α-Toxin Induces Platelet Aggregation and Liver Injury during Staphylococcus aureus Sepsis

Abstract

During sepsis, small blood vessels can become occluded by large platelet aggregates of poorly understood etiology. During Staphylococcal aureus infection, sepsis severity is linked to the bacterial α-toxin (α-hemolysin, AT) through unclear mechanisms. In this study, we visualized intravascular events in the microcirculation and found that intravenous AT injection induces rapid platelet aggregation, forming dynamic micro-thrombi in the microcirculation. These aggregates are retained in the liver sinusoids and kidney glomeruli, causing multi-organ dysfunction. Acute staphylococcal infection results in sequestration of most bacteria by liver macrophages. Platelets are initially recruited to these macrophages and help eradicate S. aureus. However, at later time points, AT causes aberrant and damaging thrombosis throughout the liver. Treatment with an AT neutralizing antibody (MEDI4893) prevents platelet aggregation and subsequent liver damage, without affecting the initial and beneficial platelet recruitment. Thus, AT neutralization may represent a promising approach to combat staphylococcal-induced intravascular coagulation and organ dysfunction.

Antimicrobial and Antivirulence Action of Eugenia brejoensis Essential Oil in vitro and in vivo Invertebrate Models

“…Further, S. aureus grown in the presence of EbEO displayed reduced hemolytic activity and less ability to survival in whole blood. α-Hemolysin induces toxicity toward a broad range of cells and is associated to severe injuries in cutaneous (skin necrosis) and systemic infections (Berube and Bubeck Wardenburg, 2013;Geoghegan et al, 2018;Surewaard et al, 2018).…”

Unraveling the host's immune response to infection: Seeing is believing

“…The group found that platelets rapidly formed aggregates after exposure to alpha‐toxin secreted by Staphylococcus aureus . This caused damaging thrombosis throughout the liver and subsequent organ dysfunction . Neutralizing alpha‐toxin with a therapeutic antibody effectively prevented platelet aggregation and liver damage, without affecting initial bacterial capture, and thus offered a new approach that may help combat staphylococcal‐induced microvascular coagulation and organ dysfunction …”

“…37 Platelets can help trap and bundle circulating bacteria to promote infection clearance 38,39 ; albeit, this can similarly cause significant microvascular dysfunction and tissue injury. In a recent study, Surewaard et al 40 used IVM to investigate the mechanisms and treatment of microvascular dysfunction and thrombosis associated with systemic Staphylococcus aureus infections. The group found that platelets rapidly formed aggregates after exposure to alpha-toxin secreted by Staphylococcus aureus.…”

“…This caused damaging thrombosis throughout the liver and subsequent organ dysfunction. 40 Neutralizing alpha-toxin with a therapeutic antibody effectively prevented platelet aggregation and liver damage, without affecting initial bacterial capture, and thus offered a new approach that may help combat staphylococcal-induced microvascular coagulation and organ dysfunction. 40 Another study used liver IVM to examine sex-biased differences in the capture of blood-borne bacteria by Kupffer cells.…”

“…40 Neutralizing alpha-toxin with a therapeutic antibody effectively prevented platelet aggregation and liver damage, without affecting initial bacterial capture, and thus offered a new approach that may help combat staphylococcal-induced microvascular coagulation and organ dysfunction. 40 Another study used liver IVM to examine sex-biased differences in the capture of blood-borne bacteria by Kupffer cells. 30 Interestingly, Zeng et al 30 found that while male mice relied on complement opsonisation to capture systemic enteropathogenic Escherichia coli (EPEC), females were privy to faster capture due to preexisting natural antibodies against EPEC.…”