{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T16:52:33Z","timestamp":1791219153202,"version":"4.1.0"},"reference-count":55,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T00:00:00Z","timestamp":1740096000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012395","name":"Canadian Immunization Research Network","doi-asserted-by":"publisher","award":["CT20ON31"],"award-info":[{"award-number":["CT20ON31"]}],"id":[{"id":"10.13039\/501100012395","id-type":"DOI","asserted-by":"publisher"}]},{"name":"NOSM University Faculty Association Research Development Grant","award":["CT20ON31"],"award-info":[{"award-number":["CT20ON31"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pathogens"],"abstract":"<jats:p>Non-typeable Haemophilus influenzae (NTHi) is often asymptomatically carried in the upper airways but can cause a wide spectrum of disease conditions, from local respiratory tract infections to invasive disease such as sepsis or meningitis. The factors driving NTHi\u2019s transition from benign carriage to severe systemic disease remain poorly understood. It is unknown whether NTHi strains associated with invasive or non-invasive disease differ in their capacity to trigger inflammatory responses in innate immune cells. To address this question, we have used an in vitro infection model of human THP-1 cells differentiated to macrophages. To evaluate inflammatory responses, we studied the expression of 3 prototypic pro-inflammatory molecules, ICAM-1, TNF-\u03b1, and IL-1\u03b2. The role of lipooligosaccharide in triggering inflammatory responses was assessed using inhibition of Toll-like receptor 4 signaling. Our experiments demonstrated that NTHi strains isolated from cases of invasive and non-invasive infections were similarly able to induce strong activations of macrophage pro-inflammatory responses. Our findings support the hypothesis that the development of invasive versus non-invasive NTHi disease may be more significantly influenced by the adaptive immune response than the innate immune response.<\/jats:p>","DOI":"10.3390\/pathogens14030210","type":"journal-article","created":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T06:39:07Z","timestamp":1740119947000},"page":"210","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Inflammatory Responses to Non-Typeable Haemophilus influenzae Clinical Isolates from Invasive and Non-Invasive Infections"],"prefix":"10.3390","volume":"14","author":[{"given":"Brenda","family":"Huska","sequence":"first","affiliation":[{"name":"Medical Sciences Division, Northern Ontario School of Medicine University, Thunder Bay, ON P7B 5E1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Ulanova","sequence":"additional","affiliation":[{"name":"Medical Sciences Division, Northern Ontario School of Medicine University, Thunder Bay, ON P7B 5E1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,21]]},"reference":[{"key":"ref_1","unstructured":"Mandell, G.L., Bennett, J.E., and Dolin, R. (2010). Haemophilus species (including H. influenzae and Chancroid). Mandell Gerald L, Bennett J E, Dolin R. Mandell, Douglas, and Bennett\u2019s Principles and Practice of Infectious Diseases, Churchill Livingstone Elsevier. [7th ed.]."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1281","DOI":"10.1016\/S1473-3099(14)70734-0","article-title":"Non-typeable Haemophilus influenzae, an under-recognised pathogen","volume":"14","author":"Slack","year":"2014","journal-title":"Lancet Infect. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1711","DOI":"10.3201\/eid2110.150004","article-title":"Invasive Disease Caused by Nontypeable Haemophilus influenzae","volume":"21","author":"Langereis","year":"2015","journal-title":"Emerg. Infect. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"396","DOI":"10.3201\/eid2303.161552","article-title":"Epidemiology of Invasive Haemophilus influenzae Disease, Europe, 2007\u20132014","volume":"23","author":"Whittaker","year":"2017","journal-title":"Emerg. Infect. Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1889","DOI":"10.1093\/cid\/ciad054","article-title":"Epidemiology of Invasive Nontypeable Haemophilus influenzae Disease-United States, 2008\u20132019","volume":"76","author":"Oliver","year":"2023","journal-title":"Clin. Infect. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1139\/cjm-2019-0210","article-title":"Continuing surveillance of invasive Haemophilus influenzae disease in northwestern Ontario emphasizes the importance of serotype A and non-typeable strains as causes of serious disease","volume":"65","author":"Cerqueira","year":"2019","journal-title":"Can. J. Microbiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1139\/cjm-2022-0208","article-title":"Epidemiology of invasive Haemophilus influenzae disease in northwestern Ontario: Comparison of invasive and noninvasive H. influenzae clinical isolates","volume":"69","author":"Ulanova","year":"2023","journal-title":"Can. J. Microbiol."