Exploiting the struggle for haem: a novel therapeutic approach against Haemophilus influenzae
Brianna Atto A C , David Gell B and Stephen Tristram A
+ Author Affiliations
- Author Affiliations
A School of Health Sciences, University of Tasmania, Newnham Drive, Launceston, Tas. 7248, Australia
B School of Medicine, University of Tasmania, 17 Liverpool Street, Hobart, Tas. 7000, Australia
C Email: brianna.atto@utas.edu.au
Microbiology Australia 42(3) 116-119 https://doi.org/10.1071/MA21032
Submitted: 1 July 2021 Accepted: 5 August 2021 Published: 6 September 2021
Journal Compilation © The Authors 2021 Open Access CC BY-NC-ND, published (by CSIRO Publishing) on behalf of the ASM
Abstract
Over the past decade, nontypeable Haemophilus influenzae (NTHi) has gained recognition as a major opportunistic pathogen of the respiratory tract that imposes a substantial global burden of disease, owing to a high rate of morbidity and ensuing complications. Further amplifying the global impact of NTHi infections is the increasing spectrum and prevalence of antibiotic resistance, leading to higher rates of treatment failure with first- and second-line antibiotics regimes. The threat of antibiotic resistance was recognised by the World Health Organization in 2017, listing NTHi as a priority pathogen for which new therapies are urgently needed. Despite significant efforts, there are currently no effective vaccine strategies available that can slow the growing burden of NTHi disease. Consequently, alternative preventative or therapeutic approaches that do not rely on antibiotic susceptibility or stable vaccine targets are becoming more attractive. The nutritional dependency for haem at all stages of NTHi pathogenesis exposes a vulnerability that may be exploited for the development of such therapies. This article will discuss the therapeutic potential of strategies that limit NTHi access to this vital nutrient, with particular focus on a novel bacteriotherapeutic approach under development.
References
[1] Chi, D.H. et al. (2003) Nhasopharyngeal reservoir of bacterial otitis media and sinusitis pathogens in adults during wellness and viral respiratory illness. Am. J. Rhinol. 17, 209–214.| Nhasopharyngeal reservoir of bacterial otitis media and sinusitis pathogens in adults during wellness and viral respiratory illness.Crossref | GoogleScholarGoogle Scholar | 12962190PubMed |
[2] Greenberg, D. et al. (2004) Relative importance of nasopharyngeal versus oropharyngeal sampling for isolation of Streptococcus pneumoniae and Haemophilus influenzae from healthy and sick individuals varies with age. J. Clin. Microbiol. 42, 4604–4609.
| Relative importance of nasopharyngeal versus oropharyngeal sampling for isolation of Streptococcus pneumoniae and Haemophilus influenzae from healthy and sick individuals varies with age.Crossref | GoogleScholarGoogle Scholar | 15472316PubMed |
[3] Mackenzie, G.A. et al. (2010) Epidemiology of nasopharyngeal carriage of respiratory bacterial pathogens in children and adults: cross-sectional surveys in a population with high rates of pneumococcal disease. BMC Infect. Dis. 10, 304.
| Epidemiology of nasopharyngeal carriage of respiratory bacterial pathogens in children and adults: cross-sectional surveys in a population with high rates of pneumococcal disease.Crossref | GoogleScholarGoogle Scholar | 20969800PubMed |
[4] Rawlings, B.A. et al. (2013) Bacterial pathogens in the nasopharynx, nasal cavity, and osteomeatal complex during wellness and viral infection. Am. J. Rhinol. Allergy 27, 39–42.
| Bacterial pathogens in the nasopharynx, nasal cavity, and osteomeatal complex during wellness and viral infection.Crossref | GoogleScholarGoogle Scholar | 23406599PubMed |
[5] Van Eldere, J. et al. (2014) Non-typeable Haemophilus influenzae, an under-recognised pathogen. Lancet Infect. Dis. 14, 1281–1292.
| Non-typeable Haemophilus influenzae, an under-recognised pathogen.Crossref | GoogleScholarGoogle Scholar | 25012226PubMed |
[6] Cerquetti, M. and Giufrè, M. (2016) Why we need a vaccine for non-typeable Haemophilus influenzae. Hum. Vaccin. Immunother. 12, 2357–2361.
| Why we need a vaccine for non-typeable Haemophilus influenzae.Crossref | GoogleScholarGoogle Scholar | 27171854PubMed |
[7] Tristram, S. et al. (2007) Antimicrobial resistance in Haemophilus influenzae. Clin. Microbiol. Rev. 20, 368–389.
| Antimicrobial resistance in Haemophilus influenzae.Crossref | GoogleScholarGoogle Scholar | 17428889PubMed |
[8] Venekamp, R.P. et al. (2015) Antibiotics for acute otitis media in children. Cochrane Database Syst. Rev. , .
| Antibiotics for acute otitis media in children.Crossref | GoogleScholarGoogle Scholar | 26465274PubMed |
[9] Ito, M. et al. (2010) Clonal spread of β-lactamase-producing amoxicillin–clavulanate-resistant (BLPACR) strains of non-typeable Haemophilus influenzae among young children attending a day care in Japan. Int. J. Pediatr. Otorhinolaryngol. 74, 901–906.
| Clonal spread of β-lactamase-producing amoxicillin–clavulanate-resistant (BLPACR) strains of non-typeable Haemophilus influenzae among young children attending a day care in Japan.Crossref | GoogleScholarGoogle Scholar | 20846501PubMed |
[10] World Health Organization (2017) Prioritization of pathogens to guide discovery, research and development of new antibiotics for drug-resistant bacterial infections, including tuberculosis.
