Pertactin contributes to shedding and transmission of Bordetella bronchiseptica

Abstract

Whooping cough is resurging in the United States despite high vaccine coverage. The rapid rise of Bordetella pertussis isolates lacking pertactin (PRN), a key vaccine antigen, has led to concerns about vaccine-driven evolution. Previous studies showed that pertactin can mediate binding to mammalian cells in vitro and act as an immunomodulatory factor in resisting neutrophil-mediated clearance. To further investigate the role of PRN in vivo, we examined the functions of pertactin in the context of a more naturally low dose inoculation experimental system using C3H/HeJ mice that is more sensitive to effects on colonization, growth and spread within the respiratory tract, as well as an experimental approach to measure shedding and transmission between hosts. A B. bronchiseptica pertactin deletion mutant was found to behave similarly to its wild-type (WT) parental strain in colonization of the nasal cavity, trachea, and lungs of mice. However, the pertactin-deficient strain was shed from the nares of mice in much lower numbers, resulting in a significantly lower rate of transmission between hosts. Histological examination of respiratory epithelia revealed that pertactin-deficient bacteria induced substantially less inflammation and mucus accumulation than the WT strain and in vitro assays verified the effect of PRN on the induction of TNF-α by murine macrophages. Interestingly, only WT B. bronchiseptica could be recovered from the spleen of infected mice and were further observed to be intracellular among isolated splenocytes, indicating that pertactin contributes to systemic dissemination involving intracellular survival. These results suggest that pertactin can mediate interactions with immune cells and augments inflammation that contributes to bacterial shedding and transmission between hosts. Understanding the relative contributions of various factors to inflammation, mucus production, shedding and transmission will guide novel strategies to interfere with the reemergence of pertussis.

The Fim and FhaB adhesins play a crucial role in nasal cavity infection and Bordetella pertussis transmission in a novel mouse catarrhal infection model

“…Moreover, Prn was also reported to mediate resistance to neutrophil-mediated clearance [ 51 ] and was recently implicated in triggering of shedding of the related B . bronchiseptica bacteria from the nasal cavity of mice [ 52 ]. Therefore, we constructed and tested an array of isogenic B .…”

“…Finally, it was recently shown to play an important role in triggering of shedding and transmission of the B . bronchiseptica bacteria from the nasal cavity of the TLR4-deficient C3H/HeJ mice [ 52 ]. However, we did not observe here any major contribution of PRN to the nasal colonization and shedding capacity of B .…”

Probing Immune-Mediated Clearance of Acute Middle Ear Infection in Mice

“…Although B. bronchiseptica is not a primary human pathogen, the efficient colonization of the middle ears of mice and the unparalleled tools available to study the immune response in mice are likely to make this experimental system valuable for the study of the mechanistic detail of the workings of functional immunity in the middle ear. In addition, B. bronchiseptica harbors an array of well-studied virulence factors, for which the corresponding deleted mutant strains are available to probe host–pathogen interactions ( Cotter et al., 1998 ; Mattoo et al., 2000 ; Mattoo et al., 2001 ; Irie et al., 2004 ; Dewan et al., 2017 ; Gestal et al, 2019 ; Ma et al., 2021 ). Identifying the factors involved in overcoming physiological barriers to ascend the host Eustachian tube and/or overcome innate host immunity to naturally colonize the middle ears would significantly inform our understanding of how middle ear infections are established.…”

Accelerated Evolution by Diversity-Generating Retroelements

“…Bordetella pertussis and related species alternate between virulent (Bvg + ) and nonvirulent (Bvg − ) phases in response to environmental signals transduced through the BvgAS phosphorelay (9, 67) (Figure 1c). Uniquely in the Bvg + state, Bordetella express adhesins, toxins, and other factors that facilitate colonization of the respiratory tract, including an autotransporter protein called pertactin (59). While investigating ligand-receptor interactions between pertactin and a Bordetella phage that preferentially infects Bvg + phase cells, called BPP-1 (Bvg-plus phage 1), Liu and colleagues (54) made a seminal observation: While the majority of BPP-1 progeny infected Bvg + cells as expected, a small number acquired the ability to efficiently infect Bvg − phase cells (termed BMP, or Bvg-minus phage), indicating that a tropism switch had occurred.…”