},{"key":"ref_8","first-page":"20","article-title":"Carriage of Haemophilus influenzae serotype A in children: Canadian Immunization Research Network (CIRN) study","volume":"9","author":"Ulanova","year":"2024","journal-title":"J. Assoc. Med. Microbiol. Infect. Dis. Can."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/j.ijmm.2007.03.007","article-title":"Expression and structural diversity of the lipopolysaccharide of Haemophilus influenzae: Implication in virulence","volume":"297","author":"Schweda","year":"2007","journal-title":"Int. J. Med. Microbiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"20177","DOI":"10.1074\/jbc.R500001200","article-title":"Peptidoglycan signaling in innate immunity and inflammatory disease","volume":"280","author":"McDonald","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2075","DOI":"10.1128\/IAI.73.4.2075-2082.2005","article-title":"Differential Involvement of Toll-like Receptors 2 and 4 in the Host Response to Acute Respiratory Infections with Wild-type and Mutant Haemophilus Influenzae Strains","volume":"73","author":"Lorenz","year":"2005","journal-title":"Infect. Immun."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Su, Y.C., Jalalvand, F., Thegerstr\u00f6m, J., and Riesbeck, K. (2018). The Interplay Between Immune Response and Bacterial Infection in COPD: Focus Upon Non-typeable Haemophilus influenzae. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.02530"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"220008","DOI":"10.1183\/16000617.0008-2022","article-title":"Non-typeable Haemophilus influenzae airways infection: The next treatable trait in asthma?","volume":"31","author":"Brown","year":"2022","journal-title":"Eur. Respir. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1159\/000540582","article-title":"The Study of Pro-Inflammatory Molecules Induced by Genetically and Phenotypically Diverse Strains of Haemophilus influenzae Type a in an in vitro Infection Model","volume":"1","author":"Huska","year":"2024","journal-title":"Immune Syst."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e01245-14","DOI":"10.1128\/genomeA.01245-14","article-title":"Complete Genome Sequence of Haemophilus Influenzae Strain 375 from the Middle Ear of a Pediatric Patient with Otitis Media","volume":"2","author":"Mell","year":"2014","journal-title":"Genome Announc."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1623","DOI":"10.1128\/JCM.41.4.1623-1636.2003","article-title":"Characterization of encapsulated and noncapsulated Haemophilus influenzae and determination of phylogenetic relationships by multilocus sequence typing","volume":"41","author":"Meats","year":"2003","journal-title":"J. Clin. Microbiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1941","DOI":"10.1016\/j.vaccine.2015.02.060","article-title":"Naturally occurring bactericidal antibodies specific for Haemophilus influenzae lipooligosaccharide are present in healthy adult individuals","volume":"33","author":"Choi","year":"2015","journal-title":"Vaccine"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"34","DOI":"10.20411\/pai.v2i1.162","article-title":"The Immunostimulatory Capacity of Nontypeable Haemophilus influenzae Lipooligosaccharide","volume":"2","author":"Gaultier","year":"2017","journal-title":"Pathog. Immun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1128\/IAI.74.2.830-838.2006","article-title":"Nontypeable Haemophilus influenzae adheres to intercellular adhesion molecule 1 (ICAM-1) on respiratory epithelial cells and upregulates ICAM-1 expression","volume":"74","author":"Avadhanula","year":"2006","journal-title":"Infect. Immun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e00093-19","DOI":"10.1128\/IAI.00093-19","article-title":"Analysis of Invasive Nontypeable Haemophilus influenzae Isolates Reveals Selection for the Expression State of Particular Phase-Variable Lipooligosaccharide Biosynthetic Genes","volume":"87","author":"Phillips","year":"2019","journal-title":"Infect. Immun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1786","DOI":"10.1093\/cid\/civ194","article-title":"Neonatal invasive Haemophilus influenzae disease in England and Wales: Epidemiology, clinical characteristics, and outcome","volume":"60","author":"Collins","year":"2015","journal-title":"Clin. Infect. Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1080\/14760584.2018.1484286","article-title":"Update on non-typeable Haemophilus influenzae-mediated disease and vaccine development","volume":"17","author":"Jalalvand","year":"2018","journal-title":"Expert. Rev. Vaccines"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1097\/QCO.0000000000000645","article-title":"Unraveling Haemophilus Influenzae Virulence Mechanisms Enable Discovery of New Targets for Antimicrobials and Vaccines","volume":"33","author":"Langereis","year":"2020","journal-title":"Curr. Opin. Infect. Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"5853","DOI":"10.1128\/IAI.73.9.5853-5863.2005","article-title":"Characterization of genetic and phenotypic diversity of invasive nontypeable Haemophilus influenzae","volume":"73","author":"Erwin","year":"2005","journal-title":"Infect. Immun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e00604-18","DOI":"10.1128\/IAI.00604-18","article-title":"Nontypeable Haemophilus influenzae Invasive Blood Isolates Are Mainly Phosphorylcholine Negative and Show Decreased Complement-Mediated Killing That Is Associated with Lower Binding of IgM and CRP in Comparison to Colonizing Isolates from the Oropharynx","volume":"87","author":"Langereis","year":"2019","journal-title":"Infect. Immun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e00454-20","DOI":"10.1128\/IAI.00454-20","article-title":"Antibody Binding and Complement-Mediated Killing of Invasive Haemophilus influenzae Isolates from Spain, Portugal, and the Netherlands","volume":"88","author":"Dudukina","year":"2020","journal-title":"Infect. Immun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"107785","DOI":"10.1016\/j.isci.2023.107785","article-title":"Phase variable acetylation of lipooligosaccharide modifies antibody production and opsonophagocytic killing of non-typeable Haemophilus influenzae","volume":"26","author":"Wills","year":"2023","journal-title":"iScience"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e00462-19","DOI":"10.1128\/IAI.00462-19","article-title":"Discovery and Contribution of Nontypeable Haemophilus influenzae NTHI1441 to Human Respiratory Epithelial Cell Invasion","volume":"87","author":"Ahearn","year":"2019","journal-title":"Infect. Immun."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Brown, M.A., Morgan, S.B., Donachie, G.E., Horton, K.L., Pavord, I.D., Arancibia-C\u00e1rcamo, C.V., and Hinks, T.S.C. (2023). Epithelial immune activation and intracellular invasion by non-typeable Haemophilus influenzae. Front. Cell Infect. Microbiol., 13.","DOI":"10.3389\/fcimb.2023.1141798"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"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.","DOI":"10.3389\/fcimb.2011.00001"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Ackland, J., Heinson, A.I., Cleary, D.W., Christodoulides, M., Wilkinson, T.M.A., and Staples, K.J. (2021). Dual RNASeq Reveals NTHi-Macrophage Transcriptomic Changes During Intracellular Persistence. Front. Cell Infect. Microbiol., 11.","DOI":"10.3389\/fcimb.2021.723481"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"00614","DOI":"10.1183\/23120541.00614-2020","article-title":"Chronic infection by nontypeable Haemophilus influenzae fuels airway inflammation","volume":"7","author":"Saliu","year":"2021","journal-title":"ERJ Open Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e0056521","DOI":"10.1128\/iai.00565-21","article-title":"Characterization of the Phase-Variable Autotransporter Lav Reveals a Role in Host Cell Adherence and Biofilm Formation in Nontypeable Haemophilus influenzae","volume":"90","author":"Phillips","year":"2022","journal-title":"Infect. Immun."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1002\/JLB.2MR0220-549R","article-title":"ICAM-1: A Master Regulator of Cellular Responses in Inflammation, Injury Resolution, and Tumorigenesis","volume":"108","author":"Bui","year":"2020","journal-title":"J. Leukoc. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1111\/cmi.12575","article-title":"Intercellular Adhesion Molecule 1 Serves as a Primary Cognate Receptor for the Type IV Pilus of Nontypeable Haemophilus Influenzae","volume":"18","author":"Novotny","year":"2016","journal-title":"Cell Microbiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1038\/nri2634","article-title":"Transcriptional Control of the Inflammatory Response","volume":"9","author":"Medzhitov","year":"2009","journal-title":"Nat. Rev. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1146\/annurev.biochem.76.060605.122847","article-title":"Signaling pathways downstream of pattern-recognition receptors and their cross talk","volume":"76","author":"Lee","year":"2007","journal-title":"Annu. Rev. Biochem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1891","DOI":"10.1096\/fj.201600772R","article-title":"Soluble CD14 Acts as a DAMP in Human Macrophages: Origin and Involvement in Inflammatory Cytokine\/Chemokine Production","volume":"31","author":"Jouneau","year":"2017","journal-title":"FASEB J."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2885","DOI":"10.4049\/jimmunol.150.7.2885","article-title":"Involvement of CD14 in Lipopolysaccharide-Induced Tumor Necrosis Factor-Alpha, IL-6 and IL-8 Release by Human Monocytes and Alveolar Macrophages","volume":"150","author":"Dentener","year":"1993","journal-title":"J. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1111\/imr.12621","article-title":"Overview of the IL-1 Family in Innate Inflammation and Acquired Immunity","volume":"281","author":"Dinarello","year":"2018","journal-title":"Immunol. Rev."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1038\/ni.2231","article-title":"Sensing and Reacting to Microbes Through the Inflammasomes","volume":"13","author":"Franchi","year":"2012","journal-title":"Nat. