Protective effect of IgM against colonization of the respiratory tract by nontypeable Haemophilus influenzae in patients with hypogammaglobulinemia

Patients with cystic fibrosis (CF) experience lifelong respiratory infections which are a significant cause of morbidity and mortality. These infections are polymicrobial in nature, and the predominant bacterial species undergo a predictable series of changes as patients age. Young patients have populations dominated by opportunists that are typically found within the microbiome of the human nasopharynx, such as nontypeable Haemophilus influenzae (NTHi); these are eventually supplanted and the population within the CF lung is later dominated by pathogens such as Pseudomonas aeruginosa ( Pa ). In this study, we investigated how initial colonization with NTHi impacts colonization and persistence of Pa in the respiratory tract. Analysis of polymicrobial biofilms in vitro by confocal microscopy revealed that NTHi promoted greater levels of Pa biofilm volume and diffusion. However, sequential respiratory infection of mice with NTHi followed by Pa resulted in significantly lower Pa as compared to infection with Pa alone. Coinfected mice also had reduced airway tissue damage and lower levels of inflammatory cytokines as compared with Pa infected mice. Similar results were observed after instillation of heat-inactivated NTHi bacteria or purified NTHi lipooligosaccharide (LOS) endotoxin prior to Pa introduction. Based on these results, we conclude that NTHi significantly reduces susceptibility to subsequent Pa infection, most likely due to priming of host innate immunity rather than a direct competitive interaction between species. These findings have potential significance with regard to therapeutic management of early life infections in patients with CF.

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Antibodies against outer membrane proteins of Moraxella catarrhalis and nontypeable Haemophilus influenzae cross-react with various pathogens of human respiratory tract

Frontiers in Immunology ◽

10.3389/conf.fimmu.2013.02.00907 ◽

2013 ◽

Vol 4 ◽

Author(s):

Augustyniak Daria ◽

Bonarowska Joanna ◽

Mackiewicz Pawel ◽

Drulis-Kawa Zuzanna

Keyword(s):

Membrane Proteins ◽

Respiratory Tract ◽

Haemophilus Influenzae ◽

Outer Membrane ◽

Moraxella Catarrhalis ◽

Outer Membrane Proteins ◽

Nontypeable Haemophilus Influenzae ◽

Human Respiratory Tract

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Nontypeable Haemophilus influenzae isolates from the lower respiratory tract in Western Sichuan, China: MIC value of ofloxacin and Mutation characteristics of Quinolones Resistance determining region gene

10.21203/rs.3.rs-19694/v1 ◽

2020 ◽

Author(s):

Wang Xiaolei ◽

Xie Jiang ◽

Guo YuanBiao ◽

Shao ZhuJun ◽

Zhu BingQing ◽

...

Keyword(s):

