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1.
J Bacteriol ; 198(19): 2619-30, 2016 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-27044626

RESUMEN

UNLABELLED: Nontypeable Haemophilus influenzae (NTHI), a commensal of the human nasopharynx (hNP), is a common cause of biofilm-associated diseases of the respiratory tract. However, NTHI biofilm biology at the average hNP temperature, i.e., 34°C, has not been well studied. Here we grew NTHI biofilms at 34°C and 37°C, to evaluate relative biofilm growth, expression, and function of the type IV pilus (Tfp), a critical adhesin important for NTHI biofilm formation. The kinetics and regulation of Tfp expression in NTHI biofilms are unclear, especially at 34°C. Tfp expression, as estimated by pilA promoter activity, was distributed throughout the biofilms, with a unique pattern that was dependent on temperature, time in culture, and position within the maturing biofilm. Tfp expression was required for the formation of the characteristic tower structures of NTHI biofilms and was significantly upregulated in NTHI biofilms formed at 34°C versus 37°C. This increase correlated with significantly greater twitching motility at 34°C than at 37°C. Treatment with antisera targeting the major subunit of Tfp (PilA) significantly inhibited NTHI biofilm formation at both temperatures, confirming the importance of this critical adhesin in biofilm formation. Additionally, treatment of preestablished biofilms with antisera against PilA significantly decreased biofilm biomass and mean thickness at both temperatures. These results demonstrated a pivotal role for Tfp in NTHI biofilm formation and stability at the temperature of the hNP, and they underscore the utility of PilA as a vaccine candidate for treatment and/or prevention of NTHI biofilm-associated diseases. IMPORTANCE: NTHI is an important cause of chronic respiratory tract infections, including otitis media, chronic rhinosinusitis, and exacerbations of chronic obstructive pulmonary disease and cystic fibrosis. The chronic and recurrent nature of these diseases is attributed to the presence of bacterial biofilms, which are highly resistant to antimicrobials. We characterized NTHI biofilm growth and expression of PilA, the major subunit of the Tfp, at the temperature of the hNP, which is the commensal habitat of NTHI. Our results expand the current understanding of the role of Tfp during biofilm formation and maturation at the temperature of both the hNP and the middle ear, and they strengthen support for PilA as a vaccine candidate for the prevention and treatment of NTHI biofilm-associated diseases.


Asunto(s)
Biopelículas/crecimiento & desarrollo , Fimbrias Bacterianas/metabolismo , Haemophilus influenzae/clasificación , Haemophilus influenzae/fisiología , Nasofaringe/fisiología , Temperatura , Técnicas Bacteriológicas , Proteínas Fimbrias/genética , Proteínas Fimbrias/metabolismo , Fimbrias Bacterianas/genética , Humanos , Regulación hacia Arriba
2.
Mol Microbiol ; 96(2): 276-92, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25597921

RESUMEN

Despite resulting in a similar overall outcome, unlike antibodies directed against the DNABII protein, integration host factor (IHF), which induce catastrophic structural collapse of biofilms formed by nontypeable Haemophilus influenzae (NTHI), those directed against a recombinant soluble form of PilA [the majority subunit of Type IV pili (Tfp) produced by NTHI], mediated gradual 'top-down' dispersal of NTHI from biofilms. This dispersal occurred via a mechanism that was dependent upon expression of both PilA (and by inference, Tfp) and production of AI-2 quorum signaling molecules by LuxS. The addition of rsPilA to a biofilm-targeted therapeutic vaccine formulation comprised of IHF plus the powerful adjuvant dmLT and delivered via a noninvasive transcutaneous immunization route induced an immune response that targeted two important determinants essential for biofilm formation by NTHI. This resulted in significantly earlier eradication of NTHI from both planktonic and adherent populations in the middle ear, disruption of mucosal biofilms already resident within middle ears prior to immunization and rapid resolution of signs of disease in an animal model of experimental otitis media. These data support continued development of this novel combinatorial immunization approach for resolution and/or prevention of multiple diseases of the respiratory tract caused by NTHI.


Asunto(s)
Anticuerpos Antibacterianos/inmunología , Anticuerpos/inmunología , Proteínas Bacterianas/inmunología , Biopelículas , Liasas de Carbono-Azufre/inmunología , Fimbrias Bacterianas/inmunología , Infecciones por Haemophilus/microbiología , Haemophilus influenzae/inmunología , Otitis Media/microbiología , Animales , Proteínas Bacterianas/genética , Liasas de Carbono-Azufre/genética , Chinchilla , Femenino , Fimbrias Bacterianas/genética , Infecciones por Haemophilus/inmunología , Infecciones por Haemophilus/prevención & control , Haemophilus influenzae/genética , Haemophilus influenzae/fisiología , Humanos , Inmunización , Masculino , Otitis Media/inmunología , Otitis Media/prevención & control
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