MAP kinase phosphatase-2 plays a key role in the control of infection with Toxoplasma gondii by modulating iNOS and arginase-1 activities in mice

Tools

Woods, Stuart and Schroeder, Juliane and McGachy, Helen A and Plevin, Robin and Roberts, Craig W and Alexander, James (2013) MAP kinase phosphatase-2 plays a key role in the control of infection with Toxoplasma gondii by modulating iNOS and arginase-1 activities in mice. PLOS Pathogens, 9 (8). e1003535. (https://doi.org/10.1371/journal.ppat.1003535)

[thumbnail of Woods-etal-PLOSP-2013-MAP-kinase-phosphatase-2-plays-a-key-role-in-the-control-of-infection]
Preview
 Other. Filename: Woods_etal_PLOSP_2013_MAP_kinase_phosphatase_2_plays_a_key_role_in_the_control_of_infection.PDF
Final Published Version
License: Creative Commons Attribution 4.0 logo
Download (2MB)| Preview

Abstract

The dual specific phosphatase, MAP kinase phosphatase-2 (MKP-2) has recently been demonstrated to negatively regulate macrophage arginase-1 expression, while at the same time to positively regulate iNOS expression. Consequently, MKP-2 is likely to play a significant role in the host interplay with intracellular pathogens. Here we demonstrate that MKP-2(-/-) mice on the C57BL/6 background have enhanced susceptibility compared with wild-type counterparts following infection with type-2 strains of Toxoplasma gondii as measured by increased parasite multiplication during acute infection, increased mortality from day 12 post-infection onwards and increased parasite burdens in the brain, day 30 post-infection. MKP-2(-/-) mice did not, however, demonstrate defective type-1 responses compared with MKP-2(+/+) mice following infection although they did display significantly reduced serum nitrite levels and enhanced tissue arginase-1 expression. Early resistance to T. gondii in MKP-2(+/+), but not MKP-2(-/-), mice was nitric oxide (NO) dependent as infected MKP-2(+/+), but not MKP-2(-/-) mice succumbed within 10 days post-infection with increased parasite burdens following treatment with the iNOS inhibitor L-NAME. Conversely, treatment of infected MKP-2(-/-) but not MKP-2(+/+) mice with nor-NOHA increased parasite burdens indicating a protective role for arginase-1 in MKP-2(-/-) mice. In vitro studies using tachyzoite-infected bone marrow derived macrophages and selective inhibition of arginase-1 and iNOS activities confirmed that both iNOS and arginase-1 contributed to inhibiting parasite replication. However, the effects of arginase-1 were transient and ultimately the role of iNOS was paramount in facilitating long-term inhibition of parasite multiplication within macrophages.

ORCID iDs

Woods, Stuart ORCID logoORCID: https://orcid.org/0000-0002-3798-2074, Schroeder, Juliane, McGachy, Helen A, Plevin, Robin ORCID logoORCID: https://orcid.org/0000-0002-7849-1220, Roberts, Craig W ORCID logoORCID: https://orcid.org/0000-0002-0653-835X and Alexander, James;
CORE (COnnecting REpositories)