis-induced ascending experimental otitis media.
Otitis media (OM) is a polymicrobial disease wherein prior or concurrent infection with an upper respiratory tract virus plays an essential role, predisposing the middle ear to bacterial invasion. In episodes of acute bacterial OM, respiratory syncytial virus (RSV) is the most commonly isolated virus and thus serves as an important co-pathogen. Of the predominant bacterial agents of OM, the pathogenesis of disease due to Moraxella catarrhalis is the least well understood. Rigorous study of M. catarrhalis in the context of OM has been significantly hindered by lack of an animal model. To bridge this gap, we assessed whether co-infection of chinchillas with M. catarrhalis and RSV would facilitate ascension of M. catarrhalis from the nasopharynx into the middle ear. Chinchillas were challenged intranasally with M. catarrhalis followed 48 hours later by intranasal challenge with RSV. Within 7 days, 100% of nasopharynges were colonized with M. catarrhalis and homogenates of middle ear mucosa were also culture-positive. Moreover, within the middle ear space, the mucosa exhibited hemorrhagic foci, and a small volume of serosanguinous effusion was present in one of six ears. To improve upon this model, and based on epidemiologic data, nontypeable Haemophilus influenzae (NTHI) was included as an additional bacterial co-pathogen via intranasal administration four days before M. catarrhalis challenge. With this latter protocol, M. catarrhalis was cultured from the nasopharynx and middle ear homogenates of a maximum of 88% and 79% animals, respectively, for up to 17 days after intranasal challenge with M. catarrhalis. Additionally, hemorrhagic foci were observed in 79% of middle ears upon sacrifice. Thus, these data demonstrated that co-infection with RSV and NTHI predisposed to M. catarrhalis-induced ascending experimental OM. This model can be used both in studies of pathogenesis as well as to investigate strategies to prevent or treat OM due to M. catarrhalis.
Article Reference ERK2-dependent activation of c-Jun is required for nontypeable Haemophilus influenzae-induced CXCL2 upregulation in inner ear fibrocytes.
The inner ear, composed of the cochlea and the vestibule, is a specialized sensory organ for hearing and balance. Although the inner ear has been known as an immune-privileged organ, there is emerging evidence indicating an active immune reaction of the inner ear. Inner ear inflammation can be induced by the entry of proinflammatory molecules derived from middle ear infection. Because middle ear infection is highly prevalent in children, middle ear infection-induced inner ear inflammation can impact the normal development of language and motor coordination. Previously, we have demonstrated that the inner ear fibrocytes (spiral ligament fibrocytes) are able to recognize nontypeable Haemophilus influenzae, a major pathogen of middle ear infection, and upregulate a monocyte-attracting chemokine through TLR2-dependent NF-κB activation. In this study, we aimed to determine the molecular mechanism involved in nontypeable H. influenzae-induced cochlear infiltration of polymorphonuclear cells. The rat spiral ligament fibrocytes were found to release CXCL2 in response to nontypeable H. influenzae via activation of c-Jun, leading to the recruitment of polymorphonuclear cells to the cochlea. We also demonstrate that MEK1/ERK2 signaling pathway is required for nontypeable H. influenzae-induced CXCL2 upregulation in the rat spiral ligament fibrocytes. Two AP-1 motifs in the 5'-flanking region of CXCL2 appeared to function as a nontypeable H. influenzae-responsive element, and the proximal AP-1 motif was found to have a higher binding affinity to nontypeable H. influenzae-activated c-Jun than that of the distal one. Our results will enable us better to understand the molecular pathogenesis of middle ear infection-induced inner ear inflammation.
Article Reference Biological roles of nontypeable Haemophilus influenzae type IV pilus proteins encoded by the pil and com operons.
We previously demonstrated that one or more products of the genes in the pil and com gene clusters of the opportunistic human respiratory pathogen nontypeable Haemophilus influenzae (NTHI) are required for type IV pilus (Tfp) biogenesis and function. Here, we have now demonstrated that the pilABCD and comABCDEF gene clusters are operons and that the product of each gene is essential for normal pilus function. Mutants with nonpolar deletions in each of the 10 pil and com genes had an adherence defect when primary human airway cells were used as the target. These mutants were also diminished in their ability to form a biofilm in vitro and, additionally, were deficient in natural transformation. Collectively, our data demonstrate that the product of each gene within these operons is required for the normal biogenesis and/or function of NTHI Tfp. Based on the similarity of PilA to other type IV pilins, we further predicted that the product of the pilA gene would be the major pilin subunit. Toward that end, we also demonstrated by immunogold labeling and mass spectrometry that PilA is indeed the majority type IV pilin protein expressed by NTHI. These new observations set the stage for experiments designed to dissect the function of each of the proteins encoded by genes within the pil and com gene clusters. The ability to characterize individual proteins with vital roles in NTHI colonization or pathogenesis has the potential to reduce the burden of NTHI-induced diseases through development of a Tfp-derived vaccine or a pilus-directed therapeutic.
