The transcription factor T-bet regulates parasitemia and promotes pathogenesis during Plasmodium berghei ANKA murine malaria.

Abstract

The pathogenesis of experimental cerebral malaria (ECM) is an immunologic process, mediated in part by Th1 CD4(+) T cells. However, the role of the Th1 CD4(+) T cell differentiation program on the ability to control parasitemia and susceptibility to ECM disease during blood stage malaria has never been assessed directly. Using the Plasmodium berghei ANKA murine model of ECM and mice deficient for the transcription factor T-bet (the master regulator of Th1 cells) on the susceptible C57BL/6 background, we demonstrate that although T-bet plays a role in the regulation of parasite burden, it also promotes the pathogenesis of ECM. T-bet-deficient (Tbx21(-/-)) mice had higher parasitemia than wild type controls did during the ECM phase of disease (17.7 ± 3.1% versus 10.9 ± 1.5%). In addition, although 100% (10/10) of wild type mice developed ECM by day 9 after infection, only 30% (3/10) of Tbx21(-/-) mice succumbed to disease during the cerebral phase of infection. Resistance to ECM in Tbx21(-/-) mice was associated with diminished numbers of IFN-γ-producing CD4(+) T cells in the spleen and a lower accumulation of CD4(+) and CD8(+) T cells in the brain. An augmented Th2 immune response characterized by enhanced production of activated GATA-3(+) CD4(+) T cells and elevated levels of the eotaxin, MCP-1, and G-CSF cytokines was observed in the absence of T-bet. Our results suggest that in virulent malarias, immune modulation or therapy resulting in an early shift toward a Th2 response may help to ameliorate the most severe consequences of malaria immunopathogenesis and the prospect of host survival.

• Authors: Miranda S Oakley, Bikash R Sahu, Leda Lotspeich-Cole, Nehal R Solanki, Victoria Majam, Phuong Thao Pham, Rajdeep Banerjee, Yukiko Kozakai, Steven C Derrick, Sanjai Kumar, Sheldon L Morris
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 191 Issue 9 Pg. 4699-708 (Nov 01 2013) ISSN: 1550-6606 [Electronic] United States
• PMID: 24078698 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Ccl2 protein, mouse
• Chemokine CCL11
• Chemokine CCL2
• GATA3 Transcription Factor
• Gata3 protein, mouse
• T-Box Domain Proteins
• T-box transcription factor TBX21
• Granulocyte Colony-Stimulating Factor
• Interferon-gamma

Topics

• Animals
• Brain (cytology, immunology)
• CD4-Positive T-Lymphocytes (immunology, metabolism)
• CD8-Positive T-Lymphocytes (immunology)
• Cell Differentiation (immunology)
• Chemokine CCL11 (biosynthesis)
• Chemokine CCL2 (biosynthesis)
• Female
• GATA3 Transcription Factor (metabolism)
• Granulocyte Colony-Stimulating Factor (biosynthesis)
• Interferon-gamma (biosynthesis)
• Lymphocyte Activation (immunology)
• Malaria, Cerebral (immunology, parasitology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Parasitemia (immunology)
• Plasmodium berghei (immunology, pathogenicity)
• T-Box Domain Proteins (deficiency, genetics, immunology)