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Adenylate cyclase toxin (CyaA) is released from bacterium Bordetella pertussis by the T1SS (Type 1 secretion system) and released in the host’s respiratory tract in order to suppress its early innate and subsequent adaptive immune defense.
CyaA plays a particular role in the early phases of airway colonization. It is able to instantly ablate the bactericidal oxidative burst, along with the opsonophagocytic killing capacities of neutrophils and macrophages. As a result, it enables establishment of Bordetella infection of airway mucosa and promotes immune evasion of B. pertussis, by affecting the host’s immune cells.
Structure
The toxin is a 1706 residue-long polypeptide that consists of an N-terminal ~400 residue-long adenylate cyclase (AC) enzyme that is linked to a characteristic RTX hemolysin (Hly) moiety of ~1300 residues. This Hly moiety itself consists of four functional subdomains, comprising: (i) a hydrophobic pore-forming domain ; (ii) an activation domain, with the two posttranslationally acylated lysine residues; (iii) a receptor-binding RTX domain consisting of ~40 typical calcium-binding RTX nonapeptide repeats]; and (iv) a non-processed C-terminal secretion signal recognized by a bacterial type I secretion system (T1SS), respectively.
Mode of action in host cells
Once in host cells, CyaA binds the complement receptor 3 (CR3), the αMβ2 integrin known also as CD11b/CD18 or Mac-1. Then, the toxin translocates its AC enzyme domain across the cytoplasmic membrane of CR3-expressing myeloid cells, such as macrophages, neutrophils and dendritic cells.
Inserting in the cell’s membrane results in an influx of calcium ions that leads to a calpain-mediated cleavage of talin. The CyaA–CR3 complex relocates into lipid rafts and the AC domain is translocated across the cellular membrane into the transmembrane region, where signaling complexes, such as protein kinase A, are clustered.
Inside the cells, the AC enzyme binds calmodulin and catalyzes unregulated conversion of ATP into the key second messenger molecule 3',5'-cyclic adenosine monophosphate (cAMP). cAMP is responsible for the incapacitation of the bactericidal activities of the target cells. The RTX hemolysin part of CyaA is functionally independent of AC domain and forms oligomeric cation-selective pores that allow cytosolic potassium ions to leak from cells via the cellular membrane.
Interference with immune defence
The fast production of very high levels of intracellular cAMP in CD11b-expressing immune cells that encounter CyaA, immediately interferes with the physiological functions of phagocytes. In monocytes and macrophages, the CyaA-produced cAMP signaling through the cAMP/protein kinase A (PKA) pathway blocks the production of reactive oxygen species (ROS). This also halts the complement-mediated uptake of opsonized particles. At higher CyaA doses, FcR-mediated phagocytosis is also inhibited.
Through cAMP signaling, CyaA also alters TLR-triggered maturation of dendritic cells, inhibiting proinflammatory IL-12 and TNF-α secretion and enhancing IL-10 production and Treg expansion, preventing the induction of adaptive immune responses to Bordetella infections.
The enzymatic AC activity of CyaA also seems to prolong the intracellular survival of non-opsonized internalized (invading) B. pertussis bacteria that enter into human and murine macrophages by a non-phagocytic mechanism.
See also
Pertussis toxin
Anthrax toxin
References
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Christian Youth Athletics Association
CYAA is a non-profit ministry that provides an uplifting alternative for youth athletes ages 4-18 years old. Participants develop fundamental skills in the younger age divisions, while growing and being more competitive in the challenging older age divisions.
About CYAA
CYAA exists to provide a Christ-Centered, enjoyable, and competitive sports outlet for boys and girls ages 4 through 18. We currently offer Soccer, Basketball, and Flag Football. Participants develop fundamental skills in the younger age divisions, while growing and being more competitive as they move to the older age divisions.
Basketball Registration is OPEN! - Christian Youth Athletics …
Our coaches and volunteers are invaluable to CYAA and our players, maybe more now than ever. We have all seen the impact that recent challenges have had on our children and families. If …
CYAA 2024 FLAG FOOTBALL REGISTRATION IS CLOSED
cyaa 2024 flag football registration is closed Our coaches and volunteers are invaluable to CYAA and our players, maybe more now than ever. We have all seen the impact that the challenges …
Sports - Christian Youth Athletics Association
The philosophy of CYAA is to create an atmosphere of fun, development, excitement and sportsmanship, while keeping focus on God-given value. Our goal is to always teach …
SOCCER 2024 REGISTRATION IS OPEN!! - Christian Youth …
Sep 24, 2023 · Hello CYAA Soccer Families! We are excited to announce that registration for our 2024 Soccer Season is OPEN! Take advantage of our Sibling Discount and save and extra $20 on regular registration fees on each registration after the first full price registration!
SOCCER 2025 REGISTRATION IS CLOSED - Christian Youth …
Our coaches and volunteers are invaluable to CYAA and our players, maybe more now than ever. We have all seen the impact that recent societal challenges have had on our children and families. If you are interested in impacting the lives of these youth for the GOOD, please click on the Volunteer Registration Link below. Together, in the love of ...
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There will be a table set up at the entrance to the gym and a CYAA Board Member will be there to check in your child every week as well as provide any information or handouts you may need.
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Involvement with CYAA may provide spiritual growth and fellowship, but in no way should it be seen as a substitute for commitment to a local church. Commitment to CYAA – Volunteers believe in and agree with the mission and ministry of CYAA.
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May 19, 2021 · Assessments are mandatory for players in Div. 1 thru Div. 4 (ages 6-15). No special equipment needed, just cleats if your child owns them already. If you have any questions please feel free to reach out at: admin@cyaa.org. God Bless, CYAA