Leishmaniadisease development depends on the presence of apoptotic promastigotes in the virulent inoculum

Abstract

The obligate intracellular pathogen Leishmania major survives and multiplies in professional phagocytes. The evasion strategy to circumvent killing by host phagocytes and establish a productive infection is poorly understood. Here we report that the virulent inoculum of Leishmania promastigotes contains a high ratio of annexin A5-binding apoptotic parasites. This subpopulation of parasites is characterized by a round body shape, a swollen kinetoplast, nuclear condensation, and a lack of multiplication and represents dying or already dead parasites. After depleting the apoptotic parasites from a virulent population, Leishmania do not survive in phagocytes in vitro and lose their disease-inducing ability in vivo . TGF-β induced by apoptotic parasites is likely to mediate the silencing of phagocytes and lead to survival of infectious Leishmania populations. The data demonstrate that apoptotic promastigotes, in an altruistic way, enable the intracellular survival of the viable parasites.

Apoptotic-likeLeishmaniaexploit the host´s autophagy machinery to reduce T-cell-mediated parasite elimination

“…6 Indeed, we have also found that during Leishmania infection, disease development relies on the presence of apoptotic-like promastigotes as infection of mice with only viable Leishmania promastigotes does not result in disease development. 1 In this study employing human primary cells, we could confirm apoptotic-like parasites to be crucial for an enhanced parasite survival. To clarify how the apoptotic-like population secures survival of the viable ones, we analyzed their intracellular fate.…”

“…23 Focusing on the latter one, we could already show that the virulent Leishmania inoculum consists partially of apoptotic-like parasites, through which disease development can occur. 1 In the present study we first characterized the apoptotic population and then determined the fate of apoptoticlike Leishmania parasites in human host macrophages and its significance for T-cell activation. We demonstrated apoptotic-like parasites to activate the macrophages´autophagy machinery, hereby dampening T-cell responses and enhancing parasite survival.…”

“…The infective inoculum of Leishmania consists of both viable and apoptotic-like parasites, the latter also being required for disease development. 1 The exact mechanism for how apoptosis in unicellular organisms may support infectivity remains elusive. Apoptosis-like programmed cell death has been described in various unicellular protists, including the protozoan parasites Plasmodium and Trypanosoma.…”

Leishmania, the phagosome, and host responses: The journey of a parasite

“…Indeed, death of a sub-population of L. major is crucial for the infection process since injection of live parasite only leads to parasite clearance and to the development of host immunity [4]. This parasite mortality occurs naturally within the gut of infected sand flies and generates apoptotic-like L. amazonensis promastigotes that display phosphatidylserine (PS) at their surface, a lipid found on apoptotic cells, which are recognized by phagocytes [5].…”

Correlation of meta 1 expression with culture stage, cell morphology and infectivity in Leishmania (Leishmania) amazonensis promastigotes

“…In contrast, infectivity correlated with the increase of apoptotic cells present in the culture (Pearson r = 0.8433; 95% confidence interval 0.4555-0.9621; p < 0.0025), supporting the importance of altruistic apoptotic cells for macrophage inactivation (van Zandbergen et al 2006, Wanderley et al 2006.…”