Amino Acid ◽

Respiratory Tract ◽

Haemophilus Influenzae ◽

Lower Respiratory Tract ◽

Amino Acid Sequences ◽

Quinolone Resistance ◽

Nontypeable Haemophilus Influenzae ◽

Western Sichuan ◽

Tract Infections ◽

Mic Value

Abstract Background: Fluoroquinolones are one of the most widely used antibiotics in the treatment of respiratory tract infections, and the mechanism of resistance to fluoroquinolones is considered to be related to the amino acid substitution of gyrA, gyrB, parC, and parE, the Quinolone Resistance-Determining Regions (QRDRs) of DNA cyclase type II topoisomerase and IV topoisomerase. The purpose of this study was to explore the molecular mechanism of quinolone resistance of Nontypeable Haemophilus influenzae(NTHi ) isolates and analyze the mutation law of the QRDRs gene. Results: MIC value of ofloxacin of 280 NTHi isolates from lower respiratory tract secretions in children group during 2003~2004 and in whole age group during 2013~2014 in Western Sichuan, China were monitored and the amino acid sequences of gyrA, gyrB, parC and parE gene in QRDRs were detected. The resistance rate of ofloxacin in adult group was 1.92% (n=52), while the NTHi strains with ofloxacin MIC value≥0.5 showed an upward trend in all age groups. No ofloxacin-resistant strains were found in 57 NTHi strains isolated from the children patient. Four amino acid substitutions were found in GyrA genes, four in GyrB, three in parC and nine in parE genes. The results showed that different amino acid replacement patterns of the gyrA , gyrB, parC and parE gene had different effects on ofloxacin MIC values. Conclusions: Ser-84-leu and asp-88-tyr/asn mutation of the gyrA, ser-84-lys/ile and ser -133-ala mutations of the parC and ala-400-val variation of the gyrB were the main factors leading to the increase of MIC value of ofloxacin of NTHi strains in Western Sichuan, China. It can be predicted that with the increase of quinolones exposure, the susceptibility of isolates from children to quinolones will be further reduced.

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Nontypeable Haemophilus influenzae infection impedes Pseduomonas aeruginosa colonization and persistence in mouse respiratory tract

10.1101/2021.08.05.455360 ◽

2021 ◽

Author(s):

Natalie Lindgren ◽

Lea Novak ◽

Benjamin Carter Hunt ◽

Melissa S. McDaniel ◽

W. Edward Swords

Keyword(s):

Respiratory Tract ◽

Haemophilus Influenzae ◽

Respiratory Infections ◽

Bacterial Species ◽

Young Patients ◽

Nontypeable Haemophilus Influenzae ◽

Immune Priming ◽

And Diffusion ◽

Sequential Infection

Patients with cystic fibrosis (CF) experience lifelong respiratory infections which are a significant cause of morbidity and mortality. These infections are polymicrobial in nature wherein the predominant bacterial species changes as patients age. Young patients have populations dominated by pathobiont such as nontypeable Haemophilus influenzae (NTHi), that are eventually supplanted by pathogens such as Pseudomonas aeruginosa (Pa), which are more typical of late-stage CF disease. In this study, we investigated how initial colonization with NTHi impacts colonization and persistence of Pa in the respiratory tract. Analysis of polymicrobial biofilms in vitro by confocal microscopy revealed that NTHi promoted greater levels of Pa biofilm volume and diffusion. However, sequential infection of mice with NTHi followed by Pa showed significant reduction in Pa in the lungs as compared to infection with Pa alone. Coinfected mice also had reduced severity of airway tissue damage and lower levels of inflammatory cytokines as compared mice infected with Pa alone. Similar results were observed using heat-inactivated NTHi bacteria prior to Pa introduction. Based on these results, we conclude that NTHi can significantly reduce susceptibility to subsequent Pa infection, most likely due to immune priming rather than a direct competitive interaction between species. These findings have potential significance with regard to therapeutic management of early life infections in patients with CF

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The HMW1 and HMW2 Adhesins Enhance the Ability of Nontypeable Haemophilus influenzae To Colonize the Upper Respiratory Tract of Rhesus Macaques

Infection and Immunity ◽

10.1128/iai.00153-16 ◽

2016 ◽

Vol 84 (10) ◽

pp. 2771-2778 ◽

Cited By ~ 3

Author(s):

Katherine A. Rempe ◽

Eric A. Porsch ◽

Jolaine M. Wilson ◽

Joseph W. St. Geme

Keyword(s):

