Pertussis Toxin (PT) is a protein toxin produced and secreted by the bacterium Bordetella pertussis, which causes the highly contagious respiratory illness known as whooping cough, or pertussis. PT is a major virulence factor that plays a role in the development of the disease’s most severe symptoms. By targeting specific communication pathways within human cells, the toxin causes widespread dysfunction that disrupts the body’s natural defense mechanisms. The toxin’s presence dictates the severity and clinical course of a B. pertussis infection.
Origin and Structure of Pertussis Toxin
Bordetella pertussis secretes Pertussis Toxin as a large, multi-component protein. The toxin is classified as an A-B type toxin, a structure common among bacterial poisons where one part is the active enzyme (A) and the other is the binding and delivery mechanism (B). PT is an AB5 structure, consisting of six total subunits: a single active subunit (S1) and five binding subunits (S2, S3, S4, and S5, with two copies of S4) that form a ring-shaped base.
The S1 subunit is the enzymatically active portion, carrying the harmful function of the toxin once it enters a host cell. The other five subunits (S2 through S5) form the B-oligomer, whose primary function is to recognize and bind to receptors on the surface of host cells. This binding allows the entire toxin complex to attach to the cell membrane and initiate its internalization. The B-oligomer then facilitates the delivery of the active S1 subunit into the cell’s interior, where it disrupts cellular machinery.
How Pertussis Toxin Hijacks Cells
After the toxin binds to the surface of a respiratory cell, the active S1 subunit is released into the cytoplasm. The S1 subunit functions as an enzyme that chemically modifies specific regulatory proteins inside the cell, a process called ADP-ribosylation. The specific targets of PT are the inhibitory G-proteins, known as G$\text{i}$ proteins, which normally turn off certain cellular signals.
By attaching a chemical group (ADP-ribose) to the alpha subunit of the G$\text{i}$ protein, PT permanently locks the protein in an inactive state. This paralysis prevents the G$\text{i}$ protein from inhibiting the production of the signaling molecule cyclic AMP (cAMP). With the G$\text{i}$ protein disabled, internal signaling pathways run unchecked, leading to abnormally high and sustained levels of cAMP. This regulatory failure breaks down the cell’s ability to communicate and respond to external signals.
Why the Toxin Causes Whooping Cough Symptoms
The widespread G-protein disruption caused by Pertussis Toxin translates directly into the characteristic and severe symptoms of whooping cough. The uncontrolled surge of cyclic AMP alters the function of ciliated epithelial cells lining the respiratory tract, leading to excessive fluid and mucus secretion. This excessive production, combined with other bacterial toxins that directly damage the cilia, overwhelms the airway’s clearance mechanisms, resulting in the prolonged, severe coughing fits.
Pertussis Toxin also severely impairs the host’s immune response, contributing to the severity and duration of the illness. The toxin’s activity on immune cells prevents them from migrating correctly to the site of infection in the lungs. This disruption leads to a dramatic increase in the number of lymphocytes in the bloodstream, a condition known as lymphocytosis, which is a hallmark of pertussis infection. Furthermore, the toxin heightens the sensitivity of the respiratory tract to substances like histamine, causing inflammation and swelling of the airways, which exacerbates the difficulty in breathing and the paroxysmal nature of the cough.
Pertussis Toxin in Vaccine Development
The powerful immune response generated against Pertussis Toxin makes it a crucial component in modern disease prevention strategies. PT is included in all current acellular pertussis vaccines, such as DTaP and Tdap, because the immune system produces protective antibodies against it. However, because the native toxin is highly potent and harmful, it must first be rendered completely safe through a process called detoxification.
Detoxification converts the toxin into a toxoid, which retains the original structure necessary for immune recognition but loses all its toxic enzymatic activity. This is typically achieved by chemical treatment, such as with formaldehyde or glutaraldehyde, which modifies the active S1 subunit to prevent ADP-ribosylation without altering the overall shape of the protein. The resulting Pertussis Toxoid stimulates the body to produce antibodies that can neutralize the real toxin upon future infection, providing a defense that is considered the major protective mechanism of the vaccine.