Naturally circulating pertactin-deficient Bordetella pertussis strains induce distinct gene expression and inflammatory signatures in human dendritic cells

Abstract

Respiratory infections caused by Bordetella pertussis are reemerging despite high pertussis vaccination coverage. Since the introduction of the acellular pertussis vaccine in the late twentieth century, circulating B. pertussis strains increasingly lack expression of the vaccine component pertactin (Prn). In some countries, up to 90% of the circulating B. pertussis strains are deficient in Prn. To better understand the resurgence of pertussis, we investigated the response of human monocyte-derived dendritic cells (moDCs) to naturally circulating Prn-expressing (Prn-Pos) and Prn-deficient (Prn-Neg) B. pertussis strains from 2016 in the Netherlands. Transcriptome analysis of moDC showed enriched IFNα response-associated gene expression after exposure to Prn-Pos B. pertussis strains, whereas the Prn-Neg strains induced enriched expression of interleukin- and TNF-signaling genes, as well as other genes involved in immune activation. Multiplex immune assays confirmed enhanced proinflammatory cytokine secretion by Prn-Neg stimulated moDC. Comparison of the proteomes from the Prn-Pos and Prn-Neg strains revealed, next to the difference in Prn, differential expression of a number of other proteins including several proteins involved in metabolic processes. Our findings indicate that Prn-deficient B. pertussis strains induce a distinct and stronger immune activation of moDCs than the Prn-Pos strains. These findings highlight the role of pathogen adaptation in the resurgence of pertussis as well as the effects that vaccine pressure can have on a bacterial population.

Bordetella pertussis-infected innate immune cells drive the anti-pertussis response of human airway epithelium

“…Another study showed the ability of recombinant adenylate cyclase toxin (ACT), a virulence factor produced by B. pertussis , to inhibit IL-17A induced CXCL8 secretion by HAE cells 34 . We showed that the live naturally circulating B. pertussis strain used in this study, which has previously been shown to produce ACT 22 , was unable to inhibit IL-1β-induced CXCL8 secretion. Future studies should investigate whether live B. pertussis is able to inhibit IL-17A-induced chemokine secretion by the HAE and whether this is dependent on B. pertussis -derived ACT.…”

“…However, this was most likely due to the low amount of donors available for the RNA-seq and does not necessarily reflect actual differences between the strains. Whether these differences are due to the variation among the stains which may differently express other antigens besides pertactin 22 , 23 could be investigated in future studies using more B. pertussis strains per group. To make sure we analyzed genes differently expressed after B. pertussis infection we only included the genes commonly up- or downregulated after incubation with any of the tested B. pertussis strains.…”

“…In this study we used three B. pertussis strains isolated from Dutch pertussis patients: two isolated in 2016 (Bp1 and Bp2) and another isolated in 1998 (Bp3), Bp2 was deficient for the virulence factor pertactin. All strains were selected based on the grouping described by Kroes et al 22 . In short, all strains have comparable genotypes (pertussis toxin (ptx) promoter 3, pertactin type 2, ptxA type 1, fimbriae 2/3 type 1) and only differ in pertactin expression or year of isolation.…”

“…Total RNA was extracted from HAE cells exposed to medium only, and after a 6 h incubation with B. pertussis . Library preparation and RNA sequencing were performed as previously described 22 . FASTQ files were aligned to the Homo sapiens reference genome (GRCh38) and most recent transcript annotations using kallisto (v0.46.1) 40 .…”

Long Lasting Antibodies From Convalescent Pertussis Patients Induce ROS Production and Bacterial Killing by Human Neutrophils

“…Statistical analysis was performed as previously described ( Kroes et al., 2021 ). Briefly, the permutation based exact Wilcoxon-Mann-Whitney test was used ( wilcox_test function from rstatix R package).…”