Chemokines: A key driver for inflammation in protozoan infection.

Chemokines belong to the group of small proteins within the cytokine family having strong chemo-attractant properties. In most cases, the strong immuno-modulatory role of chemokines is crucial for generating the immune response against pathogens in various protozoan diseases. In this review, we have given a brief update on the classification, characterization, homeostasis, transcellular migration, and immuno-modulatory role of chemokines. Here we will evaluate the potential role of chemokines and their regulation in various protozoan diseases. There is a significant direct relationship between parasitic infection and the recruitment of effector cells of the immune response. Chemokines play an indispensable role in mediating several defense mechanisms against infection, such as leukocyte recruitment and the generation of innate and cell-mediated immunity that aids in controlling/eliminating the pathogen. This process is controlled by the chemotactic movement of chemokines induced as a primary host immune response. We have also addressed that chemokine expressions during infection are time-dependent and orchestrated in a systematic pattern that ultimately assists in generating a protective immune response. Taken together, this review provides a systematic understanding of the complexity of chemokines profiles during protozoan disease conditions and the rationale of targeting chemokines for the development of therapeutic strategies.

IL-10 Producing Regulatory B Cells Mediated Protection against Murine Malaria Pathogenesis.

Various immune cells are known to participate in combating infection. Regulatory B cells represent a subset of B cells that take part in immunomodulation and control inflammation. The immunoregulatory function of regulatory B cells has been shown in various murine models of several disorders. In this study, a comparable IL-10 competent B-10 cell subset (regulatory B cells) was characterized during lethal and non-lethal infection with malaria parasites using the mouse model. We observed that infection of Balb/c mice with P. yoelii I 7XL was lethal, and a rapid increase in dynamics of IL-10 producing B220+CD5+CD1d+ regulatory B cells over the course of infection was observed. However, animals infected with a less virulent strain of the parasite P. yoelii I7XNL attained complete resistance. It was observed that there is an increase in the population of regulatory B cells with an increase of parasitemia; however, a sudden drop in the frequency of these cells was observed with parasite clearance. Adoptive transfer of regulatory B cells to naïve mice followed by infection results in slow parasite growth and enhancement of survival in P. yoelii 17XL (lethal) infected animals. Adoptively transferred regulatory B cells also resulted in decreased production of pro-inflammatory cytokine (IFN-γ) and enhanced production of anti-inflammatory cytokine (IL-10). It infers that these regulatory B cells may contribute in immune protection by preventing the inflammation associated with disease and inhibiting the parasite growth.

Mesenchymal Stem Cells: A Novel Therapeutic Approach to Enhance Protective Immunomodulation and Erythropoietic Recovery in Malaria.

Mesenchymal stem cells (MSCs) are self-renewing, multi-potent heterogeneous stem cells that display strong tissue protective and restorative properties by differentiating into cells of the mesodermal lineages. In addition to multi-lineage differentiation capacity, MSCs play important roles in regulating immune responses, inflammation, and tissue regeneration. MSCs play a role in the outcome of the pathogenesis of several infectious diseases. A unique subset of MSCs accumulates in secondary lymphoid organs during malaria disease progression. These MSCs counteract the capacity of malaria parasites to subvert activating co-stimulatory molecules and to regulate expression of negative co-stimulatory molecules on T lymphocytes. Consequently, MSCs have the capacity to restore the functions of CD34+ haematopoietic cells and CD4+ and CD8+ T cells during malaria infection. These observations suggest that cell-based therapeutics for intervention in malaria may be useful in achieving sterile clearance and preventing disease reactivation. In addition, MSCs provide host protection against malaria by reprogramming erythropoiesis through accelerated formation of colony-forming-units-erythroid (CFU-E) cells in the bone marrow. These findings suggest that MSCs are positive regulators of erythropoiesis, making them attractive targets for treatment of malarial anemia. MSC-based therapies, unlike anti-malarial drugs, display therapeutic effects by targeting a large variety of cellular processes rather than a single pathway. In the present review we focus on these recent research findings and discuss clinical applications of MSC-based therapies for malaria.

Mesenchymal stem cells protect against malaria pathogenesis by reprogramming erythropoiesis in the bone marrow.

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.

EGCG, a tea polyphenol, as a potential mitigator of hematopoietic radiation injury in mice.

Agents capable of providing protection, mitigation or therapy against radiation injuries have long been of interest of radiation biologists owing to the ever expanding application of radiation in our day to day life despite the well reported ill effects of exposure. The current study investigates radiomitigating potential of EGCG (epigallocatechin gallate), a tea polyphenol with known DNMT inhibitory property, in C57 Bl/6 mice model. Treatment with 0.1833mg/kg body weight EGCG, 1.5h post-irradiation to lethally whole body irradiated mice rendered 45% survival for 30days and also helped restoring the body weight of the animals. An early recovery of various hematological parameters was observed in EGCG treated animals compared to radiation alone group. Significant recovery in the number of bone marrow colony forming cells was observed in EGCG treated irradiated animals. EGCG reduced cytogenetic damage to bone marrow cells in radiation exposed mice significantly as studied by micronucleus assay without any significant affect on cell cycle distribution of the bone marrow cells. ELISA assay with bone marrow cell lysates showed EGCG as an inhibitor of HDAC activity and DNase accessibility assay showed EGCG treatment increased the accessibility of chromatin to the enzyme. The results suggest EGCG provides mitigation against radiation injury to the hemopoietic system of mice and also inhibits HDAC enzyme activity. However, further studies are required to understand its mechanism of action.

Role of some epigenetic factors in DNA damage response pathway.

The current review gives a brief account of the DNA damage response pathway and involvement of various epigenetic mechanisms in DNA damage response pathway. The main focus is on histone modifications leading to structural alterations in chromatin since the compact chromatin structure poses a major limitation in the DNA repair process. Based on this hypothesis, our laboratory has also evaluated certain histone deacetylase inhibitors as potential radiomitigators and the same has been discussed in brief at the end of the review.