Pertussis toxin is a protein-based exotoxin from the bacterium Bordetella pertussis, which causes whooping cough. As a primary virulence factor, the toxin is responsible for the severe symptoms of the disease. It operates by entering human cells and disrupting their communication and regulatory functions, which underlies many physiological effects, from the characteristic cough to impacts on the immune system.
Toxin Structure and Cellular Entry
Pertussis toxin (PTx) is an A-B type toxin, a structure with two main components. It has one active “A” subunit, S1, and a binding “B” oligomer, a ring-like structure made of five subunits: S2, S3, two copies of S4, and S5. The B oligomer makes initial contact with a host cell, recognizing and attaching to specific glycoconjugate molecules, which are proteins or lipids with attached sugar chains, on the cell’s surface. The toxin primarily targets ciliated respiratory epithelial cells and immune cells called phagocytes.
Once the B oligomer binds to surface receptors, the cell engulfs the toxin through receptor-mediated endocytosis. The toxin is brought into the cell within a vesicle called an endosome. From there, it travels through a retrograde transport pathway via the Golgi apparatus and endoplasmic reticulum. It is within these compartments that the active A subunit prepares for release into the cell’s cytosol.
Core Molecular Action
Once inside the host cell’s cytoplasm, the active S1 subunit acts as an ADP-ribosyltransferase. Its target is the alpha subunit (Gαi) of a family of inhibitory G-proteins (Gi/o), which are involved in cellular signaling. The S1 subunit catalyzes a reaction that transfers an ADP-ribose group from nicotinamide adenine dinucleotide (NAD+) onto a cysteine residue on the Gαi subunit.
This chemical modification prevents the G-protein from interacting with its corresponding receptor on the cell membrane. This uncouples the G-protein from its activation signal, locking it into an inactive state. The enzymatic nature of the S1 subunit means a single toxin molecule can modify numerous G-protein targets, amplifying its disruptive impact within the cell.
Disruption of Cellular Signaling
The inactivation of inhibitory G-proteins (Gi) disrupts the cell’s internal communication. The primary role of Gi proteins is to inhibit the enzyme adenylyl cyclase. With Gi proteins locked in an “off” state by the toxin, this inhibition is lifted, and adenylyl cyclase becomes constitutively active, meaning it is continuously “on” without any regulation.
This uncontrolled activity leads to a massive accumulation of a signaling molecule. The enzyme relentlessly converts adenosine triphosphate (ATP) into cyclic adenosine monophosphate (cAMP). Under normal conditions, cAMP levels are tightly controlled, as it functions as a second messenger to regulate cellular processes. The overproduction of cAMP throws these processes into disarray, impairing immune cell functions and leading to other systemic effects.
Physiological Consequences
The cellular disruption from elevated cAMP levels manifests as the clinical symptoms of whooping cough. In the ciliated cells lining the respiratory tract, the surge in cAMP increases mucus production and fluid secretion. This contributes to airway congestion and the violent, persistent coughing fits that characterize the disease.
The toxin also has a profound effect on the immune system. In immune cells such as neutrophils and macrophages, high cAMP levels impair their functions, including their ability to move toward an infection site, engulf bacteria, and signal for help. This paralysis of the initial immune response allows Bordetella pertussis to colonize the respiratory tract more effectively.
A hallmark of pertussis infection is an increase in lymphocytes in the bloodstream, a condition known as lymphocytosis. The toxin’s modification of G-proteins in these white blood cells inhibits their ability to leave the bloodstream and enter lymph nodes. This trapping of lymphocytes in circulation leads to their abnormally high counts in blood tests, serving as a diagnostic indicator.
Relevance in Vaccine Development
Understanding the pertussis toxin’s mechanism was foundational for creating modern acellular pertussis vaccines, often given as part of the DTaP combination. The goal was to neutralize the toxin’s harmful activity while preserving its ability to generate an immune response. This is achieved by creating a pertussis toxoid.
The native toxin is purified and then chemically inactivated, which destroys the S1 subunit’s enzymatic activity but leaves the overall protein structure intact. When this harmless toxoid is injected, the body mounts a protective antibody response that can neutralize the real toxin during an infection, preventing severe symptoms.