[11] Jalalvand, F. and Riesbeck, K. (2018) Update on non-typeable Haemophilus influenzae-mediated disease and vaccine development. Expert Rev. Vaccines 17, 503–512.
| Update on non-typeable Haemophilus influenzae-mediated disease and vaccine development.Crossref | GoogleScholarGoogle Scholar | 29863956PubMed |
[12] Duell, B.L. et al. (2016) Host–pathogen interactions of nontypeable Haemophilus influenzae: from commensal to pathogen. FEBS Lett. 590, 3840–3853.
| Host–pathogen interactions of nontypeable Haemophilus influenzae: from commensal to pathogen.Crossref | GoogleScholarGoogle Scholar | 27508518PubMed |
[13] Clementi, C.F. and Murphy, T.F. (2011) Non-typeable Haemophilus influenzae invasion and persistence in the human respiratory tract. Front. Cell. Infect. Microbiol. 1, 1.
| Non-typeable Haemophilus influenzae invasion and persistence in the human respiratory tract.Crossref | GoogleScholarGoogle Scholar | 22919570PubMed |
[14] Goyal, M. et al. (2015) Cellular interaction of nontypeable Haemophilus influenzae triggers cytotoxicity of infected type II alveolar cells via apoptosis. Pathog. Dis. 73, 1.
| 25227327PubMed |
[15] Moriyama, S. et al. (2009) Formation of biofilm by Haemophilus influenzae isolated from pediatric intractable otitis media. Auris Nasus Larynx 36, 525–531.
| Formation of biofilm by Haemophilus influenzae isolated from pediatric intractable otitis media.Crossref | GoogleScholarGoogle Scholar | 19135325PubMed |
[16] Harrison, A. et al. (2013) Ferric uptake regulator and its role in the pathogenesis of nontypeable Haemophilus influenzae. Infect. Immun. 81, 1221–1233.
| Ferric uptake regulator and its role in the pathogenesis of nontypeable Haemophilus influenzae.Crossref | GoogleScholarGoogle Scholar | 23381990PubMed |
[17] Rodríguez-Arce, I. et al. (2019) Moonlighting of Haemophilus influenzae heme acquisition systems contributes to the host airway-pathogen interplay in a coordinated manner. Virulence 10, 315–333.
| Moonlighting of Haemophilus influenzae heme acquisition systems contributes to the host airway-pathogen interplay in a coordinated manner.Crossref | GoogleScholarGoogle Scholar | 30973092PubMed |
[18] Morton, D.J. et al. (2004) Reduced severity of middle ear infection caused by nontypeable Haemophilus influenzae lacking the hemoglobin/hemoglobin–haptoglobin binding proteins (Hgp) in a chinchilla model of otitis media. Microb. Pathog. 36, 25–33.
| Reduced severity of middle ear infection caused by nontypeable Haemophilus influenzae lacking the hemoglobin/hemoglobin–haptoglobin binding proteins (Hgp) in a chinchilla model of otitis media.Crossref | GoogleScholarGoogle Scholar | 14643637PubMed |
[19] Morton, D.J. et al. (2009) The heme-binding protein (HbpA) of Haemophilus influenzae as a virulence determinant. Int. J. Med. Microbiol. 299, 479–488.
| The heme-binding protein (HbpA) of Haemophilus influenzae as a virulence determinant.Crossref | GoogleScholarGoogle Scholar | 19451029PubMed |
[20] Seale, T.W. et al. (2006) Complex role of hemoglobin and hemoglobin-haptoglobin binding proteins in Haemophilus influenzae virulence in the infant rat model of invasive infection. Infect. Immun. 74, 6213–6225.
| Complex role of hemoglobin and hemoglobin-haptoglobin binding proteins in Haemophilus influenzae virulence in the infant rat model of invasive infection.Crossref | GoogleScholarGoogle Scholar | 16966415PubMed |
[21] Szelestey, B.R. et al. (2013) Haemophilus responses to nutritional immunity: epigenetic and morphological contribution to biofilm architecture, invasion, persistence and disease severity. PLoS Pathog. 9, e1003709.
| Haemophilus responses to nutritional immunity: epigenetic and morphological contribution to biofilm architecture, invasion, persistence and disease severity.Crossref | GoogleScholarGoogle Scholar | 24130500PubMed |
[22] Latham, R.D. et al. (2017) An isolate of Haemophilus haemolyticus produces a bacteriocin-like substance that inhibits the growth of nontypeable Haemophilus influenzae. Int. J. Antimicrob. Agents 49, 503–506.