Article Reference Antibody against Haemophilus influenzae protein D in patients with chronic conditions causing secondary immunodeficiency.
Prevalence of non-typeable Haemophilus influenzae (NTHi) in the etiology of invasive infections in immunocompromised individuals is increasing. Serum IgG antibody levels to H. influenzae protein D (PD) were significantly lower in adults suffering from chronic conditions causing secondary immunodeficiency (COPD, cancer, chronic renal failure, and diabetes) compared to age-matched healthy controls. A lack of naturally acquired antibody against this highly conserved antigen may contribute to an increased susceptibility to invasive NTHi disease. As COPD patients frequently infected with NTHi during disease exacerbations were unable to develop antibody response to PD, such defect could potentially contribute to the pathogenesis. Considering that pediatric PD-containing vaccines show protective effect against NTHi-caused otitis media, our data suggest the possibility of improving the defense against NTHi in COPD patients using immunization against PD. Although more research on the role of anti-PD antibody in protection against invasive NTHi disease is warranted, development of adult formulations of PD-based vaccines may be advantageous for prevention of severe infections in immunocompromised individuals.
Article Reference Elastase/LPS-exposed mice exhibit impaired innate immune responses to bacterial challenge: role of scavenger receptor A.
Nontypeable Haemophilus influenzae (NTHi) is an important bacterial pathogen associated with lower respiratory tract colonization and with acute exacerbations and disease progression in chronic obstructive pulmonary disease (COPD). Why the immune system fails to eliminate NTHi and the exact contribution of the organism to COPD progression are not well understood, in part because we lack an animal model that mimics all aspects of COPD. For this study, we used an established murine model that exhibits typical features of COPD. Elastase/LPS-exposed mice infected with NTHi showed persistence of bacteria up to 5 days after infection, whereas mice exposed to elastase, LPS, or PBS cleared all bacteria by 3 days. Elastase/LPS-exposed mice also showed sustained lung neutrophilic inflammation, goblet cell metaplasia, airway hyperresponsiveness, and progression of emphysema at 15 days after infection. Alveolar macrophages isolated from elastase/LPS-exposed mice showed impaired bacterial phagocytosis, reduced expression of MARCO and of mannose receptor, and absent expression of scavenger receptor-A (SR-A). Neutralization of SR-A significantly decreased phagocytosis of NTHi by normal alveolar macrophages. Our results suggest that elastase/LPS-exposed mice show impaired bacterial clearance and sustained lung inflammation. Lack of SR-A expression may, in part, be responsible for impaired phagocytosis of bacteria by alveolar macrophages of elastase/LPS-exposed mice. These data validate the suitability of elastase/LPS model for investigating NTHi pathogenesis and progression of disease in COPD.
Article Reference Critical role of type 1 plasminogen activator inhibitor (PAI-1) in early host defense against nontypeable Haemophilus influenzae (NTHi) infection.
Respiratory systems are constantly being challenged by pathogens. Lung epithelial cells serve as a first line of defense against microbial pathogens by detecting pathogen-associated molecular patterns (PAMPs) and activating downstream signaling pathways, leading to a plethora of biological responses required for shaping both the innate and adaptive arms of the immune response. Acute-phase proteins (APPs), such as type 1 plasminogen activator inhibitor (PAI-1), play important roles in immune/inflammatory responses. PAI-1, a key regulator for fibrinolysis and coagulation, acts as an APP during acute phase response (APR) such as acute lung injury (ALI), inflammation, and sepsis. However, the role of PAI-1 in the pathogenesis of these diseases still remains unclear, especially in bacterial pneumonia. In this study, we showed that PAI-1 expression is upregulated following nontypeable Haemophilus influenzae (NTHi) infection. PAI-1 knockout (KO) mice failed to generate early immune responses against NTHi. Failure of generating early immune responses in PAI-1 KO mice resulted in reduced bacterial clearance and prolonged disease process, which in turn led to enhanced inflammation at late stage of infection. Moreover, we also found that NTHi induces PAI-1 via activation of TLR2-MyD88-MKK3-p38 MAPK signaling pathway. These data suggest that PAI-1 plays critical role in earl host defense response against NTHi infection. Our study thus reveals a novel role of PAI-1 in infection caused by NTHi, one of the most common gram-negative bacterial pathogens in respiratory systems.
