Disrupting Bordetella Immunosuppression Reveals a Role for Eosinophils in Coordinating the Adaptive Immune Response in the Respiratory Tract

Abstract

Recent findings revealed pivotal roles for eosinophils in protection against parasitic and viral infections, as well as modulation of adaptive immune responses in the gastric mucosa. However, the known effects of eosinophils within the respiratory tract remain predominantly pathological, associated with allergy and asthma. Simulating natural respiratory infections in mice, we examined how efficient and well-adapted pathogens can block eosinophil functions that contribute to the immune response. Bordetella bronchiseptica, a natural pathogen of the mouse, uses the sigma factor btrS to regulate expression of mechanisms that interfere with eosinophil recruitment and function. When btrS is disrupted, immunomodulators are dysregulated, and eosinophils are recruited to the lungs, suggesting they may contribute to much more efficient generation of adaptive immunity induced by this mutant. Eosinophil-deficient mice failed to produce pro-inflammatory cytokines, to recruit lymphocytes, to organize lymphoid aggregates that resemble Bronchus Associated Lymphoid Tissue (BALT), to generate an effective antibody response, and to clear bacterial infection from the respiratory tract. Importantly, the failure of eosinophil-deficient mice to produce these lymphoid aggregates indicates that eosinophils can mediate the generation of an effective lymphoid response in the lungs. These data demonstrate that efficient respiratory pathogens can block eosinophil recruitment, to inhibit the generation of robust adaptive immune responses. They also suggest that some post-infection sequelae involving eosinophils, such as allergy and asthma, might be a consequence of bacterial mechanisms that manipulate their accumulation and/or function within the respiratory tract.

“NETs and EETs, a Whole Web of Mess”

“…Transcriptomic data of macrophages challenged with this mutant indicate some Th2-related signatures [131]. Further studies in eosinophil-deficient mice, revealed that while the wildtype mice clear the infection in 14 days, mice lacking eosinophils present a long-term infections characteristic of the wildtype bacteria [17]. These results suggest that wildtype bacteria somehow block eosinophil influx in the lungs to prevent the generation of prompt and robust adaptive immunity and to promote long term bacterial persistence.…”

“…The compelling evidence that EETs are involved in infectious pathologies such as septicemia or fungal and viral respiratory diseases leads to the question of the implication of these traps in other bacterial infections. A recent study reveals how well-adapted pathogens can efficiently block eosinophilic influx in the lungs, causing a defect in adaptive responses associated with an increased pathogen persistence [17]. The Bordetella bronchiseptica sigma factor, btrS, regulates many immunomodulators associated with suppressing different aspects of the immune response [202].…”

“…This will be followed by a comparison between neutrophils and eosinophils as well as the traps they both form, and we outline similarities and differences between them. We will also dedicate a small section to exploring how pathogens can escape or evade neutrophils and their traps, as well as the recent discovery of bacterial modulation of eosinophils [17]. We give examples of some of the pathogens executing these defense mechanisms as well as some of the diseases that involve them ( Figure 1).…”

Eosinophils and Bacteria, the Beginning of a Story

“…infections is the increased risk for asthma and allergies [ 84 , 85 , 86 ], which suggests that bacteria trigger this hyper-reactive eosinophilic state. However, recent literature has revealed that B. bronchiseptica can suppress eosinophil influx in the lungs to promote bacterial persistence [ 87 ], suggesting that eosinophils, in fact, actively participate in the immune responses to Bordetella spp. infections.…”

“…Mice lacking eosinophils develop a long-term persistent respiratory infection due to a failure during the generation of adaptive immune responses [ 22 ]. Based on these results, Gestal et al have proposed a novel role for eosinophils in promoting pro-inflammatory responses during bacterial lung infections [ 87 ], suggesting a shift in the classical view of eosinophils as T H 2 associated cells, even during bacterial infections.…”