| An isolate of Haemophilus haemolyticus produces a bacteriocin-like substance that inhibits the growth of nontypeable Haemophilus influenzae.Crossref | GoogleScholarGoogle Scholar | 28242259PubMed |
[23] Latham, R.D. et al. (2020) A heme‐binding protein produced by Haemophilus haemolyticus inhibits non‐typeable Haemophilus influenzae. Mol. Microbiol. 113, 381–398.
| A heme‐binding protein produced by Haemophilus haemolyticus inhibits non‐typeable Haemophilus influenzae.Crossref | GoogleScholarGoogle Scholar | 31742788PubMed |
[24] Atto, B. et al. (2020) In vitro anti-NTHi activity of haemophilin-producing strains of Haemophilus haemolyticus. Pathogens 9, 243.
| In vitro anti-NTHi activity of haemophilin-producing strains of Haemophilus haemolyticus.Crossref | GoogleScholarGoogle Scholar |
[25] Avadhanula, V. et al. (2006) Nontypeable Haemophilus influenzae adheres to intercellular adhesion molecule 1 (ICAM-1) on respiratory epithelial cells and upregulates ICAM-1 expression. Infect. Immun. 74, 830–838.
| Nontypeable Haemophilus influenzae adheres to intercellular adhesion molecule 1 (ICAM-1) on respiratory epithelial cells and upregulates ICAM-1 expression.Crossref | GoogleScholarGoogle Scholar | 16428725PubMed |
[26] Atto, B. et al. (2021) Oropharyngeal carriage of hpl-containing Haemophilus haemolyticus predicts lower prevalence and density of NTHi colonisation in healthy adults. Pathogens 10, 577.
| Oropharyngeal carriage of hpl-containing Haemophilus haemolyticus predicts lower prevalence and density of NTHi colonisation in healthy adults.Crossref | GoogleScholarGoogle Scholar | 34068621PubMed |
[27] de Gier, C. et al. (2019) PCV7-and PCV10-vaccinated otitis-prone children in New Zealand have similar pneumococcal and Haemophilus influenzae densities in their nasopharynx and middle ear. Vaccines (Basel) 7, 14.
| PCV7-and PCV10-vaccinated otitis-prone children in New Zealand have similar pneumococcal and Haemophilus influenzae densities in their nasopharynx and middle ear.Crossref | GoogleScholarGoogle Scholar |
[28] Hill, A.T. et al. (2000) Association between airway bacterial load and markers of airway inflammation in patients with stable chronic bronchitis. Am. J. Med. 109, 288–295.
| Association between airway bacterial load and markers of airway inflammation in patients with stable chronic bronchitis.Crossref | GoogleScholarGoogle Scholar | 10996579PubMed |
[29] Hood, D. et al. (2016) A new model for non-typeable Haemophilus influenzae middle ear infection in the Junbo mutant mouse. Dis. Model. Mech. 9, 69–79.
| 26611891PubMed |
[30] Smith-Vaughan, H. et al. (2006) Measuring nasal bacterial load and its association with otitis media. BMC Ear Nose Throat Disord. 6, 10.
| Measuring nasal bacterial load and its association with otitis media.Crossref | GoogleScholarGoogle Scholar | 16686940PubMed |
[31] Desai, H. et al. (2014) Bacterial colonization increases daily symptoms in patients with chronic obstructive pulmonary disease. Ann. Am. Thorac. Soc. 11, 303–309.
| Bacterial colonization increases daily symptoms in patients with chronic obstructive pulmonary disease.Crossref | GoogleScholarGoogle Scholar | 24423399PubMed |
[32] Pfaffl, M.W. (2001) A new mathematical model for relative quantification in real-time RT–PCR. Nucleic Acids Research 29, e45.
| A new mathematical model for relative quantification in real-time RT–PCR.Crossref | GoogleScholarGoogle Scholar | 11328886PubMed |
[33] Kirkham, L.-A.S. et al. (2010) Nasopharyngeal carriage of Haemophilus haemolyticus in otitis-prone and healthy children. J. Clin. Microbiol. 48, 2557–2559.
| Nasopharyngeal carriage of Haemophilus haemolyticus in otitis-prone and healthy children.Crossref | GoogleScholarGoogle Scholar |
[34] Murphy, T.F. et al. (2007) Haemophilus haemolyticus: a human respiratory tract commensal to be distinguished from Haemophilus influenzae. J. Infect. Dis. 195, 81–89.
| Haemophilus haemolyticus: a human respiratory tract commensal to be distinguished from Haemophilus influenzae.Crossref | GoogleScholarGoogle Scholar | 17152011PubMed |
[35] De Boeck, I. et al. (2021) Lactic acid bacteria as probiotics for the nose? Microb. Biotechnol. 14, 859–869.
| Lactic acid bacteria as probiotics for the nose?Crossref | GoogleScholarGoogle Scholar | 33507624PubMed |
[36] Hols, P. et al. (2019) Mobilization of microbiota commensals and their bacteriocins for therapeutics. Trends Microbiol. 27, 690–702.
| Mobilization of microbiota commensals and their bacteriocins for therapeutics.Crossref | GoogleScholarGoogle Scholar | 30987817PubMed |
