# Besnoitia besnoiti-Induced Neutrophil Extracellular Traps (NETs): Metabolic Signature, Signaling Pathways, Receptors and Implications on Pathogenesis

## TL;DR

This paper reviews how the parasite Besnoitia besnoiti triggers neutrophil extracellular traps in cattle, contributing to disease progression and suggesting new treatment approaches.

## Contribution

The paper provides a comprehensive review of the metabolic and signaling mechanisms of B. besnoiti-induced NETs and their role in disease pathogenesis.

## Key findings

- B. besnoiti tachyzoites and bradyzoites trigger excessive neutrophil extracellular trap formation in cattle.
- NETs contribute to endothelial damage and inflammation, worsening bovine besnoitiosis pathogenesis.
- Understanding NETs' metabolic and signaling pathways could lead to novel therapeutic strategies.

## Abstract

Bovine besnoitiosis is a neglected debilitating parasitic disease of cattle caused by the apicomplexan parasite Besnoitia besnoiti, resulting in significant economic losses for livestock producers. Due to expansion of the disease into previous non-endemic European countries as well as the lack of effective treatments and control strategies to manage it, there is a need to elucidate early host innate immune reactions during acute- and chronic bovine besnoitiosis. Polymorphonuclear neutrophils (PMN) are the first leukocytes recruited to the site of infection. Consequently, an important defense mechanism displayed by bovine PMN to combat invading pathogens is the extrusion of neutrophil extracellular traps (NETs). However, acute and chronic B. besnoiti parasitic stages (i.e., tachyzoites and bradyzoites) elicit an excessive host innate immune response, leading to possible NET-associated inflammation and tissue injury, thereby contributing to the pathogenesis of this cattle parasitosis. Thus, to provide insights into potential therapeutic approaches to avoid excessive NETs extrusion in vivo, the present review will focus on the metabolic signature, signaling pathways, receptors, and pathogenesis of B. besnoiti-triggered bovine NETs formation.

Besnoitia besnoiti is an apicomplexan parasite responsible for bovine besnoitiosis, a debilitating disease in cattle resulting in local and systemic clinical signs with detrimental effects on reproductive performance and productivity in livestock. Fast-replicating tachyzoites and slowly proliferating bradyzoites elicit an excessive host innate immune response, mainly by activated polymorphonuclear neutrophils (PMN), which extrude neutrophil extracellular traps (NETs) as a defense mechanism. These PMN-derived structures, composed principally of DNA, histones, and peptides, play a crucial role not only in parasite entrapment but also in NET-associated endothelial damage, thereby most likely contributing to the pathogenesis of this neglected cattle parasitosis. Uncontrolled production of NETs or their inadequate removal may perpetuate an inflammatory environment in the vasculature and epidermis. Thus, novel alternative treatment of animals with chronic bovine besnoitiosis displaying severe clinical manifestations such as hyperkeratosis, vulvovaginitis and orchitis, could be considered for future study to either hampering NETs release or reducing NETs concentrations in affected tissues. Since effective treatments and control strategies for bovine besnoitiosis do not yet exist, this review serves as a guide for further research on the metabolic signature, signaling pathways, receptors, and pathogenesis of B. besnoiti-triggered NETs formation, providing insights into potential therapeutic approaches to avoid excessive NETs extrusion.