Nasopharyngeal Colonization with Nontypeable
            <i>Haemophilus influenzae</i>
            in Chinchillas

Yang, Yanping; Loosmore, Sheena M.; Underdown, Brian J.; Klein, Michel

doi:10.1128/iai.66.5.1973-1980.1998

Cited by 17 publications

(8 citation statements)

References 30 publications

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“…Efforts to develop a successful vaccine against NTHi are ongoing, with several antigenic virulence factors that contribute to the early stages of bacterial colonization under consideration as potential vaccine candidates (11)(12)(13). Several proteins are under investigation as vaccine candidates (11,14), including fimbriae (OMP P5-homologous fimbriae (15)), outer membrane proteins (OMPs) (P2, P6) (16,17), transferrin binding proteins (TbpB) (18), protein D (19), PilA (major subunit of type IV pili) (20), Hia (21), Hap (22), and HMW1/2 (14,23). However, vaccine development is impeded by the high variability and heterogeneity of NTHi, especially of their surface molecules (13,24).…”

Section: Introductionmentioning

confidence: 99%

Phase-Variable Glycosylation in Nontypeable Haemophilus influenzae

Elango

Schulz

2019

J. Proteome Res.

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Non-typeable Haemophilus influenzae (NTHi) is a leading cause of respiratory tract infections worldwide and continues to be a global health burden. Adhesion and colonisation of host cells are crucial steps in bacterial pathogenesis, and in many strains of NTHi interaction with the host is mediated by the high molecular weight adhesins HMW1A and HMW2A. These adhesins are N-glycoproteins which are modified by cytoplasmic glycosyltransferases HMW1C and HMW2C. Phase variation in the number of short sequence repeats in the promoters of hmw1A and hmw2A directly affects their expression. Here, we report the presence of similar variable repeat elements in the promoters of hmw1C and hmw2C in diverse NTHi isolates. In an ex vivo assay, we systematically altered substrate and glycosyltransferase expression and showed that both of these factors affected the site-specific efficiency of glycosylation on HMW-A. Glycosylation occupancy was incomplete at many sites, variable between sites, and generally lower close to the C-terminus of HMW-A. We investigated the causes of this variability. As HMW-C glycosylates HMW-A in the cytoplasm, we tested how secretion affected glycosylation on HMW-A and showed that retaining HMW-A in the cytoplasm indeed increased glycosylation occupancy across the full length of the protein. Sitedirected mutagenesis showed that HMW-C had no inherent preference for glycosylating asparagines in NxS or NxT sequons. This work provides key insights into factors contributing to the heterogenous modifications of NTHi HMW-A adhesins, expands knowledge of NTHi population diversity and pathogenic capability, and is relevant to vaccine design for NTHi and related pathogens..

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Section: Introductionmentioning

confidence: 99%

Phase-Variable Glycosylation in Nontypeable Haemophilus influenzae

Elango

Schulz

2019

J. Proteome Res.

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“…Animal models of nasopharyngeal colonization by microbial pathogens, including Streptococcus pneumoniae (20,33,34) and Haemophilus influenzae (15,35), have been developed for the study of bacterial colonization factors and protective mucosal immunity. Although numerous animal models of staphylococcal infection have contributed to the knowledge of virulence factors involved in disease, only a few reported studies have examined the interactions of S. aureus with the nasal mucosa in an animal model (23,24,27).…”

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confidence: 99%

Development and Characterization of a Staphylococcus aureus Nasal Colonization Model in Mice

