Design and Characterization of Protein E-PilA, a Candidate Fusion Antigen for Nontypeable Haemophilus influenzae Vaccine

Blais, Normand; Somers, Don O.; Faubert, Denis; Labbé, Steve; Castado, Cindy; Ysebaert, Carine; Gagnon, Louis-Patrick; Champagne, Josée; Gagné, Martin; Martin, Denis

doi:10.1128/iai.00022-19

Cited by 9 publications

(8 citation statements)

References 53 publications

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“…One possible explanation is the potent antigenicity of the mature NTHI1441 peptide predicted by VaxiJen ( Table 1). The antigenicity score of NTHI1441 is quite high (2.0) compared to those of other NTHi proteins that are known to be immunogenic (P2, 0.72; P4, 0.82; P5, 0.73; and PilA, 0.74) (Table S1) (28,56,57). An alternative explanation is that NTHI1441 could be expressed at higher levels in the environment of the human respiratory tract than in nutrient-rich laboratory media.…”

Section: Discussionmentioning

confidence: 99%

Discovery and Contribution of Nontypeable Haemophilus influenzae NTHI1441 to Human Respiratory Epithelial Cell Invasion

et al. 2019

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Nontypeable Haemophilus influenzae (NTHi) is the primary cause of bacterially induced acute exacerbations of chronic obstructive pulmonary disease (COPD). NTHi adheres to and invades host respiratory epithelial cells as a means to persist in the lower airways of adults with COPD. Therefore, we mined the genomes of NTHi strains isolated from the airways of adults with COPD to identify novel proteins to investigate their role in adherence and invasion of human respiratory epithelial cells. An isogenic knockout mutant of the open reading frame NTHI1441 showed a 76.6% ± 5.5% reduction in invasion of human bronchial and alveolar epithelial cells at 1, 3, and 6 h postinfection. Decreased invasion of the NTHI1441 mutant was independent of either intracellular survival or adherence to cells. NTHI1441 is conserved among NTHi genomes. Results of whole-bacterial-cell enzyme-linked immunosorbent assay (ELISA) and flow cytometry experiments identified that NTHI1441 has epitopes expressed on the bacterial cell surface. Adults with COPD develop increased serum IgG against NTHI1441 after experiencing an exacerbation with NTHi. This study reveals NTHI1441 as a novel NTHi virulence factor expressed during infection of the COPD lower airways that contributes to invasion of host respiratory epithelial cells. The role in host cell invasion, conservation among strains, and expression of surface-exposed epitopes suggest that NTHI1441 is a potential target for preventative and therapeutic interventions for disease caused by NTHi.

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Section: Discussionmentioning

confidence: 99%

Discovery and Contribution of Nontypeable Haemophilus influenzae NTHI1441 to Human Respiratory Epithelial Cell Invasion

et al. 2019

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“…Development of a vaccine aiming at controlling infections, preferentially acute otitis media and exacerbations in COPD caused by NTHi and M. catarrhalis, is a final goal for many researches both in the academia and in the pharmaceutical industry. Importantly, GSK has developed a vaccine consisting of protein D, and a fusion protein of the major subunit of the NTHi type IV pilus (PilA) and Protein E [96]. This vaccine preparation is protective in the mouse and chinchilla [97] and has also been found safe in a phase 2 clinical trial giving a partial protection against exacerbations in COPD patients [98].…”

Section: Discussionmentioning

confidence: 99%

Complement evasion by the human respiratory tract pathogens Haemophilus influenzae and Moraxella catarrhalis

Riesbeck

2020

FEBS Letters

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All infective bacterial species need to conquer the innate immune system in order to colonize and survive in their hosts. The human respiratory pathogens Haemophilus influenzae and Moraxella catarrhalis are no exceptions and have developed sophisticated mechanisms to evade complement-mediated killing. Both bacterial species carry lipooligosaccharides preventing complement attacks and attract and utilize host complement regulators C4b binding protein and factor H to inhibit the classical and alternative pathways of complement activation, respectively. In addition, the regulator of the terminal pathway of complement activation, vitronectin, is hijacked by both bacteria. An array of different outer membrane proteins (OMP) in H. influenzae and M. catarrhalis simultaneously binds complement regulators, but also plasminogen. Several of the bacterial complement-binding proteins are important adhesins and contain highly conserved regions for interactions with the host. Thus, some of the OMP are viable targets for new therapeutics, including vaccines aimed at preventing respiratory tract diseases such as otitis media in children and exacerbations in patients suffering from chronic obstructive pulmonary disease.

