Leishmania major drives host phagocyte death and cell-to-cell transfer depending on intracellular pathogen proliferation rate

Abstract

The virulence of intracellular pathogens relies largely on the ability to survive and replicate within phagocytes but also on release and transfer into new host cells. Such cell-to-cell transfer could represent a target for counteracting microbial pathogenesis. However, our understanding of the underlying cellular and molecular processes remains woefully insufficient. Using intravital 2-photon microscopy of caspase-3 activation in the Leishmania major –infected ( L . major –infected) live skin, we showed increased apoptosis in cells infected by the parasite. Also, transfer of the parasite to new host cells occurred directly without a detectable extracellular state and was associated with concomitant uptake of cellular material from the original host cell. These in vivo findings were fully recapitulated in infections of isolated human phagocytes. Furthermore, we observed that high pathogen proliferation increased cell death in infected cells, and long-term residency within an infected host cell was only possible for slowly proliferating parasites. Our results therefore suggest that L . major drives its own dissemination to new phagocytes by inducing host cell death in a proliferation-dependent manner.

Investigating pyroptosis as a mechanism of L. major cell‐to‐cell spread in the human BLaER1 infection model

“…Since Carneiro et al (2020) showed upregulation of IL1β during this phase of the infection, it is tempting to speculate that pyroptosis might play a role in the spread of parasites to new host cells. However, it has been recently demonstrated that the cell-to-cell spread of L. major can be driven by the parasites proliferation and the induction of apoptosis (Baars et al, 2023;Heyde et al, 2018). Interestingly, transcriptomic profiling of tissue from lesions of cutaneous leishmaniasis patients infected with L. braziliensis revealed an upregulation of inflammasome as well as apoptosisassociated genes, suggesting the activation of both pathways during leishmaniasis (Novais et al, 2015).…”