Role of GR-1+ monocytes in dissemination and invasion of the brain by T. gondii, and defense against toxoplasmosis
Final Report Abstract
The intracellular parasite Toxoplasma gondii is controlled by a strong innate Thi response In the murine model. In this study we demonstrate, that following oral infection the parasite rapidly elicits recruitment of Gr1+ F4/80+ monocytes to build a defensive line in the place of their entry. Gr1+ monocytes are localized at the basement membrane in the small intestine, specialy in the lamina propria and in the crypts. The results by Flow cytometry demonstrate, that this inflammatory monocyte subset are Cd11b+ Ly6C+ and Ly6G-, and are not neutrophils or myeloid DCs. Knock out mice lacking the chemokine receptor CCR2 or the ligand MCP1, fall to recruit Gr1+ inflammatory monocytes, while dendrific cell recruitment remain unaltered. The selective lack of Gr1+ inflammatory monocytes resulted in an inability to control replication of the parasite, influx of neutrophils, extensive intestinal necrosis. Death of mice occured within 10 days, and high levels of peripherial Th1 cytokines were detected. Adoptive transfer of sorted Gr1+ inflammatory monocytes confirmed their ability to home to the intestine and protect CCR2-/- mice, which were otherwise unable to recruit inflammatory monocytes. Failure to recruit Gr1+ monocytes was shown to be due the inability to exit bone marrow, rather than homing to the intestine. The inflammatory monocytes upregulate iNOS, and secrete IL-12 and TNFα, which may contribute to elimination of the parasites. These findings illustrate the critical importance of inflammatory monocytes as a first line of defense in the control of intestinal pathogens. While inflammatory monocytes were protective in the control of acute toxoplasmosis in the studies described here, neutrophils were not protective but rather contribute to the pathology. It is also possible that increased infiltration of inflammatory monocytes also sets up a chronic condition that would be more prone to inflammation. Thus, T. gondii Infection in the mouse offers an attractive model for studying the role of monocytes in host defense and inflammation in acute and in a chronic phase of the Infection.
Publications
- Autophagosome-independent essential function for the autophagy protein Atg5 in cellular immunity to intracellular pathogens. Cell Host Microbe. 2008 Nov 13; 4(5):458-69
Zhao Z., Fux B., Goodwin M., Dunay I.R., Strong D., Miller B.C., Cadwell K., Delgado M.A., Ponpuak M., Schmidt R.E., Mizushima N., Deretic V., Sibley L.D., Virgin H.W.
- Gr1+ Inflammatory Monocytes are Required for Mucosal Resistance to the Pathogen Toxoplasma gondii. Immunity. 2008 Aug 29(2):306-17
Dunay I.R., DaMatta R.A., Fux B., Presti R., Greco S. E., Colonna M., Sibley L.D.
- Artemisone and Artemiside Control Acute and Reactivated Toxoplasmosis in the Murine Model. Antimicrobial Agents and Chemotherapy, 2009 Oct;53(10):4450-6
Ildiko R. Dunay, Richard K. Haynes, L. David Sibley