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“…NTHI T4P are essential for many important biological processes that include adherence, twitching motility, colonization, biofilm formation, and competence (16)(17)(18)(19)(20). Due to the importance of NTHI T4P during both asymptomatic colonization and infection, and because expression of the majority subunit of T4P, PilA, is highly conserved among diverse NTHI isolates (16,26,27), the vaccine candidate immunogen PilA is in clinical trials for protection against NTHI-induced exacerbations of COPD (28,29).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, antibodies against PilA prevent the development of, as well as therapeutically resolve, existing experimental NTHI-induced OM in chinchilla models (21,(23)(24)(25). Due to the importance of T4P for NTHI colonization and pathogenesis, and as a result of the conservation of the amino acid sequence of PilA among diverse NTHI strains (16,26,27), PilA is in clinical trials as a candidate vaccine immunogen for the prevention of NTHI-induced exacerbations of COPD (28,29). To further validate the strategy of immunization with PilA against multiple NTHI-induced diseases, it is important to demonstrate T4P expression under microenvironmental conditions that commonly predispose to these diseases and, specifically, under conditions of viral coinfection.…”

mentioning

confidence: 99%

Nontypeable Haemophilus influenzae Responds to Virus-Infected Cells with a Significant Increase in Type IV Pilus Expression

Mokrzan

Dairo

Novotny

2020

mSphere

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Nontypeable Haemophilus influenzae (NTHI) colonizes the human nasopharynx, but when the host immune response is dysregulated by upper respiratory tract (URT) virus infection, NTHI can gain access to more distal airway sites and cause disease. The NTHI type IV pilus (T4P) facilitates adherence, benign colonization, and infection, and its majority subunit PilA is in clinical trials as a vaccinogen. To further validate the strategy of immunization with PilA against multiple NTHI-induced diseases, it is important to demonstrate T4P expression under microenvironmental conditions that predispose to NTHI infection of the airway. Because URT infection commonly facilitates NTHI-induced diseases, we examined the influence of ongoing virus infection of respiratory tract epithelial cells on NTHI T4P expression in vitro. Polarized primary human airway epithelial cells (HAEs) were sequentially inoculated with one of three common URT viruses, followed by NTHI. Use of a reporter construct revealed that NTHI upregulated pilA promoter activity when cultured with HAEs infected with adenovirus (AV), respiratory syncytial virus (RSV), or rhinovirus (RV) versus that in mock-infected HAEs. Consistent with these results, pilA expression and relative PilA/pilin abundance, as assessed by quantitative reverse transcription-PCR (qRT-PCR) and immunoblot, respectively, were also significantly increased when NTHI was cultured with virus-infected HAEs. Collectively, our data strongly suggest that under conditions of URT virus infection, PilA vaccinogen induction of T4P-directed antibodies is likely to be highly effective against multiple NTHI-induced diseases by interfering with T4P-mediated adherence. We hypothesize that this outcome could thereby limit or prevent the increased load of NTHI in the nasopharynx that characteristically precedes these coinfections. IMPORTANCE Nontypeable Haemophilus influenzae (NTHI) is the predominant bacterial causative agent of many chronic and recurrent diseases of the upper and lower respiratory tracts. NTHI-induced chronic rhinosinusitis, otitis media, and exacerbations of cystic fibrosis and chronic obstructive pulmonary disease often develop during or just after an upper respiratory tract viral infection. We have developed a vaccine candidate immunogen for NTHI-induced diseases that targets the majority subunit (PilA) of the type IV twitching pilus (T4P), which NTHI uses to adhere to respiratory tract epithelial cells and that also plays a role in disease. Here, we showed that NTHI cocultured with virus-infected respiratory tract epithelial cells express significantly more of the vaccine-targeted T4P than NTHI that encounters mock-infected (healthy) cells. These results strongly suggest that a vaccine strategy that targets the NTHI T4P will be effective under the most common predisposing condition: when the human host has a respiratory tract virus infection.

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Design and Characterization of Protein E-PilA, a Candidate Fusion Antigen for Nontypeable Haemophilus influenzae Vaccine

Cited by 9 publications

References 53 publications

Discovery and Contribution of Nontypeable Haemophilus influenzae NTHI1441 to Human Respiratory Epithelial Cell Invasion

Discovery and Contribution of Nontypeable Haemophilus influenzae NTHI1441 to Human Respiratory Epithelial Cell Invasion

Complement evasion by the human respiratory tract pathogens Haemophilus influenzae and Moraxella catarrhalis

Nontypeable Haemophilus influenzae Responds to Virus-Infected Cells with a Significant Increase in Type IV Pilus Expression

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