Respiratory Tract ◽

Haemophilus Influenzae ◽

Parent Strain ◽

Double Mutant ◽

Rhesus Macaques ◽

Upper Respiratory Tract ◽

Nontypeable Haemophilus Influenzae ◽

Upper Respiratory

NontypeableHaemophilus influenzae(NTHi) initiates infection by colonizing the upper respiratory tract and is a common cause of localized respiratory tract disease. Previous work has established that the NTHi HMW1 and HMW2 proteins are potent adhesins that mediate efficientin vitroadherence to cultured human respiratory epithelial cells. In this study, we used a rhesus macaque model to assess the contributions of HMW1 and HMW2 toin vivocolonization. In experiments involving inoculation of individual isogenic derivatives of NTHi strain 12, the parent strain expressing both HMW1 and HMW2 and the mutant strains expressing either HMW1 or HMW2 were able to colonize more frequently than the double mutant strain lacking HMW1 and HMW2. In competition experiments, the parent strain efficiently outcompeted the double mutant lacking HMW1 and HMW2. Colonization with strains expressing HMW2 resulted in development of antibody against HMW2 in a number of the animals, demonstrating that colonization can stimulate an antibody response. In conclusion, we have established that the HMW1 and HMW2 adhesins play a major role in facilitating colonization of the upper respiratory tract of rhesus macaques, in some cases associated with stimulation of an immune response.

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Immunoglobulin A Protease Variants Facilitate Intracellular Survival in Epithelial Cells By Nontypeable Haemophilus influenzae That Persist in the Human Respiratory Tract in Chronic Obstructive Pulmonary Disease

The Journal of Infectious Diseases ◽

10.1093/infdis/jix471 ◽

2017 ◽

Vol 216 (10) ◽

pp. 1295-1302 ◽

Cited By ~ 8

Author(s):

Timothy F Murphy ◽

Charmaine Kirkham ◽

Mary C Gallo ◽

Yang Yang ◽

Gregory E Wilding ◽

...

Keyword(s):

Chronic Obstructive Pulmonary Disease ◽

Epithelial Cells ◽

Respiratory Tract ◽

Haemophilus Influenzae ◽

Pulmonary Disease ◽

Immunoglobulin A ◽

Chronic Obstructive ◽

Nontypeable Haemophilus Influenzae ◽

Human Respiratory Tract ◽

Obstructive Pulmonary Disease

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Sialic acid protects nontypeable Haemophilus influenzae from natural IgM and promotes survival in murine respiratory tract

Infection and Immunity ◽

10.1128/iai.00676-20 ◽

2021 ◽

Author(s):

Mary Darby Jackson ◽

Sandy M. Wong ◽

Brian J. Akerley

Keyword(s):

Sialic Acid ◽

Respiratory Tract ◽

Haemophilus Influenzae ◽

Immune Evasion ◽

Immune Defense ◽

Wild Type ◽

Nontypeable Haemophilus Influenzae ◽

Upper Airways ◽

Mucosal Tissues ◽

Tract Infections

Nontypeable Haemophilus influenzae (NTHi), a common inhabitant of the human nasopharynx and upper airways, causes opportunistic respiratory tract infections that are frequently recurring and chronic. NTHi utilizes sialic acid from the host to evade antibacterial defenses and persist in mucosal tissues, however the role of sialic acid scavenged by NTHi during infection is not fully understood. We previously showed that sialylation protects specific epitopes on NTHi lipooligosaccharide (LOS) targeted by bactericidal IgM in normal human serum. Here, we evaluated the importance of immune evasion mediated by LOS sialylation in the mouse respiratory tract using wild-type H. influenzae and an isogenic siaB mutant incapable of sialylating the LOS. Sialylation protected common NTHi glycan structures recognized by human and murine IgM, and protected NTHi from complement-mediated killing directed by IgM against these structures. Protection from IgM binding by sialylated LOS correlated with decreased survival of the siaB mutant versus wild-type in the murine lung. Complement depletion with cobra venom factor increased survival of the siaB mutant in the nasopharynx but not in the lungs, suggesting differing roles of sialylation at these sites. Prior infection increased IgM against H. influenzae but not against sialic acid-protected epitopes, consistent with sialic acid-mediated immune evasion during infection. These results provide mechanistic insight into an NTHi evasive strategy against an immune defense conserved across host species, highlighting the potential of the mouse model for development of anti-infective strategies targeting LOS antigens of NTHi.

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