Malaria-Infected Erythrocyte-Derived Microvesicles Mediate Cellular Communication within the Parasite Population and with the Host Immune System

Abstract

Summary Humans and mice infected with different Plasmodium strains are known to produce microvesicles derived from the infected red blood cells (RBC), denoted RMVs. Studies in mice have shown that RMVs are elevated during infection and have pro-inflammatory activity. Here we present a detailed characterization of RMV composition and function in the human malaria parasite Plasmodium falciparum. Proteomics profiling revealed the enrichment of multiple host and parasite proteins, in particular of parasite antigens associated with host cell membranes and proteins involved in parasite invasion into RBCs. RMVs are quantitatively released during the asexual parasite cycle prior to parasite egress. RMVs demonstrate potent immunomodulatory properties on human primary macrophages and neutrophils. Additionally, RMVs are internalized by infected red blood cells and stimulate production of transmission stage parasites in a dose-dependent manner. Thus, RMVs mediate cellular communication within the parasite population and with the host innate immune system.

The languages of parasite communication

“…Both host and parasite proteins are present in the vesicles and their composition, together with the requirement for the parasite protein PfPTP2, is consistent with them being derived from Maurer's clefts and specific sub-domains of the red blood cell membrane [10,11]. Once released, the vesicles can bind to both infected and uninfected erythrocytes, but internalisation appears to be specific to infected cells [10]. Again, it seems that not all cells are equally receptive, since fewer than half the infected cells take up microvesicles, even when they are present at very high concentrations [10].…”

“…Once again, there needs to be a balance between virulent replicative forms and transmissible forms, and once again there seems to be a quorum sensing mechanism that can tip the equilibrium towards gametocyte production. In this case, however, the messengers are membrane-bound vesicles that are released by infected red blood cells; these are termed red blood cell microvesicles [10] or exosome-like vesicles [11] by the two groups that discovered them. Although both groups report the same effect on gametocyte production, the vesicles they characterised differed in size.…”

“…Release of these vesicles peaks in late schizogony [10,11] and is independent of parasite egress [10]. Both host and parasite proteins are present in the vesicles and their composition, together with the requirement for the parasite protein PfPTP2, is consistent with them being derived from Maurer's clefts and specific sub-domains of the red blood cell membrane [10,11]. Once released, the vesicles can bind to both infected and uninfected erythrocytes, but internalisation appears to be specific to infected cells [10].…”

Phospholipases during membrane dynamics in malaria parasites

“…Both uRBCs and iRBCs release microvesicles into the host serum, which are suggested to arise by blebbing from lipid rafts (Mantel et al, 2013;Nantakomol et al, 2011; reviewed in Mantel and Marti, 2014). These structures are likely involved in mediating cell-cell communication between parasites and in the induction of gametocyte formation (Mantel et al, 2013;Nantakomol et al, 2011;Regev-Rudzki et al, 2013).…”

“…These structures are likely involved in mediating cell-cell communication between parasites and in the induction of gametocyte formation (Mantel et al, 2013;Nantakomol et al, 2011;Regev-Rudzki et al, 2013). Isolated microvesicles exhibited enriched PS and PI levels compared to the RBCM (Gulati et al, 2015).…”