Testing in Mice the Hypothesis That Melanin Is Protective in Malaria Infections

Malaria has had the largest impact of any infectious disease on shaping the human genome, exerting enormous selective pressure on genes that improve survival in severe malaria infections. Modern humans originated in Africa and lost skin melanization as they migrated to temperate regions of the globe. Although it is well documented that loss of melanization improved cutaneous Vitamin D synthesis, melanin plays an evolutionary ancient role in insect immunity to malaria and in some instances melanin has been implicated to play an immunoregulatory role in vertebrates. Thus, we tested the hypothesis that melanization may be protective in malaria infections using mouse models. Congenic C57BL/6 mice that differed only in the gene encoding tyrosinase, a key enzyme in the synthesis of melanin, showed no difference in the clinical course of infection by Plasmodium yoelii 17XL, that causes severe anemia, Plasmodium berghei ANKA, that causes severe cerebral malaria or Plasmodium chabaudi AS that causes uncomplicated chronic disease. Moreover, neither genetic deficiencies in vitamin D synthesis nor vitamin D supplementation had an effect on survival in cerebral malaria. Taken together, these results indicate that neither melanin nor vitamin D production improve survival in severe malaria

Probing host pathogen cross-talk by transcriptional profiling of both Mycobacterium tuberculosis and infected human dendritic cells and macrophages

This study provides the proof of principle that probing the host and the microbe transcriptomes simultaneously is a valuable means to accessing unique information on host pathogen interactions. Our results also underline the extraordinary plasticity of host cell and pathogen responses to infection, and provide a solid framework to further understand the complex mechanisms involved in immunity to M. tuberculosis and in mycobacterial adaptation to different intracellular environments

Dendritic Cells in Chronic Mycobacterial Granulomas Restrict Local Anti-Bacterial T Cell Response in a Murine Model

Background: Mycobacterium-induced granulomas are the interface between bacteria and host immune response. During acute infection dendritic cells (DCs) are critical for mycobacterial dissemination and activation of protective T cells. However, their role during chronic infection in the granuloma is poorly understood. Methodology/Principal Findings: We report that an inflammatory subset of murine DCs are present in granulomas induced by Mycobacteria bovis strain Bacillus Calmette-guerin (BCG), and both their location in granulomas and costimulatory molecule expression changes throughout infection. By flow cytometric analysis, we found that CD11c + cells in chronic granulomas had lower expression of MHCII and co-stimulatory molecules CD40, CD80 and CD86, and higher expression of inhibitory molecules PD-L1 and PD-L2 compared to CD11c + cells from acute granulomas. As a consequence of their phenotype, CD11c + cells from chronic lesions were unable to support the reactivation of newly-recruited, antigen 85Bspecific CD4 + IFNc + T cells or induce an IFNc response from naïve T cells in vivo and ex vivo. The mechanism of this inhibition involves the PD-1:PD-L signaling pathway, as ex vivo blockade of PD-L1 and PD-L2 restored the ability of isolated CD11c + cells from chronic lesions to stimulate a protective IFNc T cell response. Conclusions/Significance: Our data suggest that DCs in chronic lesions may facilitate latent infection by down-regulating protective T cell responses, ultimately acting as a shield that promotes mycobacterium survival. This DC shield may explai

SUPPRESSION OF MICE IMMUNE RESPONSE BY ANTIMACROPHAGE SERUM TREATEMENT AND ITS RECONSTITUATION BY MACROPHAGE TRANSPLANTATION

The immunosuppressive effect of antimacrophage serum (AMS) on the primary immune response of mice to sheep red blood cells (SRBC) was studied. AMS, given before a small dose of antigen, abrogated the immune response. Transplantation of normal, galss-adherent macrophages enabled AMS-treated animals to respond to SRBC, while administration of lymph node lymphocytes did not reveres AMS - induced immunosuppression significantly

Effect of protein deficiency on suppressor cells.

The effects of moderate protein deficiency on the in vitro response of spleen cells to phytohemagglutinin in A/Jax mice were studied. The response of spleen cells from protein-deficient mice to phytohemagglutinin was found to be enhanced as compared with that of cells from control animals. Since inadequate development or function of suppressor cells in the protein-deficient mice offered a possible explanation for the enhanced lymphoproliferative activity, cocultures of spleen cells from protein-deficient and control animals were tested for their responses to phytohemagglutinin. Suppression of [3H]thymidine incorporation was detected in coculture of 25% mitomycin-treated spleen cells from control animals and 75% spleen cells from protein-deficient mice. The suppressor (regulator) elements in control spleens were found to reside in the adherent cell population

SERUM PROTEINS, TRANSAMINASES AND PHOSPHATASES IN MALNUTRITION

The levels of serum tota1 protein, albumin, transaminases and phosphatases were estimated in a group of children with severe Marasmus or mild malnutrition in order to identify some of the associated deficiencies in these syndromes. The biochemical pattern was similar in the normal and malnourished children