Article Reference Elicitation of epithelial cell-derived immune effectors by outer membrane vesicles of nontypeable Haemophilus influenzae.
Outer membrane vesicles (OMVs) are produced by all Gram-negative microorganisms studied to date. The contributions of OMVs to biological processes are diverse and include mediation of bacterial stress responses, selective packaging and secretion of virulence determinants, modulation of the host immune response, and contributions to biofilm formation and stability. First characterized as transformasomes in Haemophilus, these membranous blebs facilitate transfer of DNA among bacteria. Nontypeable Haemophilus influenzae (NTHI), an opportunistic pathogen of the upper and lower respiratory tracts, produces OMVs in vivo, but there is a paucity of information regarding both the composition and role of OMVs during NTHI colonization and pathogenesis. We demonstrated that purified NTHI vesicles are 20 to 200 nm in diameter and contain DNA, adhesin P5, IgA endopeptidase, serine protease, and heme utilization protein, suggesting a multifaceted role in virulence. NTHI OMVs can bind to human pharyngeal epithelial cells, resulting in a time- and temperature-dependent aggregation on the host cell surface, with subsequent internalization. OMVs colocalize with the endocytosis protein caveolin, indicating that internalization is mediated by caveolae, which are cholesterol-rich lipid raft domains. Upon interaction with epithelial cells, NTHI OMVs stimulate significant release of the immunomodulatory cytokine interleukin-8 (IL-8) as well as the antimicrobial peptide LL-37. Thus, we demonstrated that NTHI OMVs contain virulence-associated proteins that dynamically interact with and invade host epithelial cells. Beyond their ability to mediate DNA transfer in Haemophilus, OMV stimulation of host immunomodulatory cytokine and antimicrobial peptide release supports a dynamic role for vesiculation in NTHI pathogenesis and clinically relevant disease progression.
Article Reference Role of nontypeable Haemophilus influenzae in otitis media and chronic obstructive pulmonary disease.
In both infants and adults, infections with non-typeable Haemophilus influenzae (NTHI) results in morbidity and mortality. NTHI strains are the leading cause of bacterial otitis media infections (both acute and recurrent) in young children and are also responsible for chronic obstructive pulmonary disease (COPD) exacerbations in current and former smokers. The realization that NTHI causes serious infections in humans has generated interest in the study of the pathogenesis associated with this bacterium and also stimulated considerable efforts towards the evaluation of candidate vaccines that will elicit protective immunity. As NTHI is exclusively a human pathogen and has not been associated with any diseases in other mammals, special efforts have been necessary to establish animal models of NTHI infection to generate useful data on the pathogenesis of infection and efficacy of potential vaccines. This article provides a brief summary of the role of NTHI in disease and the work that has been accomplished by us and several other investigators.
Article Reference Murine model of chronic respiratory inflammation.
The respiratory mucosa is exposed to the external environment each time we breathe and therefore requires a robust and sophisticated immune defense system. As with other mucosal sites, the respiratory mucosal immune system must balance its response to pathogens while also regulating inflammatory immune cell-mediated tissue damage. In the airways, a failure to tightly control immune responses to a pathogen can result in chronic inflammation and tissue destruction with an overzealous response being deleterious for the host. Chronic obstructive pulmonary disease (COPD) is the fourth most common cause of death in the US and both the prevalence of and mortality rate of this disease is increasing annually. COPD is characterized by intermittent disease exacerbation. The causal contribution of bacterial infections to exacerbations of COPD is now widely accepted, accounting for at least 50% of all exacerbations. Non-typeable Haemophilus influenzae and Moraxella catarrhalis (both gram-negative bacteria) along with Streptococcus pneumoniae (a gram-positive bacterium) are the three most common bacterial pathogens that cause respiratory tract infections in COPD patients. The colonization of bacteria in the lower airways is similar to a low-grade smoldering infection that induces chronic airway inflammation. Chronic low-grade infection can induce a persistent inflammatory response in the airways and parenchyma. Inefficient removal of bacteria from the lower respiratory tract is characteristic of chronic bronchitis. Inflammation is believed to be central to the pathogenesis of exacerbations, but a clear understanding of the inflammatory changes during an exacerbation of COPD has yet to emerge. As bacterial colonization of the lung in COPD patients is a chronic inflammatory condition highlighted by frequent bouts of exacerbation and clearance, we sought to reproduce this chronic pathogen-mediated inflammation in a murine model by repeatedly delivering the intact, whole, live bacteria intra-tracheally to the lungs.