Bacterial virulence plays a crucial role in MRSA sepsis

Abstract

Bacterial sepsis is a major global cause of death. However, the pathophysiology of sepsis has remained poorly understood. In industrialized nations, Staphylococcus aureus represents the pathogen most commonly associated with mortality due to sepsis. Because of the alarming spread of antibiotic resistance, anti-virulence strategies are often proposed to treat staphylococcal sepsis. However, we do not yet completely understand if and how bacterial virulence contributes to sepsis, which is vital for a thorough assessment of such strategies. We here examined the role of virulence and quorum-sensing regulation in mouse and rabbit models of sepsis caused by methicillin-resistant S. aureus (MRSA). We determined that leukopenia was a predictor of disease outcome during an early critical stage of sepsis. Furthermore, in device-associated infection as the most frequent type of staphylococcal blood infection, quorum-sensing deficiency resulted in significantly higher mortality. Our findings give important guidance regarding anti-virulence drug development strategies for the treatment of staphylococcal sepsis. Moreover, they considerably add to our understanding of how bacterial sepsis develops by revealing a critical early stage of infection during which the battle between bacteria and leukocytes determines sepsis outcome. While sepsis has traditionally been attributed mainly to host factors, our study highlights a key role of the invading pathogen and its virulence mechanisms. Bacterial infections often develop sepsis as a complication. Sepsis is a severe blood infection and one of the main reasons for death, especially in hospitals of the developed world. Sepsis is believed to be due to an overshooting immune reaction to structures that most bacteria share. However, this model fails to explain why some bacteria cause more frequent and severe sepsis than others. In our study, which we performed with the main sepsis-causing bacteria, Staphylococcus aureus, we show that the outcome of sepsis depends on the battle between bacteria and white blood cells that happens early during infection. Many of the weapons that bacteria use for that battle are controlled by a quorum-sensing regulator, which implies that so-called anti-virulence strategies directed at that regulator may work to treat sepsis. However, we also show that targeting quorum-sensing is counterproductive when sepsis originates from biofilms on implanted catheters, which it often does. Our study shows that bacterial weaponry plays a key role in sepsis and gives important advice on how to use this finding for alternative drug development.