Abstract
A number of medically important microbial pathogens target and proliferate within macrophages and other phagocytic cells in their mammalian hosts. While the majority of these pathogens replicate within the host cell cytosol or non-hydrolytic vacuolar compartments, a few, including protists belonging to the genus Leishmania, proliferate long-term within mature lysosome compartments. How these parasites achieve this feat remains poorly defined. In this review, we highlight recent studies that suggest that Leishmania virulence is intimately linked to programmed changes in the growth rate and carbon metabolism of the obligate intra-macrophage stages. We propose that activation of a slow growth and a stringent metabolic response confers resistance to multiple stresses (oxidative, temperature, pH), as well as both nutrient limitation and nutrient excess within this niche. These studies highlight the importance of metabolic processes as key virulence determinants in Leishmania.
Highlights
Macrophages play key roles in the mammalian innate and adaptive immune responses[1]
Leishmania parasites are unusual in their capacity to proliferate long-term within the mature phagolysosome compartment of host macrophages
Successful colonization of this niche must have been linked to the parallel evolution of strategies for combating a range of host cell microbicidal processes (ROS, reactive nitrogen species (RNS), hydrolases) that are normally effective at eradicating pathogens that are delivered to this compartment
Summary
Macrophages play key roles in the mammalian innate and adaptive immune responses[1]. These cells are actively recruited to sites of tissue damage and infection and are able to kill a wide range of invading bacterial, fungal, and protozoan pathogens following phagocytosis and their delivery to the lysosome compartment[1]. Lesion amastigotes have dramatically reduced rates of glucose and amino acid uptake and use these carbon sources much more efficiently than rapidly replicating or non-dividing promastigotes[27] (Figure 2) Both dividing and non-dividing promastigote stages take up more glucose than is needed to maintain or increase biomass and exhibit high levels of overflow metabolism (secretion of partially oxidized glucose end-products, such as acetate, succinate, and alanine). Sugar levels in the phagolysosome could fluctuate in response to changes in membrane transport and the delivery of cargo to this compartment, leading to periods of sugar starvation and transient dependency on gluconeogenesis for the synthesis of essential glycoconjugates, DNA/RNA synthesis, and production of reducing equivalents via the pentose phosphate pathway[63] In this context, co-expression of both FBPase and PFK could allow Leishmania amastigotes to rapidly respond to changes in carbon source availability. Whether metabolic cycling between FBPase and PFK occurs in the Leishmania amastigote’s glycosome and the extent to which it regulates glycolytic fluxes remains to be determined
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