transforming-growth-factor-beta and Pneumococcal-Infections

Pneumonia, the most typical and frequent lower respiratory tract infection (LRTI), is a leading cause of health problems in the United States. Bacteria represent the most prevailing cause of pneumonia in both children and adults. Although pneumonia with a single bacterial infection is common, a significant portion of patients with pneumonia is polymicrobial. This infection is often complexed with other physiological factors such as cytokines and growth factors. Nontypeable Haemophilus influenzae (NTHi) is the most frequently recovered Gram-negative bacterial pathogen in the respiratory system and induces strong inflammatory responses. NTHi also synergizes with other respiratory pathogens, such as Streptococcus pneumoniae and respiratory viruses and pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α). It is noteworthy that NTHi not only synergizes with growth factors such as transforming growth factor-beta (TGF-β), but also utilizes growth factor receptors such as TGF-β receptor and epidermal growth factor receptor (EGFR), to enhance inflammatory responses. Although appropriate inflammation is a protective response against invading pathogens, an uncontrolled inflammatory response is often detrimental to the host. Thus, inflammation must be tightly regulated. The human immune system has evolved strategies for controlling overactive inflammatory response. One such important mechanism is via regulation of negative feedback regulators for inflammation. CYLD, a multifunctional deubiquitinase, was originally reported as a tumor suppressor, but was recently identified as a negative regulator for nuclear factor-kappa B (NF-κB) signaling. It is induced by NTHi and TNF-α via a NF-κB-dependent mechanism, thereby serving as an inducible negative feedback regulator for tightly controlling inflammation in NTHi infection.

Topics: Animals; Deubiquitinating Enzyme CYLD; ErbB Receptors; Feedback, Physiological; Haemophilus Infections; Haemophilus influenzae; Humans; NF-kappa B; Pneumococcal Infections; Pneumonia, Bacterial; Respiratory System; Signal Transduction; Streptococcus pneumoniae; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Tumor Suppressor Proteins; Ubiquitin-Protein Ligases

Topics: Animals; Asthma; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Coinfection; Disease Models, Animal; Disease Susceptibility; Humans; Influenza A virus; Influenza, Human; Interferon-gamma; Mice, Inbred BALB C; Mice, Inbred C57BL; Pneumococcal Infections; Streptococcus pneumoniae; Survival Analysis; Transforming Growth Factor beta

Pneumococcal carriage in the nasopharynx is a primary means of transmission and a necessary prerequisite for pneumococcal disease.. We analyzed the relationship between expressions of Foxp3+ regulatory T (Treg) cells and Th17 cells, and pneumococcal carriage in the adenoids of children who were either positive or negative for pneumococci.. We collected adenoidal tissue and nasopharyngeal swab samples from children undergoing an adenoidectomy. Adenoidal mononuclear cells were isolated, cultured and then stimulated with culture concentrated supernatant (CCS) obtained from a D39 bacterial strain.. Foxp3+ Treg cells were upregulated and Th17 cells were downregulated in populations of adenoidal mononuclear cells obtained from the pneumococcus-positive group. Following CCS stimulation, the increment in Foxp3+ Treg cells in the pneumococcus-positive group was significantly greater than that in the pneumococcus-negative group, while the increment in Th17 cells was less as compared to that in the pneumococcus-negative group. These results were consistent with variations in levels of Foxp3 mRNA and retinoic acid receptor-related orphan receptor-γt mRNA in adenoidal mononuclear cells. Levels of IL-17A and IL-6 in adenoid tissue were higher in the pneumococcus-negative group, and the levels of TGF-β in adenoid tissue were lower in the pneumococcus-negative group compared to the pneumococcus-positive group. Pneumococcal carriage in children was closely associated with the expressions of Foxp3+ Treg and Th17 cells in the adenoid.. Upregulation of Foxp3+ Treg cells might downregulate the production of Th17 cells in the adenoid, resulting in decreased scavenging of Streptococcus pneumoniae and chronic pneumococcal carriage.

Topics: Adenoids; Carrier State; Child; Child, Preschool; Female; Forkhead Transcription Factors; Humans; Interleukin-17; Interleukin-6; Male; Nasopharynx; Nuclear Receptor Subfamily 1, Group F, Member 3; Pneumococcal Infections; RNA, Messenger; Streptococcus pneumoniae; T-Lymphocytes, Regulatory; Th17 Cells; Transforming Growth Factor beta

Granulation tissue is common in otitis media (OM), yet little is known about the signaling pathways in the formation of granulation tissue in response to infections. In this study, we sought to investigate the activation of the transforming growth factor beta (TGF-beta) signaling pathway in the formation of granulation tissue in response to middle ear pathogens.. Rat OM models were made by inoculating pneumococcus type 6A or nontypeable Haemophilus influenzae into the middle ear cavity or by obstructing the eustachian tube. Various pathway activities in the middle ear mucosa were analyzed with microarrays.. The TGF-beta signaling pathway was highly regulated in the middle ear cleft with bacterial OM, but not in the ears with eustachian tube obstruction. In ears with bacterial OM, the TGF-beta signaling pathway products were higher in Haemophilus-infected ears than in pneumococcus-infected ears.. Bacterial OM triggers granulation tissue to thrive in the middle ear cleft of rats. Nontypeable H influenzae is more potent than pneumococcus type 6A in the formation of granulation tissue. Eustachian tube obstruction alone did not contribute to granulation tissue formation in the middle ear.

