MicrobiologyBytes

Leishmania remains a major public health problem with 350 million people at risk, 12 million infected, and 2 million new infections per year. Despite the considerable progress in cellular and molecular biology and in evolutionary genetics since 1990, the debate on the population structure and reproductive mode of Leishmania is far from being settled and deserves further investigation. Two major hypotheses coexist: clonality versus sexuality. Because of the lack of clear evidence (experimental or biological confirmation) of sexuality in Leishmania parasites, until today it has been suggested and even accepted that Leishmania species were mainly clonal with infrequent genetic recombination.

Two recent publications, one on Leishmania major (an in vitro experimental study) and one on Leishmania braziliensis (a population genetics analysis), once again have challenged the hypothesis of clonal reproduction. The first study experimentally evidenced genetic recombination and proposed that Leishmania parasites are capable of having a sexual cycle consistent with meiotic processes inside the insect vector. The second investigation, based on population genetics studies, showed strong homozygosities, an observation that is incompatible with a predominantly clonal mode of reproduction at an ecological time scale (~20–500 generations). These studies highlight the need to advance the knowledge of Leishmania biology. This paper reviews the reasons stimulating the continued debate and then detail the next essential steps to be taken to clarify the Leishmania reproduction model. It widens the discussion to other Trypanosomatidae and show that the progress in Leishmania biology can improve our knowledge of the evolutionary genetics of American and African trypanosomes.

Everything You Always Wanted to Know about Sex (but Were Afraid to Ask) in Leishmania after Two Decades of Laboratory and Field Analyses. PLoS Pathog 6(8): e1001004. doi:10.1371/journal.ppat.1001004

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Leishmania donovani is a protozoan parasite that causes severe disease in humans with associated pathology in the spleen and liver. In experimental models of L. donovani infection, the hepatic response to infection is characterised by the presence of a focal mononuclear cell-rich inflammatory response (a granuloma) surrounding cells infected with intracellular amastigotes. Granulomas provide focus to the ensuing immune response, helping to contain parasite dissemination and providing the major effector site responsible for parasites elimination from the liver. Although granulomas are believed to form around infected resident liver macrophages (Kupffer cells), the role of these cells in intra-granuloma antigen presentation is currently unknown. Researchers used sophisticated microscopy to identify how killer T lymphocytes behaved when they enter sites of inflammation caused by L. donovani, and which infected cells they were able to recognise.

Leishmaniasis is a globally important but neglected disease, affecting approximately two million people every year. For most people, infection results in a slow-to-heal skin ulcer. In others, however, the parasite targets the liver, spleen and bone marrow, leading to over 70,000 deaths annually. The Leishmania parasite is eventually contained by a characteristic type of inflammatory response that forms cellular structures called granulomas. Little is known about the inner workings of these granulomas, in spite of their occurrence in other human diseases, from tuberculosis to rheumatoid arthritis. The scientists used an advanced laser-based microscopy technique, called “2-photon imaging”, to view the inner workings of the granuloma in mice infected with Leishmania. This enabled them to study how killer lymphocytes, such as those that can be induced by vaccination, are able to enter into the granulomas, penetrate deep into the core of the structure and seek out specific types of parasite-infected cells. Although this technique can not be used currently for the study of inflammatory disease in humans, the insights provided into the biology of granulomas and the hidden world of inflammation should help to improve vaccines and drugs, and allow researchers to now construct in silico models for this type of inflammatory process. These data have important implications for the understanding of how granulomas function to limit infection and may have important implications for the development of vaccines to Leishmania.

Dynamic Imaging of Experimental Leishmania donovani-Induced Hepatic Granulomas Detects Kupffer Cell-Restricted Antigen Presentation to Antigen-Specific CD8+ T Cells. PLoS Pathog 6(3): e1000805. doi:10.1371/journal.ppat.1000805
Kupffer cells (KCs) represent the major phagocytic population within the liver and provide an intracellular niche for the survival of a number of important human pathogens. Although KCs have been extensively studied in vitro, little is known of their in vivo response to infection and their capacity to directly interact with antigen-specific CD8+ T cells. Here, using a combination of approaches including whole mount and thin section confocal microscopy, adoptive cell transfer and intravital 2-photon microscopy, we demonstrate that KCs represent the only detectable population of mononuclear phagocytes within granulomas induced by Leishmania donovani infection that are capable of presenting parasite-derived peptide to effector CD8+ T cells. This restriction of antigen presentation to KCs within the Leishmania granuloma has important implications for the identification of new candidate vaccine antigens and for the design of novel immuno-therapeutic interventions.

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