Deletion of C-reactive protein ameliorates experimental cerebral malaria?

Abstract

Background: C-reactive protein (CRP) level correlates with parasitemia and severity of malaria, but whether this reflects causality remains unknown.Methods: Using CRP-transgenic and CRP-deficient mice we compared the onset and severity of experimental cerebral malaria (ECM) induced by Plasmodium berghei ANKA (PbA).Results: CRP-deficient mice were most resistant to ECM.Conclusions: CRP might contribute to the development of cerebral malaria, rather than protect against it.Keywords: Acute phase protein, Cerebral malaria, C-reactive protein, Parasitemia IntroductionCerebral malaria (CM), the severest form of malaria, is commonly seen in young children and travelers to endemic areas. CM has a high fatality rate and often causes long-term neurological consequences in survivors. The severity of CM is thought to be the consequence of a strong host immune and inflammatory response to the invading Plasmodium spp.1 Blood levels of C-reactive protein (CRP) are positively associated with parasite burden in malaria [2][3][4][5] and CRP levels are higher in CM compared to non-CM or mild malaria.6-8 CRP is an acute phase protein that can activate complement, bind Fc receptors and stimulate cytokine production, 9 thus, the protein's elevation in blood might be expected to exacerbate CM. Yet paradoxically, in patients from malaria-endemic regions, high parasitemia does not always induce CRP elevation and a CRP genetic variation linked to heightened blood CRP 10 associates with increased susceptibility to malaria infection. 11,12 To investigate the possible role of CRP in malaria we investigated the influence of CRP excess versus CRP deficiency on the outcome of experimental cerebral malaria (ECM) in mutant mice. Materials and methodsWe compared the outcomes of Plasmodium berghei ANKA (PbA)-induced ECM in wild type C57BL/6 mice (WT) versus their human CRP-transgenic (CRPtg) and mouse CRP-deficient (CRPko) counterparts. The CRPtg and CRPko mice have both been fully described elsewhere. [13][14][15][16] Human CRP is present in CRPtg at blood concentrations that are physiologically relevant in humans i.e., low levels under steady-state conditions (,1 to 30 mg/ml), and much higher levels during an acute phase response (100 to 500 mg/ml).13,14 In WT and CRPtg mice, mouse CRP is still expressed, but mouse CRP is not a major acute phase protein. 15In CRPko mice expression of mouse CRP is entirely eliminated by Cre-Lox recombination, as described elsewhere. 16 Mice were infected with 5×10 5 PbA-infected red blood cells (iRBCs) and clinical symptoms were monitored as previously described. 17 Briefly, mice were monitored twice daily for clinical signs of neurologic disease, using the following scoring scale: 0. asymptomatic; 1. symptomatic (ruffled fur); 2. mild disease (slow righting); 3. moderate disease (difficulty righting); 4. severe disease (ataxia, seizures, coma) and 5. dead. Mice observed having seizures were given a score of 4 regardless of other clinical signs of disease. Moribund animals were scored 4.5 and humanely sacrificed....

Prognostic Value of Procalcitonin Recovery Level for Malaria Recrudescence

“…There was no objective indicator for the evaluation of severity and prognosis of malaria formerly. According to a number of research bodies in recent years, procalcitonin and C-reactive protein (CRP) have relatively high values in the diagnosis and severity assessment of malaria (2)(3)(4).…”