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1016\/j.cell.2012.07.007","article-title":"TRIF Licenses Caspase-11-Dependent NLRP3 Inflammasome Activation by Gram-Negative Bacteria","volume":"150","author":"Rathinam","year":"2012","journal-title":"Cell"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Rotta Detto Loria, J., Rohmann, K., Droemann, D., Kujath, P., Rupp, J., Goldmann, T., and Dalhoff, K. (2013). Nontypeable Haemophilus Influenzae Infection Upregulates the NLRP3 Inflammasome and Leads to Caspase-1-Dependent Secretion of Interleukin-1\u03b2-A Possible Pathway of Exacerbations in COPD. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0066818"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.1111\/j.1462-5822.2006.00878.x","article-title":"Nod1 Mediates Cytoplasmic Sensing of Combinations of Extracellular Bacteria","volume":"9","author":"Ratner","year":"2007","journal-title":"Cell Microbiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1204","DOI":"10.1128\/IAI.72.2.1204-1209.2004","article-title":"Haemophilus Influenzae Porin Induces Toll-like Receptor 2-Mediated Cytokine Production in Human Monocytes and Mouse Macrophages","volume":"72","author":"Galdiero","year":"2004","journal-title":"Infect. Immun."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1189\/jlb.1105626","article-title":"Live Streptococcus Pneumoniae, Haemophilus Influenzae, and Neisseria Meningitidis Activate the Inflammatory Response Through Toll-like Receptors 2, 4, and 9 in Species-Specific Patterns","volume":"80","author":"Mogensen","year":"2006","journal-title":"J. Leukoc. Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1038\/nature10072","article-title":"Detection of Prokaryotic mRNA Signifies Microbial Viability and Promotes Immunity","volume":"474","author":"Sander","year":"2011","journal-title":"Nature"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Sweet, M.J., Ramnath, D., Singhal, A., and Kapetanovic, R. (2024). Inducible antibacterial responses in macrophages. Nat. Rev. Immunol., Epub ahead of print.","DOI":"10.1038\/s41577-024-01080-y"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1164\/rccm.201010-1629OC","article-title":"Bronchial secretory immunoglobulin a deficiency correlates with airway inflammation and progression of chronic obstructive pulmonary disease","volume":"184","author":"Polosukhin","year":"2011","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Staples, K.J., Taylor, S., Thomas, S., Leung, S., Cox, K., Pascal, T.G., Ostridge, K., Welch, L., Tuck, A.C., and Clarke, S.C. (2016). Relationships between Mucosal Antibodies, Non-Typeable Haemophilus influenzae (NTHi) Infection and Airway Inflammation in COPD. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0167250"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2343544","DOI":"10.1080\/21645515.2024.2343544","article-title":"Lung mucosal immunity to NTHi vaccine antigens: Antibodies in sputum of chronic obstructive pulmonary disease patients","volume":"20","author":"Baffetta","year":"2024","journal-title":"Hum. Vaccin. Immunother."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1016\/j.vaccine.2011.12.113","article-title":"Antibody against Haemophilus influenzae protein D in patients with chronic conditions causing secondary immunodeficiency","volume":"30","author":"Hawdon","year":"2012","journal-title":"Vaccine"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1638","DOI":"10.1111\/j.1469-0691.2010.03417.x","article-title":"Invasive disease caused by Haemophilus influenzae in Sweden 1997\u20132009; evidence of increasing incidence and clinical burden of non-type b strains","volume":"17","author":"Resman","year":"2011","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1128\/CVI.00506-15","article-title":"Serum Concentrations of Antibodies against Outer Membrane Protein P6, Protein D, and T- and B-Cell Combined Antigenic Epitopes of Nontypeable Haemophilus influenzae in Children and Adults of Different Ages","volume":"23","author":"Hua","year":"2015","journal-title":"Clin. Vaccine Immunol."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Martinovich, K.M., Rahman, T., de Gier, C., Seppanen, E.J., Orami, T., Granland, C.M., Francis, J., Yoannes, M., Corscadden, K.J., and Ford, R. (2021). Differences in Pneumococcal and Haemophilus influenzae Natural Antibody Development in Papua New Guinean Children in the First Year of Life. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.725244"}],"container-title":["Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-0817\/14\/3\/210\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:39:32Z","timestamp":1760027972000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-0817\/14\/3\/210"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,21]]},"references-count":55,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2025,3]]}},"alternative-id":["pathogens14030210"],"URL":"https:\/\/doi.org\/10.3390\/pathogens14030210","relation":{},"ISSN":["2076-0817"],"issn-type":[{"value":"2076-0817","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,21]]}}}