Eosinophils as drivers of bacterial immunomodulation and persistence

Abstract

Traditionally, eosinophils have been linked to parasitic infections and pathological disease states. However, emerging literature has unveiled a more nuanced and intricate role for these cells, demonstrating their key functions in maintaining mucosal homeostasis. Eosinophils exhibit diverse phenotypes and exert multifaceted effects during infections, ranging from promoting pathogen persistence to triggering allergic reactions. Our investigations primarily focus on Bordetella spp., with particular emphasis on Bordetella bronchiseptica, a natural murine pathogen that induces diseases in mice akin to pertussis in humans. Recent findings from our published work have unveiled a striking interaction between B. bronchiseptica and eosinophils, facilitated by the btrS-mediated mechanism. This interaction serves to enhance pathogen persistence while concurrently delaying adaptive immune responses. Notably, this role of eosinophils is only noted in the absence of a functional btrS signaling pathway, indicating that wild-type B. bronchiseptica, and possibly other Bordetella spp., possess such adeptness in manipulating eosinophils that the true function of these cells remains obscured during infection. In this review, we present the mounting evidence pointing toward eosinophils as targets of bacterial exploitation, facilitating pathogen persistence and fostering chronic infections in diverse mucosal sites, including the lungs, gut, and skin. We underscore the pivotal role of the master regulator of Bordetella pathogenesis, the sigma factor BtrS, in orchestrating eosinophil-dependent immunomodulation within the context of pulmonary infection. These putative convergent strategies of targeting eosinophils offer promising avenues for the development of novel therapeutics targeting respiratory and other mucosal pathogens.

Keywords: Bordetella spp.; BtrS; Th17 microenvironment; eosinophils; immune homeostasis; long-term protection; mucosal immunity; mucosal infections; persistence; pertussis; whooping cough.

Fig 1

Predicted kinetics of the immune responses to RB50 and RB50ΔbtrS. The dotted lines indicate lung bacterial burden (blue shows RB50 and red shows RB50ΔbtrS). Immune cell recruitment to the lungs is shown in green (neutrophils), magenta (macrophages), black (eosinophils), yellow (T cells), and lilac (B cells). Relative numbers are indicated in the Y-axis, while days post-infection are shown in the X-axis.

Fig 2

Multifaced roles of eosinophils. Eosinophils can be considered into two categories, more anti-inflammatory phenotype (blue) associated with bacterial persistence or more pro-inflammatory (red) where eosinophils actively contribute to bacterial killing during infection.

Fig 3

Predicted role of eosinophils during Bordetella spp. infections. Bordetella spp. secrete “Bordetella eosinophil factors” that will suppress eosinophil effector function leading to persistence. Deletion of the bacterial sigma factor btrS results in no suppression of eosinophils. In this context, eosinophils promote adaptive immune responses, formation of germinal centers in the lungs, and rapid clearance of infection.