Protein Kinase C θ Deficiency Increases Resistance of C57BL/6J Mice toPlasmodium bergheiInfection-Induced Cerebral Malaria

Abstract

Protein kinase C (PKC) functions as a core component of the immunological synapse and serves as a key protein in the integrated T-cell antigen receptor (TCR)/CD28-induced signaling cascade leading to T-cell activation. However, the involvement of PKC in host-mediated immune responses to pathogens has not been thoroughly investigated. We tested the consequences of PKC ablation on the host response to infection by Plasmodium berghei ANKA (PbA). We found that both PKC ؉/؉ and PKC ؊/؊ C57BL/6J mice are susceptible to infection with PbA. However, despite a similar parasite burden, PKC ؉/؉ mice had an earlier onset of neurological signs, characteristics of experimental cerebral malaria (ECM), resulting in an earlier death. These mice suffered from an early and pronounced splenomegaly with a concomitant increase in the total number of CD4 ؉ splenic T cells. In contrast, a large proportion of PbA-infected PKC ؊/؊ mice overcame the acute phase characterized by neurological symptoms and survived longer than PKC ؉/؉ mice. The partial resistance of PKC ؊/؊ mice to ECM was associated with an impaired production of Th1-type cytokines, including gamma interferon and tumor necrosis factor alpha/lymphotoxin-␣, which are known to exacerbate symptoms leading to ECM. In addition, PbA infection-induced LFA-1 expression in CD8 ؉ T cells was suppressed in PKC-deficient T cells, suggesting a diminished ability to adhere to endothelial cells and sequester in brain microvasculature, which may explain the decrease in neurological symptoms. These data implicate PKC in CD4 ؉ Th1 ؉ and CD8 ؉ T-cell-mediated immune responses during PbA infection that contribute to the development of ECM.

Protein Kinase C-Theta Is Required for Development of Experimental Cerebral Malaria

“…37 To address the role of PKC-in CM pathogenesis, PKC--deficient mice were investigated for several aspects of the pathophysiology of CM development. The present study demonstrated protection of PKC--deficient mice against CM after infection with PbA, in agreement with the recent study of Ohayon et al, 38 who also demonstrated that PKChas an effect on CM development; however, dissociated were the CM and the lung disease that are not affected by PKC-deficiency. Most PKC--deficient mice survived beyond day 15 without signs of CM.…”

Angiotensin II Is a New Component Involved in Splenic T Lymphocyte Responses during Plasmodium berghei ANKA Infection

“…However, it is generally accepted that the same immunological response contributes to malaria pathogenesis, with a local organ-specific inflammatory response initiated by the presence of parasite and sustained by infiltrating cells within the vasculature [2], [15], [36]–[39]. In this work, we describe an important new role for an AT 1 receptor-mediated effect of Ang II in T cell activation, migration and adhesion during P. berghei ANKA infection.…”

“…The expression of CD11a (LFA-1), an adhesion molecule expressed in activated T cells during P. berghei ANKA infection, was analyzed by flow cytometry [39]. P. berghei ANKA infection upregulates CD11a expression in splenic T cells and treatment with losartan or captopril partially inhibited it (Fig.…”

The Yin and Yang of Protein Kinase C-theta (PKCθ)

“…However, the ability of innate immunity signals to bypass the requirement for protective responses to pathogens may not be generalizable or absolute. In fact, studies demonstrated that the immune response against two unicellular protozoan parasites, Toxoplasma gondii (Nishanth, et al, 2010) or Plasmodium berghei (Ohayon, et al, 2010) was impaired in Prkcq −/− mice, reflecting defects in both Th1 and Th2 cytokines. The primary defect in these infections may lie in impaired activation of innate TLR signaling pathways (Griffith, et al, 2007; Yarovinsky, et al, 2005), with the subsequent adaptive immunity defect representing a secondary phenomenon.…”