Mesenchymal stem cells play an important role in host protective immune responses against malaria by modulating regulatory T cells

Abstract

Plasmodium spp. parasites, the causative agents of malaria, survive and replicate in human hosts by modulating host protective immune responses. In a rodent model, malaria manifests as a severe splenomegaly, with infiltration of cells and lymphoproliferation as major contributing factors of the immunopathology. However, the cellular contents and the functions of these cells have not been well studied. Here, we report that Plasmodium berghei infection of mice leads to massive recruitment of mesenchymal stem cells (MSCs) in secondary lymphoid organs. Infusion of these cells into naïve mice was able to confer host resistance against malaria. Furthermore, MSCs augmented interleukin (IL)-12 production but suppressed IL-10 production in recipient animals. In addition, we observed dramatic reductions of regulatory T (Treg) cells in animals that received MSCs. Taken together, our findings have identified recruitment of MSCs as a novel host protective mechanism adopted by the host to combat malaria by modulating Treg-cell responses.Keywords: Hemozoin r Malaria r Mesenchymal stem cell r Regulatory T cell Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionPlasmodium spp., the causative agents of malaria, are responsible for 300 million clinical cases with approximately 0.65 million deaths annually [1]. Malaria parasites survive and replicate within susceptible hosts by inhibiting host protective immune responses. Previous studies have shown that malaria parasites induce regulatory T (Treg) cells [2], which have innate effector functions and are characterized by a preactivated status, as reflected by Correspondence: Dr. Jyoti Das e-mail: jyoti@mrcindia.org expression of the activation markers CD69 and CD44, and low expression of the naïve T-cell marker CD62L. In animal models, it has clearly been shown that Treg cells inhibit host protective immune responses against malaria [3][4][5]. Thus, depletion of Treg cells promotes host resistance to malaria [6].The blood stages of the malaria parasite induce a strong proinflammatory response, which plays an important role in host resistance [7]. It is now well documented that malarial infections stimulate innate, innate-like, as well as adaptive immune responses [8]. Similar to other infections, innate immune components play an important role in host protection at the initial phase of malaria infection, whereas adaptive immunity plays a critical role in host resistance at the later stage of the disease [9]. Interestingly, unlike other intracellular parasitic infections,www.eji-journal.eu Eur. J. Immunol. 2013. 43: 2070-2077 . Accumulation of cells in the spleen of mice in response to infection with malaria pathogens is correlated with host resistance. However, the nature of the infiltrating cells and their function are not well understood. Therefore, we characterized the cellular components of infiltrated cells. Surprisingly, we found a massive accumulation of Sca-1 + CD44 + CD29 + CD34 − cells (where Sca-1 ...

Mesenchymal stem cells and infectious diseases: Smarter than drugs

“…Another unexpected effect of MSCs in vivo was found in a murine model of malaria infection driven by Plasmodium berghei. While anti-inflammatory effects might have been expected, intravenous BMSC delivery resulted in an increase in IL-12 and a decrease in IL-10 secretion resulting in a dramatic reduction in the number of regulatory T cells and a more effective host anti-microbial response [69]. It is hard to imagine a drug that would do this.…”

Molecular Medicines for Parasitic Diseases

“…After the success of direct administration of MSCs (mesenchymal stromal cells) and antigen specific T-cells stem cell therapy has recently budded in the field of infectious diseases. MSCs have been shown to be equally important in conferring resistance against P. berghei infection, by suppressing IL-10, reducing the regulatory T-cells population and inducing the production of IL-12 [75,76]. Likewise, autologous transplantation of MSCs and myoblasts has shown to significantly reduce the ventricular dysfunctions [77].…”

Mesenchymal Stem Cells — Their Antimicrobial Effects and Their Promising Future Role as Novel Therapies of Infectious Complications in High Risk Patients

“…Plasmodium berghei infection in mice leads to massive recruitment of MSCs in secondary lymphoid organs [64,65]. Also, infusion of MSCs into naive mice can confer host resistance against malaria by (1) augmentation of IL-12 production, (2) suppression of IL-10 production,…”