Topics: Animals; Collagen; Down-Regulation; Ear, Middle; Epithelial Cells; Eustachian Tube; Fibroblasts; Fibronectins; Gene Expression Profiling; Granulation Tissue; Haemophilus Infections; Microarray Analysis; Models, Animal; Otitis Media; Pneumococcal Infections; Rats; Rats, Sprague-Dawley; Receptors, Transforming Growth Factor beta; Reverse Transcriptase Polymerase Chain Reaction; RNA; Signal Transduction; Smad Proteins, Receptor-Regulated; Transforming Growth Factor beta; Up-Regulation

Streptococcus pneumoniae and Haemophilus influenzae are human pathogens that often asymptomatically colonize the mucosal surface of the upper respiratory tract, but also occasionally cause invasive disease. The ability of these species to traverse the epithelium of the airway mucosa was modeled in vitro using polarized respiratory epithelial cells in culture. Migration across the epithelial barrier was preceded by loss of transepithelial resistance. Membrane products of S. pneumoniae that included lipoteichoic acid induced disruption of the epithelial barrier in a Toll-like receptor 2-dependent manner. This result correlates with a recent genetic study that associates increased TLR2 signaling with increased rates of invasive pneumococcal disease in humans. Loss of transepithelial resistance by the TLR2 ligand correlated with activation of p38 MAP kinase and transforming growth factor (TGF)-beta signaling. Activation of p38 MAPK and TGF-beta signaling in epithelial cells upon nasal infection with S. pneumoniae was also demonstrated in vivo. Inhibition of either p38 MAPK or TGF-beta signaling was sufficient to inhibit the migration of S. pneumoniae or H. influenzae. Our data shows that diverse bacteria utilize common mechanisms, including MAPK and TGF-beta signaling pathways to disrupt epithelial barriers and promote invasion.

Topics: Animals; Caco-2 Cells; Cell Membrane; Cell Polarity; Epithelial Cells; Female; Haemophilus Infections; Haemophilus influenzae; Humans; Lipopolysaccharides; MAP Kinase Signaling System; Mice; Models, Biological; p38 Mitogen-Activated Protein Kinases; Pneumococcal Infections; Respiratory Mucosa; Streptococcus pneumoniae; Teichoic Acids; Toll-Like Receptor 2; Transforming Growth Factor beta

Acute otitis media (AOM) is the most common reason for outpatient antimicrobial therapy. Mixed infections pose a potential problem, since the first-line drug used for the treatment of AOM, amoxicillin, can be neutralized by beta-lactamase-producing pathogens of the upper respiratory tract. To study the effects of a 5-day course of amoxicillin on a mixed middle ear infection, rats were challenged with Streptococcus pneumoniae alone or in combination with beta-lactamase-producing nontypeable Haemophilus influenzae. Amoxicillin was introduced at the clinical peak of the infection. Local and systemic changes were monitored by otomicroscopy, bacterial culture, and analysis of histological changes and the expression of the transforming growth factor beta (TGF-beta) gene. beta-Lactamase-producing H. influenzae did not demonstrate an ability to protect S. pneumoniae. Amoxicillin eradicated the pneumococci in all treated animals but increased to some degree the ability of H. influenzae to persist at the site of infection. Thus, only an insignificant acceleration of the resolution of the AOM caused by a mixture of pathogens was observed during treatment. Moderate to major morphological changes could not be avoided by treatment of the mixed infections, but a slight downregulation of TGF-beta expression was observed. In contrast to infections caused by a single pathogen, the mixed infections induced white plaques in the tympanic membrane at a remarkably high frequency independent of treatment. These experimental findings constitute support for further studies of antimicrobial drugs and AOM caused by bacteria with and without mechanisms of antibiotic resistance.

Topics: Amoxicillin; Animals; beta-Lactamases; Culture Media; Ear, Middle; Haemophilus Infections; Haemophilus influenzae; Male; Otitis Media; Penicillins; Pneumococcal Infections; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Streptococcus pneumoniae; Transforming Growth Factor beta; Treatment Outcome

Acute otitis media (AOM) elicits potent inflammatory responses from the cells of the middle ear mucosa as well as from infiltrating leukocytes. To explore host responses during experimental AOM induced by Streptococcus pneumoniae type 3 and nontypeable Haemophilus influenzae (NTHi), otomicroscopy findings and expression of cytokine genes in the middle ear were monitored up to 1 month postinoculation. The mucosa and infiltrating cells responded rapidly to the bacterial challenge. Otomicroscopically, AOM appeared 1 day after NTHi inoculation and 3 days after pneumococcus inoculation. Pneumococcal AOM was more severe than NTHi otitis, but in general, lower transcript levels were detected in pneumococcus-infected than in NTHi-infected animals. Interleukin-6 (IL-6) mRNA levels peaked at 3 to 6 h for both pneumococcus-infected and NTHi-infected animals. IL-1alpha, tumor necrosis factor alpha, and IL-10 mRNA levels peaked at 6 h for NTHi otitis and 1 to 3 days for pneumococcal otitis. Comparing otomicroscopy with expression profiles, it would appear that the majority of cytokine mRNAs had passed their peak before the AOM diagnosis could be made clinically. Only transforming growth factor beta mRNA followed a slower time course, peaking very late and continuing expression even after the AOM was otomicroscopically resolved. IL-2 and IL-4 mRNAs were not detected in any animal at any time. Most of the investigated cytokines are very early markers for AOM and may be involved in initiation of inflammation, but they would be poor targets for pharmacological manipulation since their levels decline before clinical signs appear.

Topics: Acute Disease; Animals; Base Sequence; Cytokines; Disease Models, Animal; DNA Primers; Gene Expression; Haemophilus Infections; Haemophilus influenzae; Humans; Interleukins; Kinetics; Male; Otitis Media; Pneumococcal Infections; Rats; Rats, Sprague-Dawley; RNA, Messenger; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha