Haemophilin-Producing Strains of Haemophilus haemolyticus Protect Respiratory Epithelia from NTHi Colonisation and Internalisation

Atto, Brianna; Kunde, Dale; Gell, David A.; Tristram, Stephen

doi:10.3390/pathogens10010029

Cited by 6 publications

(9 citation statements)

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“…Production of the Hpl haemophore has previously been shown to mediate the in vitro inhibitory capacity of Hh against NTHi growth and the adherence/invasion of model respiratory cell lines by restricting NTHi access to the essential nutrient haem [ 22 , 23 , 24 ]. Although we postulate that the same mechanism may be involved here, the study design reports on the presence of the hpl coding region and does not assess phenotypic production of the Hpl protein.…”

Section: Resultsmentioning

confidence: 99%

“…Although we postulate that the same mechanism may be involved here, the study design reports on the presence of the hpl coding region and does not assess phenotypic production of the Hpl protein. We have previously shown that even among Hh strains containing identical hpl ORF sequences, some strains lack the capacity to express hpl and produce the Hpl protein that mediates NTHi inhibitory activity in vitro [ 23 , 24 , 44 ]. However, the majority (16/17) of Hh- hpl + detectable by our PCR assay from our culture collection produce Hpl and elicit NTHi-inhibitory activity ( Table S4 ), and there are no incidences of Hpl production in strains that do not contain the hpl ORF.…”

Section: Resultsmentioning

confidence: 99%

“…One avenue gaining attention is the use of upper respiratory tract commensals, which may have utility in altering the pharyngeal habitability for pathogens such as NTHi [ 21 ]. We have previously shown that some strains of the closely related respiratory tract commensal Haemophilus haemolyticus (Hh) produce a haem-binding protein, haemophilin (Hpl), that has been shown to inhibit NTHi growth in vitro [ 22 , 23 ] and interactions with host cells in model respiratory cell lines [ 24 ]. NTHi-inhibitory activity in these models was speculated to be mediated by Hpl haem binding that limited NTHi access to the essential nutrient haem [ 22 ], which is required for growth, survival, and pathogenicity [ 25 ].…”

Section: Introductionmentioning

confidence: 99%

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Oropharyngeal Carriage of hpl-Containing Haemophilus haemolyticus Predicts Lower Prevalence and Density of NTHi Colonisation in Healthy Adults

et al. 2021

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Nontypeable Haemophilus influenzae (NTHi) is a major respiratory pathogen that initiates infection by colonising the upper airways. Strategies that interfere with this interaction may therefore have a clinically significant impact on the ability of NTHi to cause disease. We have previously shown that strains of the commensal bacterium Haemophilus haemolyticus (Hh) that produce a novel haem-binding protein, haemophilin, can prevent NTHi growth and interactions with host cells in vitro. We hypothesized that natural pharyngeal carriage of Hh strains with the hpl open reading frame (Hh-hpl+) would be associated with a lower prevalence and/or density of NTHi colonisation in healthy individuals. Oropharyngeal swabs were collected from 257 healthy adults in Australia between 2018 and 2019. Real-time PCR was used to quantitatively compare the oropharyngeal carriage load of NTHi and Hh populations with the Hh-hpl+ or Hh-hpl− genotype. The likelihood of acquiring/maintaining NTHi colonisation status over a two- to six-month period was assessed in individuals that carried either Hh-hpl− (n = 25) or Hh-hpl+ (n = 25). Compared to carriage of Hh-hpl− strains, adult (18–65 years) and elderly (>65 years) participants that were colonised with Hh-hpl+ were 2.43 or 2.67 times less likely to carry NTHi in their oropharynx, respectively. Colonisation with high densities of Hh-hpl+ correlated with a low NTHi carriage load and a 2.63 times lower likelihood of acquiring/maintaining NTHi colonisation status between visits. Together with supporting in vitro studies, these results encourage further investigation into the potential use of Hh-hpl+ as a respiratory probiotic candidate for the prevention of NTHi infection.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Oropharyngeal Carriage of hpl-Containing Haemophilus haemolyticus Predicts Lower Prevalence and Density of NTHi Colonisation in Healthy Adults

et al. 2021

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“…H. parahaemolyticus strains possess Tf receptors whereas only some strains of H. haemolyticus do. However, the demonstrated competition between H. haemolyticus and H. influenzae (Atto et al, 2021) and similarity in adhesins (Singh et al, 2013) suggests that at least some strains of H. haemolyticus occupy the same niche. All strains of Glaesserella parasuis possess Tf receptors, with more virulent serovars possessing genes involved in binding to the mucosal surface.…”

Section: Development Of Infection Modelsmentioning

confidence: 99%

Insights from targeting transferrin receptors to develop vaccines for pathogens of humans and food production animals

Ewasechko

Chaudhuri²,

Schryvers³

2023

Front. Cell. Infect. Microbiol.

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While developing vaccines targeting surface transferrin receptor proteins in Gram-negative pathogens of humans and food production animals, the common features derived from their evolutionary origins has provided us with insights on how improvements could be implemented in the various stages of research and vaccine development. These pathogens are adapted to live exclusively on the mucosal surfaces of the upper respiratory or genitourinary tract of their host and rely on their receptors to acquire iron from transferrin for survival, indicating that there likely are common mechanisms for delivering transferrin to the mucosal surfaces that should be explored. The modern-day receptors are derived from those present in bacteria that lived over 320 million years ago. The pathogens represent the most host adapted members of their bacterial lineages and may possess factors that enable them to have strong association with the mucosal epithelial cells, thus likely reside in a different niche than the commensal members of the bacterial lineage. The bacterial pathogens normally lead a commensal lifestyle which presents challenges for development of relevant infection models as most infection models either exclude the early stages of colonization or subsequent disease development, and the immune mechanisms at the mucosal surface that would prevent disease are not evident. Development of infection models emulating natural horizontal disease transmission are also lacking. Our aim is to share our insights from the study of pathogens of humans and food production animals with individuals involved in vaccine development, maintaining health or regulation of products in the human and animal health sectors.

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“…In the absence of Hpl, H. haemolyticus growth is impaired without an alternative source of heme such as hemoglobin, which can be imported by other mechanisms ( 17 ). Importantly, Hpl binds heme in a manner that cannot be utilized by NTHi, thus inhibiting NTHi growth in vitro ( 17 – 20 ). In humans, colonization with Hpl-expressing H. haemolyticus is associated with lower NTHi burdens in the upper airway and a reduced risk of NTHi acquisition, suggesting a beneficial role for Hpl expression ( 21 ).…”

Section: Introductionmentioning

confidence: 99%

Heme sequestration by hemophilin from Haemophilus haemolyticus reduces respiratory tract colonization and infection with non-typeable Haemophilus influenzae

Fulte,

Atto,

McCarty

et al. 2024

mSphere

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Iron acquisition is a key feature dictating the success of pathogen colonization and infection. Pathogens scavenging iron from the host must contend with other members of the microbiome similarly competing for the limited pool of bioavailable iron, often in the form of heme. In this study, we identify a beneficial role for the heme-binding protein hemophilin (Hpl) produced by the non-pathogenic bacterium Haemophilus haemolyticus against its close relative, the opportunistic respiratory tract pathogen non-typeable Haemophilus influenzae (NTHi). Using a mouse model, we found that pre-exposure to H. haemolyticus significantly reduced NTHi colonization of the upper airway and impaired NTHi infection of the lungs in an Hpl-dependent manner. Further, treatment with recombinant Hpl was sufficient to decrease airway burdens of NTHi without exacerbating lung immunopathology or systemic inflammation. Instead, mucosal production of the neutrophil chemokine CXCL2, lung myeloperoxidase, and serum pro-inflammatory cytokines IL-6 and TNFα were lower in Hpl-treated mice. Mechanistically, H. haemolyticus suppressed NTHi growth and adherence to human respiratory tract epithelial cells through the expression of Hpl, and recombinant Hpl could recapitulate these effects. Together, these findings indicate that heme sequestration by non-pathogenic, Hpl-producing H. haemolyticus is protective against NTHi colonization and infection. IMPORTANCE The microbiome provides a critical layer of protection against infection with bacterial pathogens. This protection is accomplished through a variety of mechanisms, including interference with pathogen growth and adherence to host cells. In terms of immune defense, another way to prevent pathogens from establishing infections is by limiting the availability of nutrients, referred to as nutritional immunity. Restricting pathogen access to iron is a central component of this approach. Here, we uncovered an example where these two strategies intersect to impede infection with the respiratory tract bacterial pathogen Haemophilus influenzae . Specifically, we find that a non-pathogenic (commensal) bacterium closely related to H. influenzae called Haemophilus haemolyticus improves protection against H. influenzae by limiting the ability of this pathogen to access iron. These findings suggest that beneficial members of the microbiome improve protection against pathogen infection by effectively contributing to host nutritional immunity.

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Haemophilin-Producing Strains of Haemophilus haemolyticus Protect Respiratory Epithelia from NTHi Colonisation and Internalisation

Cited by 6 publications

References 59 publications

Oropharyngeal Carriage of hpl-Containing Haemophilus haemolyticus Predicts Lower Prevalence and Density of NTHi Colonisation in Healthy Adults

Oropharyngeal Carriage of hpl-Containing Haemophilus haemolyticus Predicts Lower Prevalence and Density of NTHi Colonisation in Healthy Adults

Insights from targeting transferrin receptors to develop vaccines for pathogens of humans and food production animals

Heme sequestration by hemophilin from Haemophilus haemolyticus reduces respiratory tract colonization and infection with non-typeable Haemophilus influenzae

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