Immunomodulation as a Novel Strategy for Prevention and Treatment of Bordetella spp. Infections

Gestal, Mónica Cartelle; Johnson, Hannah; Harvill, Eric T.

doi:10.3389/fimmu.2019.02869

Cited by 11 publications

(14 citation statements)

References 303 publications

(219 reference statements)

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“…It is well-established that Bordetella spp. sense details of the local host environment [ 65 , 92 , 93 , 94 , 95 ] and carefully and coordinately regulate multiple mechanisms to modulate host immune responses, suppressing the generation of robust immunity [ 55 , 92 , 96 ]. The type 3 and type 6 secretion systems [ 97 , 98 ], adenylate cyclase toxin [ 99 , 100 , 101 ], pertussis toxin [ 102 , 103 ], and other immunomodulators can affect immune cells in vitro and in vivo, and disrupting their carefully choreographed expression can lead to much more robust adaptive immunity [ 55 ].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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“…Since this topic has been extensively covered in several reviews [50,84,[128][129][130], only a few highlights are mentioned here. Bordetella pertussis harbors many immunomodulators that control several aspects of the host immune response [1,131,132] including NETs. B. pertussis suppresses the generation of ROS inhibiting NET formation.…”

Section: Bacterial Mechanisms To Escape Netsmentioning

confidence: 99%

“…The immune system is a complex myriad of signals that orchestrates the timing, length, and quantity of the immune response [1]. A classic immune response consists of very well-coordinated steps and begins with innate immunity providing the first level of protection.…”

Section: Introductionmentioning

confidence: 99%

“NETs and EETs, a Whole Web of Mess”

et al. 2020

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Neutrophils and eosinophils are granulocytes that have very distinct functions. Neutrophils are first responders to external threats, and they use different mechanisms to control pathogens. Phagocytosis, reactive oxygen species, and neutrophil extracellular traps (NETs) are some of the mechanisms that neutrophils utilize to fight pathogens. Although there is some controversy as to whether NETs are in fact beneficial or detrimental to the host, it mainly depends on the biological context. NETs can contribute to disease pathogenesis in certain types of diseases, while they are also undeniably critical components of the innate immune response. On the contrary, the role of eosinophils during host immune responses remains to be better elucidated. Eosinophils play an important role during helminthic infections and allergic responses. Eosinophils can function as effector cells in viral respiratory infections, gut bacterial infections, and as modulators of immune responses by driving the balance between Th1 and Th2 responses. In particular, eosinophils have biological activities that appear to be quite similar to those of neutrophils. Both possess bactericidal activity, can activate proinflammatory responses, can modulate adaptive immune responses, can form extracellular traps, and can be beneficial or detrimental to the host according to the underlying pathology. In this review we compare these two cell types with a focus on highlighting their numerous similarities related to extracellular traps.

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“…Both CypA and Cyp40 directly bound to PTS1 in vitro and application of pharmacological Cyp inhibitors such as cyclosporine A (CsA) protected CHO-K1 cells from intoxication with PT. In the presence of Cyp inhibitor, less PTS1 reached the cytosol and there was less ADP-ribosylated Giα, implicating that Cyps are required for uptake of PTS1 into the cytosol 29 , 34 .…”

Section: Introductionmentioning

confidence: 98%

Pharmacological targeting of host chaperones protects from pertussis toxin in vitro and in vivo

Ernst

Mittler

Winkelmann

et al. 2021

Sci Rep

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Whooping cough is caused by Bordetella pertussis that releases pertussis toxin (PT) which comprises enzyme A-subunit PTS1 and binding/transport B-subunit. After receptor-mediated endocytosis, PT reaches the endoplasmic reticulum from where unfolded PTS1 is transported to the cytosol. PTS1 ADP-ribosylates G-protein α-subunits resulting in increased cAMP signaling. Here, a role of target cell chaperones Hsp90, Hsp70, cyclophilins and FK506-binding proteins for cytosolic PTS1-uptake is demonstrated. PTS1 specifically and directly interacts with chaperones in vitro and in cells. Specific pharmacological chaperone inhibition protects CHO-K1, human primary airway basal cells and a fully differentiated airway epithelium from PT-intoxication by reducing intracellular PTS1-amounts without affecting cell binding or enzyme activity. PT is internalized by human airway epithelium secretory but not ciliated cells and leads to increase of apical surface liquid. Cyclophilin-inhibitors reduced leukocytosis in infant mouse model of pertussis, indicating their promising potential for developing novel therapeutic strategies against whooping cough.

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Immunomodulation as a Novel Strategy for Prevention and Treatment of Bordetella spp. Infections

Cited by 11 publications

References 303 publications

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

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

“NETs and EETs, a Whole Web of Mess”

Pharmacological targeting of host chaperones protects from pertussis toxin in vitro and in vivo

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