Many Leishmania spp. can cause human disease, with clinical symptoms dependent upon both host- and parasite-related factors.
During infection, leishmanial parasites may be phagocytosed by a variety of cells, including neutrophils, monocytes, monocyte-derived dendritic cells (moDCs), macrophages and stromal cells. However, host cell preference and the importance of each cell type to parasite clearance versus parasite persistence may vary following infection by different Leishmania spp.
Intracellular Leishmania parasites have multiple ways to manipulate macrophage function, including subverting the control of phagosome biogenesis and maturation. The importance of parasite virulence factors (for example, lipophosphoglycan) in this process is dependent upon leishmanial species and host cell type.
Major surface protease (MSP; also known as GP63) of Leishmania spp. has an important role in regulating intracellular survival in some host cells, by cleaving a variety of phosphotyrosine phosphatases such as SRC homology 2 domain phosphotyrosine receptor phosphate (SHP1). MSP may access these cytosolic targets after crossing lipid microdomains in the host cell membrane.
Iron has a key role in intracellular survival of leishmanial pathogens, with both host (SLC11A1) and parasite (LIT1) transporters competing to secure this essential resource.
Cell-mediated immunity to leishmanial infection is multifactorial, with different models of disease serving to exemplify different aspects, for example, the importance of CD8+ T cells and/or the involvement of moDCs.
Parasite persistence and the capacity to induce good vaccine-induced immunity are both strongly influenced by the presence of interleukin-10 (IL-10). There are multiple cellular sources of IL-10 (T helper 1 (TH1) cells, regulatory T (TReg) cells, B cells, macrophages and DCs), but whether each has similar functional significance has yet to be determined.
Leishmania is a genus of protozoan parasites that are transmitted by the bite of phlebotomine sandflies and give rise to a range of diseases (collectively known as leishmaniases) that affect over 150 million people worldwide. Cellular immune mechanisms have a major role in the control of infections with all Leishmania spp. However, as discussed in this Review, recent evidence suggests that each host–pathogen combination evokes different solutions to the problems of parasite establishment, survival and persistence. Understanding the extent of this diversity will be increasingly important in ensuring the development of broadly applicable vaccines, drugs and immunotherapeutic interventions.
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Work in the P.K. laboratory is funded by grants from the UK Medical Research Council and the Wellcome Trust. Work in the P.S. laboratory is funded by grants from the National Institute of Allergy and Infectious Diseases, US National Institutes of Health.
The authors declare no competing financial interests.
- Two-photon intravital imaging
A fluorescent-laser-based microscopy technique that allows real-time imaging of cells that are deep within the tissues of live animals.
A family of small (∼810 kDa) chemotactic cytokines that regulate cell migration and function. Different chemokine families are defined by the presence of specific motifs known as C, CC, CXC and CX3C.
Cytosolic particles within neutrophils that are referred to as primary, tertiary or specific, based on their staining characteristics and their content. Primary granules (also called azurophilic granules) contain the enzyme myeloperoxidase, which is responsible for the green colour of pus.
- RAB GTPases
A large family of monomeric guanine nucleotide binding proteins that act as important regulators of vesicle transport and docking in eukaryotic cells.
- Fc receptors
Cell surface receptors that recognize the Fc tails of antibody molecules. The binding of particles that are coated with antibody by the Fc receptors on phagocytic cells triggers internalisation and potent antimicrobial effector responses.
- Lipid microdomains
Regions of a biological membrane that are enriched in a particular protein or lipid and can vary in size, composition and function. For example, lipid rafts are highly dynamic microdomains, 10–200 nm in size, that are enriched in cholesterol and sphingolipids and serve to compartmentalize different membrane functions.
A high-molecular-mass cytosolic or membrane-bound complex that contains many of the individual proteins that are associated with a signalling pathway, often together with various scaffold proteins.
- Concomitant immunity
A situation in which immunological resistance to reinfection co-exists at the same time as persistence of the original infection.
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Kaye, P., Scott, P. Leishmaniasis: complexity at the host–pathogen interface. Nat Rev Microbiol 9, 604–615 (2011). https://doi.org/10.1038/nrmicro2608
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