How testosterone increases severity of bacterial skin infections

This laboratory image shows Staphylococcus aureus bacteria streaked in the shape of a sex steroid, like testosterone. The left shape is of wild-type S. aureus, with the lighter halo around the shape indicating hemolysis, or the breakdown of red blood cells, releasing their hemoglobin into the surrounding fluid. The right shape is a quorum-sensing mutant strain of S. aureus, which cannot damage blood cells. Photo courtesy UT Southwestern

Testosterone, long implicated in sex-based differences in cardiovascular and metabolic disease, may also help explain why men are more likely than women to develop severe skin infections caused by Staphylococcus aureus, according to new research in Nature Microbiology. Investigators at UT Southwestern Medical Center in Dallas identified cutaneous androgens as direct regulators of S. aureus virulence, and they believe that finding may point to a mirror-image testosterone analogue, called an enantiomer (ent-T), as a potential topical therapeutic strategy.

While men are known to be more susceptible than women to skin and soft-tissue infections with S. aureus, the mechanistic basis has not been determined. In this study, Tamia Harris-Tryon, MD, PhD, Associate Professor of Dermatology and Immunology at UT Southwestern and her colleagues show that testosterone activates a bacterial communication pathway known as quorum sensing, increasing skin cell death and promoting the destruction of red blood cells and white blood cells (neutrophils). 

In mouse models, males secreted higher levels of testosterone from skin than females and were significantly more susceptible to MRSA colonization and dermal injury. Mice engineered with testosterone-deficient skin were resistant to MRSA infection, while exogenous testosterone applied to female mouse skin increased disease severity.

“This research has important implications for treating Staph skin infections and conditions complicated by Staphylococcus, such as atopic dermatitis, pemphigus, abscesses, and wound infections, including the deadliest skin infections caused by methicillin-resistant Staphylococcus aureus [MRSA],” Dr. Harris-Tryon said in a press release. “It also explains why men are more susceptible to Staph infections.”

Dr. Harris-Tryon and first author Maria S. John, PhD, have filed a patent for an ent-T–based transdermal therapy and are advancing preclinical development with support from UT Southwestern’s Office for Technology Development.

“Our exciting finding suggests we can inhibit S. aureus virulence rather than killing the bacteria directly, an approach that prevents infection, preserves beneficial skin microbes, and reduces the selective pressure that drives antibiotic resistance while offering a potential new strategy to treat infections, including MRSA,” Dr. John said.