Leishmania amazonensis hijacks host cell lysosomes involved in plasma membrane repair to induce invasion in fibroblasts

Abstract

Intracellular parasites of the genus Leishmania are the causative agents of leishmaniasis. The disease is transmitted by the bite of a sand fly vector, which inoculates the parasite into the skin of mammalian hosts, including humans. During chronic infection the parasite lives and replicates inside phagocytic cells, notably the macrophages. An interesting, but overlooked finding, is that other cell types and even non-phagocytic cells have been found to be infected by Leishmania spp. Nevertheless, the mechanisms by which Leishmania invades such cells had not been previously studied. Here, we show that L. amazonensis can induce their own entry into fibroblasts independently of actin cytoskeleton activity, and, thus, through a mechanism that is distinct from phagocytosis. Invasion involves subversion of host cell functions, such as Ca 2+ signaling and recruitment and exocytosis of host cell lysosomes involved in plasma membrane repair.This article has an associated First Person interview with the first author of the paper.

Solving the secretory acid sphingomyelinase puzzle: Insights from lysosome‐mediated parasite invasion and plasma membrane repair

“…Interestingly, extracellularly added ASM also promotes T. cruzi entry in ASM‐depleted cells, indicating that these parasites subvert the ASM‐mediated plasma membrane repair process as a strategy for host cell invasion (Fernandes et al, ). This invasion strategy appears to be more widespread than originally thought, having been demonstrated for fibroblast invasion by the T. cruzi ‐related protozoan Leishmania (Cavalcante‐Costa et al, ) and for adenovirus infections (Luisoni et al, ). Earlier studies found a role for ASM in host cell entry by the bacteria Neisseria and Pseudomonas and Sindbis viruses, although in these cases the origin of the extracellular ASM generating ceramide‐enriched plasma membrane domains and pathogen internalisation was unknown (Grassme et al, ; Jan, Chatterjee, & Griffin, ; Simonis, Hebling, Gulbins, Schneider‐Schaulies, & Schubert‐Unkmeir, ).…”

Cell invasion by intracellular parasites – the many roads to infection

“…(Aikawa et al, 1978) and Toxoplasma gondii (Mordue et al, 1999). Invasion can also occur through the subversion of physiological host cell processes, such as lysosome-triggered Ca 2+ -dependent endocytosis, which is used by all nucleated cells to repair wounded PMs (Corrotte and Castro-Gomes, 2019); this pathway has previously shown to occur for Trypanosoma cruzi (Rodríguez et al, 1996;Fernandes et al, 2011), and also more recently by our lab for Leishmania amazonensis (Cavalcante-Costa et al, 2019). Large parasites can be equally phagocytosed, if they are able to resist phagocytic degradation and live within phagocytic cells, such as protozoans of the genus Leishmania (Zenian et al, 1979).…”

“…In fact, it has long been described that promastigotes can also invade nonphagocytic cells (Bogdan et al, 2000;Minero et al, 2004;Holbrook and Palczuk, 1975;Schwartzman and Pearson, 1985). Recent work from our group has unveiled a new non-phagocytic route of promastigote invasion without any involvement of the host cell cytoskeleton, thereby providing definitive evidence for an entry mechanism other than phagocytosis (Cavalcante-Costa et al, 2019). This pathway involves the Ca 2+ -dependent recruitment and exocytosis of host cell lysosomes to the parasite invasion site, where they instantly fuse with the PM, much like in the invasion mechanism described above for T. cruzi.…”

“…are transmitted by the bite of a sand fly vector, which inoculates flagellated infective parasites, the metacyclic promastigotes, into the dermis of vertebrate hosts (Handman, 1999). Promastigotes can transiently invade different cell types (Peters et al, 2008;Williams, 1988;Kautz-Neu et al, 2012;Moll et al, 1993;Bogdan et al, 2000;Cavalcante-Costa et al, 2019), before reaching macrophages, their final destination. Inside macrophages, they nest within vacuoles, where they transform into replicative oval-shaped amastigote forms, causing different clinical manifestations of the disease, depending on the species of Leishmania and on host immune responses.…”

“…This pathway involves the Ca 2+ -dependent recruitment and exocytosis of host cell lysosomes to the parasite invasion site, where they instantly fuse with the PM, much like in the invasion mechanism described above for T. cruzi. This creates a niche for the internalization of promastigotes, which most often occurs through the flagella (Cavalcante-Costa et al, 2019) (Fig. 2C).…”