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 ...
Understanding naturally acquired immune responses to Plasmodium in India is key to improving malaria surveillance and diagnostic tools. Here we describe serological profiling of immune responses at three sites in India by probing protein microarrays consisting of 515 Plasmodium vivax and 500 Plasmodium falciparum proteins with 353 plasma samples. A total of 236 malaria-positive (symptomatic and asymptomatic) plasma samples and 117 malaria-negative samples were collected at three field sites in Raurkela, Nadiad, and Chennai. Indian samples showed significant seroreactivity to 265 P. vivax and 373 P. falciparum antigens, but overall seroreactivity to P. vivax antigens was lower compared to P. falciparum antigens. We identified the most immunogenic antigens of both Plasmodium species that were recognized at all three sites in India, as well as P. falciparum antigens that were associated with asymptomatic malaria. This is the first genome-scale analysis of serological responses to the two major species of malaria parasite in India. The range of immune responses characterized in different endemic settings argues for targeted surveillance approaches tailored to the diverse epidemiology of malaria across the world.
Malaria remains a major public health problem worldwide. The immune mechanisms that mediate protection against malaria are still unclear. Previously, we reported that mesenchymal stem cells (MSCs) play a critical role in host protection against malaria by altering the dynamic balance of T regulatory cells and effector T cells producing inflammatory cytokines. Here, we report that MSCs reprogram haematopoiesis in primary (bone marrow) and secondary (spleen) lymphoid organs to provide host protection against malaria. Adoptive transfer of MSCs from malaria-infected mice to naïve recipient mice that were subsequently infected with malaria parasites dramatically accelerated the formation of colony-forming units-erythroid cells in the bone marrow. Adoptively transferred MSCs also induced expression of the key erythroid cell differentiation factor GATA-1 in the spleen of recipient animals. Interestingly, we further observed a subtle increase in the CD34+ hematopoietic stem and progenitor cells in lymphoid organs, including spleen and lymph nodes. Infusion of MSCs also enhanced T cell proliferation, resulting in increased numbers of both CD4+ and CD8+ T cells in the spleen. MSCs also inhibited the induction of the negative co-stimulatory receptor programmed death-1 by T cells in recipient animals upon infection with malaria parasites. Taken together, our findings suggest that MSCs play a critical role in host protection against malaria infection by modulating erythropoiesis and lymphopoiesis.
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