1999

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Staphylococcus aureus nasal carriage is a risk factor for infection in humans, particularly in the hospital environment. Attenuation of carriage has proven effective in reducing the prevalence of infection in some high-risk groups. To study staphylococcal factors that influence nasal colonization, a mouse model of S. aureus nasal colonization was developed. Mice were inoculated intranasally with S. aureus Reynolds, and nasal carriage was evaluated by quantitating cultures of the nasal tissues from mice sacrificed at various time points after inoculation. The majority of mice inoculated with 108 CFU of S. aureusmaintained nasal carriage for at least 20 days. Nasal colonization rates were similar for inbred (BALB/c and C57BL/6) and outbred (ICR) mice. Colonization was not affected by mouse passage of strain Reynolds. Lower inoculum doses (<107 CFU) resulted in reduced colonization after 7 days. However, mice given streptomycin in their drinking water developed long-term carriage of S. aureus, and they were colonized with inocula as low as 105 CFU. Nasal colonization was also established with two other S. aureus strains (one strain each of human and murine origins). S. aureus recovered from the nares of experimentally colonized mice expressed high levels of capsule, and the ability of a capsule-defective mutant to persist in the nares was reduced in comparison to that of the parent strain. This nasal colonization model should prove useful for studies of factors that mediate S. aureus colonization and for assessment of targets for antimicrobial intervention or vaccine development.

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“…The first essential step for colonisation for NTHi is adhering to the respiratory epithelium. This is achieved by use of one or more different adhesins which are not all ubiquitous throughout NTHi [16,22,23,37,84,94]. They are tools not only for adherence and colonisation but also demonstrate secondary roles in immune evasion and pathogenesis through biofilm development and migration deeper into the basement membrane due to the interactions with constituents of the ECM [27,62,64].…”

Section: Discussionmentioning

confidence: 99%

“…Hia and Hmw are highly immunogenic and are targets for opsonophagocytic activity [16,31]. hia however is only observed in 8.3%-33% of strains and therefore may not be effective as a single target for immunisation purposes [22,27,36,94].…”

Section: Immunogenicity and Potential Vaccine Candidatesmentioning

confidence: 99%

“…Mucins, defensive protein structures in the extracellular matrix (ECM), evasion of the immune system and penetration of the epithelial layer are all obstacles that need to be conquered for successful adherence and colonisation to occur. Like many other bacteria, NTHi have evolved to overcome these defensive mechanisms with adhesin proteins having an important role in doing so [16]. Protein expression of Hia and Hmw is mediated by phase variation.…”

mentioning

confidence: 99%

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The adhesins of non-typeableHaemophilus influenzae

Osman

Jefferies

Woelk

et al. 2018

Expert Review of Anti-infective Therapy

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Nontypeable Haemophilus influenzae (NTHi) is an opportunistic pathogen of the respiratory tract and the greatest contributor to invasive Haemophilus disease. Additionally, in children, NTHi is responsible for the majority of otitis media (OM) which can lead to chronic infection and hearing loss. In adults, NTHi infection in the lungs is responsible for the onset of acute exacerbations in chronic obstructive pulmonary disease (COPD). Unfortunately, there is currently no vaccine available to protect against NTHi infections. Areas covered: NTHi uses an arsenal of adhesins to colonise the respiratory epithelium. The adhesins also have secondary roles that aid in the virulence of NTHi, including mechanisms that avoid immune clearance, adjust pore size to avoid antimicrobial destruction, form micro-colonies and invoke phase variation for protein mediation. Bacterial adhesins can also be ideal antigens for subunit vaccine design due to surface exposure and immunogenic capabilities. Expert commentary: The host-pathogen interactions of the NTHi adhesins are not fully investigated. The relationship between adhesins and the extracellular matrix (ECM) play a part in the success of NTHi colonisation and virulence by immune evasion, migration and biofilm development. Further research into these immunogenic proteins would further our understanding and enable a basis for better combatting NTHi disease.

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Nasopharyngeal Colonization with Nontypeable Haemophilus influenzae in Chinchillas

Cited by 17 publications

References 30 publications

Phase-Variable Glycosylation in Nontypeable Haemophilus influenzae

Phase-Variable Glycosylation in Nontypeable Haemophilus influenzae

Development and Characterization of a Staphylococcus aureus Nasal Colonization Model in Mice

The adhesins of non-typeableHaemophilus influenzae

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