OC 66.3 - Lack of Plk3 Results in Reduced Platelet Reactivity that Limits Bacteria Infiltration into the Blood Following Enteric Infection

Background: Sepsis is a dysregulated host response to infection that can result in death. Platelets are known to regulate immune responses but their role in sepsis progression is poorly understood. Polo-like kinases (Plk) are evolutionarily conserved serine/threonine kinases that regulate the cell cycle. Plk3 is expressed in platelets and megakaryocytes, but its role in platelet and immune function is unknown.

Aims: Determine the effect of platelet reactivity on polymicrobial sepsis in vivo.

Methods: Platelet activity was characterized by established assays including aggregation, granule secretion, and in vitro thrombus formation using microfluidics. We used WT and Plk3-/- mice to evaluate the role of platelets in bacteremia induced by either cecal ligation and puncture (CLP) or cecal slurry (CS) injection.

Results: Plk3-/- mice survive indefinitely after CLP and CS injection whereas most WT mice died within 48 h. Because platelet reactivity is heightened during the initial phases of sepsis, we evaluated platelet function in Plk3-/- mice. Platelet reactivity to physiological agonists such as thrombin, collagen, ADP and TxA2 is significantly reduced in Plk3-/- mice compared to WT mice (p < 0.05). Consistently, thrombus growth is impaired when whole blood from Plk3-/- mice on immobilized fibrinogen or collagen compared to WT (p < 0.05). Therefore, we analyzed platelet deposition in the lung after CLP in WT and Plk3-/- mice and found less platelet deposition in Plk3-/- mouse lungs compared to WT (p < 0.05). Early bacteria infiltration into the blood in Plk3-/- mice is greatly inhibited following CS injection (p < 0.05), which could be due to limited platelet reactivity as activated platelets release factors that enhance endothelial permeability.

Conclusion(s): Collectively, our data suggest that reduced platelet reactivity seen in Plk3-/- mice control bacterial infiltration into blood which could be responsible for improved survival of these mice.