Toxoplasma gondii infection reprograms monocyte adherence and motility
Authors: Drewry Lisa L , Sibley L David 
Published: November 2023

Toxoplasma gondii is a parasitic protist and opportunistic pathogen of humans. In healthy humans, acute toxoplasmosis is typically benign, causing only flu‐like symptoms. However, parasites are not cleared when this acute infection resolves, and the host is instead left chronically infected for life. The chronic infection is caused by slow‐growing parasite cysts that are predominantly located in long‐lived, differentiated cells, including those of the central nervous system and skeletal muscle. If immunity wanes in a chronically infected host, parasite growth can re‐activate and lead to a life‐threatening infection. In this scenario, brain cysts are a particular concern as they can trigger severe toxoplasmic encephalitis.

Monocytes have been proposed as potential Trojan horses that deliver T. gondii parasites across the blood‐brain barrier and into the central nervous system. This model has been largely based on reports that adoptive transfer of T. gondii‐infected monocytes into mice results in more rapid parasite dissemination to the brain, compared to oral inoculation with extracellular parasites. However, whether T. gondii‐infected monocytes efficiently cross blood‐brain barrier endothelium has not been rigorously tested.

Using multiple in vitro models of human endothelial barriers, we have found that T. gondii infection markedly impairs monocyte adherence to and transmigration through endothelial barriers. Specifically, adherence to resting and inflamed human brain endothelial cell monolayers, as well as fibronectin and collagen is diminished. Likely contributing to this adherence block, T. gondii‐infected monocytes overwhelmingly fail to spread on ligands and mobilize integrins to their ligand‐contacting pole. Consistent with decreased endothelial adherence, infected monocytes also inefficiently transmigrate through endothelial barriers, with a more than 10‐fold defect relative to mock‐infected cells. This transmigration block is observed with in vitro barriers composed of immortalized human brain or umbilical vein endothelial cell lines, and primary human aortic endothelial cells. Curiously, this diminished adherence and transmigration is accompanied by an increase in active monocyte locomotion on the surface of endothelial cells. T. gondii‐infected monocytes travel longer path‐lengths at higher average velocities than mock infected cells, resulting in greater net displacement. In concert, these results are inconsistent with a simple Trojan horse model where parasites are ferried across the blood‐brain barrier within monocytes. Instead, we propose that the enhanced motility of infected monocytes supports dissemination of the parasite during acute infection. We are currently further characterizing the motility of T. gondii‐infected monocytes, and the molecular mechanisms underlying this aberrant motility to better understand how this reprogramming of monocyte motility contributes to T. gondii survival in mammalian hosts.

Support or Funding Information

This work is supported by an NIH award to LDS and NSF GRFP award to LLD.