Host Determinants of Toxicity and Inflammation: Learning from staphylococcal alpha-toxin

Staphylococcus aureus is a bacterium commonly found in humans. Approximately one-third of healthy adults carry this bacterium without becoming ill. However, S. aureus can cause infections with varying clinical manifestations. Most people develop only mild skin infections. In rare cases, life-threatening conditions such as necrotizing pneumonia or severe infections of the skin and soft tissues can occur. Why some people become seriously ill and others do not is not yet fully understood.
An important factor in the disease caused by S. aureus is a toxin produced by the bacterium: α-toxin. This toxin creates small pores in the membrane of human cells, causing cells to be damaged or die. In this thesis, we investigated which variables contribute to how harmful this toxin is to human cells.
We studied the molecular interaction between α-toxin and human cells and found that the toxin binds to an important and conserved component of the membrane protein ADAM10. In addition, we demonstrate that conditions within the body, such as the acidity (pH) of the environment, can strongly influence the activity of the toxin. Finally, we studied patients with a rare genetic defect in the OTULIN gene. These patients are, among other things, highly sensitive to the harmful effects of α-toxin and can consequently develop life-threatening infections.
Our findings show that the severity of S. aureus infections is determined by both the bacterium and the host. The genetic makeup and environmental conditions within the body influence the sensitivity of human cells to substances produced by S. aureus. A better understanding of these interactions could contribute to more targeted treatments for severe bacterial infections in the future.