Letter

Experimental cerebral malaria: the murine model provides crucial insight into the role of complement Theresa N. Ramos-Summerford and Scott R. Barnum Department of Microbiology, University of Alabama at Birmingham, 845 19th Street South, Bevill Biomedical Research Building Room 842, Birmingham, AL 35294, USA

Four years ago Trends in Parasitology published a series of letters highlighting the value of using murine experimental cerebral malaria (ECM) as a powerful research tool to discover the mechanisms contributing to the pathophysiology of human cerebral malaria (CM) (Volume 26, Issue 6, 2010). At the time our understanding of the role of complement in cerebral malaria was limited primarily to clinical studies quantifying the blood levels of various complement activation proteins in patients with cerebral and severe malaria compared to control patients (reviewed in [1]). Studies using complement mutant mice or antibody treatment, to inhibit aspects of complement biology, were limited in number and did not provide comprehensive insight into complement-mediated immunobiology in ECM. Since that time numerous studies employing over a dozen complement mutant mice or complement-specific inhibitors have been published (Table 1). From these we now have new insight into how complement contributes to innate immunity in CM with respect to controlling parasitemia, alternative mechanisms used by the parasite to activate complement, and potential therapeutic targets. Specifically, blood parasite levels were unchanged or modestly increased compared to wild type control mice

depending on which complement protein, receptor, or regulator was deleted [2–6]. Mice deficient in the components C3, C4, or C5, which give rise to the complement anaphylatoxins and opsonins, had parasite levels almost identical to those of wild type mice at the peak of disease. In fact, C5 / and wild type mice that survived ECM had comparable parasite levels, even as they progressed toward anemia. C5aR / and CR3 / mice had significantly elevated levels of parasitemia at the peak of disease, but the higher parasite load did not accelerate the course of disease [4,5]. This suggests that complement has a limited role in controlling circulating merozoite levels, likely due to a fast infection rate and limited circulation before their sequestration in red blood cells. In light of this, elevated parasitemia reported in mice treated with cobra venom factor (which transiently depletes complement) during ECM is likely to be an artifact due to atypical inflammation arising from treatment with this potent complement activator [7]. Studies with complement-deficient mice have also demonstrated that the classical and alternative pathways are not required for complement activation during ECM [6]. C3 / mice were susceptible to ECM. However, inhibition of ECM, by treatment with anti-C9 antibodies coupled with

Table 1. Observed outcome of ECM in complement mutant micea Classical pathway Alternative pathway Terminal pathway C3 and C3 receptors

C5 and C5 receptors

Deletion/transgene treatment C4 / CFB / a-C9 antibody

Effect on complement biology Inhibits classical pathway Inhibits alternative pathway Blocks MAC formation

C3 / CR3 / or CR4 / C3aR / C3a/GFAP C5 / C5aR / a-C5a or C5aR antibody C5L2 / C5aR/C3aR / C5a/GFAP CPN /

Inhibits at the level of C3 Reduces phagocytosis Eliminates C3a functions CNS-specific C3a expression Inhibits C5a/MAC formation Eliminates C5a functions Eliminates C5a functions Blocks decoy function? Eliminates C3a/C5a functions CNS-specific C5a expression Reduces inactivation of C3a and C5a

Observed ECM phenotype Fully susceptible Fully susceptible Delayed onset, partial protection Fully susceptible Fully susceptible Fully susceptible Resistant Susceptible Partial protection Fully susceptible Fully susceptible Fully susceptible Delayed onset, fully susceptible

a

Abbreviations: CFB, complement factor B; CNS, central nervous system; CPN, carboxypeptidase N (which inactivates C3a and C5a); GFAP, glial fibrillary acidic protein.

Corresponding author: Barnum, S.R. ([email protected]). 1471-4922/ ß 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.pt.2014.03.002

Trends in Parasitology, May 2014, Vol. 30, No. 5

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Letter the detection of C5a in the serum of C3 / mice, revealed that C5 is activated in ECM independently of the canonical C5 convertases [6]. We highlight these findings for two reasons: (i) mechanistically, they indicate that C5 is activated by coagulation enzymes through what is termed the extrinsic protease pathway [8], and (ii) therapeutically, they point to inhibition of C5, as opposed to C3 or the early activation pathways, as a crucial complement target in modulating CM. If C5 is a prime therapeutic target in CM, is there value in focusing pharmacologically on inflammation mediated by C5a? C5a receptor (C5aR) / mice are highly susceptible to ECM – there is no delayed disease onset and data from two studies demonstrate that 75–80% of C5aR / mice succumb to disease at the same rate as wild type controls [5,9]. These results, combined with studies showing significant delay in disease onset and higher survival on inhibition of C5b and the membrane attack complex (MAC) using anti-C9 antibodies, indicate that C5a is likely to be a poor therapeutic target in CM [5,6]. As a result of the ECM studies using complement mutant mice, we have made remarkably rapid progress in dissecting the role of complement in the most severe form of malaria [10,11]. The animal model provided a reproducible and interpretable experimental approach to examine disease development and progression. The consistent use of congenic C57BL/6 mice and Plasmodium berghei allowed direct comparison of the data between mutant mice and between laboratories performing the

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studies. Most importantly, we now have a solid experimental rationale for targeting complement, specifically C5, as a therapeutic approach in the most deadly form of malaria for which there is currently no treatment. References 1 Silver, K.L. et al. (2010) Complement driven innate immune response to malaria: fuelling severe malarial diseases. Cell. Microbiol. 12, 1036– 1045 2 Darley, M.M. et al. (2012) Deletion of carboxypeptidase N delays onset of experimental cerebral malaria. Parasite Immunol. 34, 444–447 3 Patel, S.N. et al. (2008) C5 deficiency and C5a or C5aR blockade protects against cerebral malaria. J. Exp. Med. 205, 1133–1143 4 Ramos, T.N. et al. (2012) Deletion of the complement phagocytic receptors CR3 and CR4 does not alter susceptibility to experimental cerebral malaria. Parasite Immunol. 34, 547–550 5 Ramos, T.N. et al. (2011) Cutting edge: the membrane attack complex of complement is required for the development of murine experimental cerebral malaria. J. Immunol. 186, 6657–6660 6 Ramos, T.N. et al. (2012) The C5 convertase is not required for activation of the terminal complement pathway in murine experimental cerebral malaria. J. Biol. Chem. 287, 24734–24738 7 Ward, P.A. et al. (1981) Complement does not facilitate plasmodial infections. J. Immunol. 126, 1826–1828 8 Amara, U. et al. (2010) Molecular intercommunication between the complement and coagulation systems. J. Immunol. 185, 5628–5636 9 Kim, H. et al. (2014) Functional roles for C5a and C5aR but not C5L2 in the pathogenesis of human and experimental cerebral malaria. Infect. Immun. 82, 371–379 10 Grau, G.E. and Craig, A.G. (2012) Cerebral malaria pathogenesis: revisiting parasite and host contributions. Future Microbiol. 7, 291–302 11 White, N.J. et al. (2014) Malaria. Lancet 383, 723–735

Experimental cerebral malaria: the murine model provides crucial insight into the role of complement.

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