Extracellular vesicles (EVs) facilitate intercellular communication and are considered a promising therapeutic tool for the treatment of infectious diseases. These vesicles involve microvesicles (MVs) and exosomes and selectively transfer proteins, lipids, mRNAs, and microRNAs from one cell to another. While MVs are formed by extrusion of the plasma membrane, exosomes are a population of vesicles of endosomal origin that are stored inside the multivesicular bodies (MVBs) as intraluminal vesicles (ILVs) and are released when the MVBs fuse with the plasma membrane. Biogenesis of exosomes may be driven by the endosomal sorting complex required for transport (ESCRT) machinery or may be ESCRT independent, and it is still debated whether these are entirely separate pathways. In this manuscript, we report that the protozoan parasite, Giardia lamblia, although lacking a classical endo-lysosomal pathway, is able to produce and release exosome-like vesicles (ElV). By using a combination of biochemical and cell biology analyses, we found that the ElVs have the same size, shape, and protein and lipid composition as exosomes described for other eukaryotic cells. Moreover, we established that some endosome/lysosome peripheral vacuoles (PVs) contain ILV during the stationary phase. Our results indicate that ILV formation and ElV release depend on the ESCRT-associated AAA+-ATPase Vps4a, Rab11, and ceramide in this parasite. Interestingly, EIV biogenesis and release seems to occur in Giardia despite the fact that this parasite has lost most of the ESCRT machinery components during evolution and is unable to produce ceramide de novo. The differences in protozoa parasite EV composition, origin, and release may reveal functional and structural properties of EVs and, thus, may provide information on cell-to-cell communication and on survival mechanisms.
Lactoferrin (LF) is an 80 KDa iron-binding glycoprotein that plays a significant role in the innate immune system and is considered to be an important microbicide molecule. It has been suggested to be effective in the treatment of giardiasis, an intestinal disease caused by the protozoan parasite G. lamblia. However, the molecular mechanisms by which LF exerts its effect on this parasite are unknown. Most of the microbicidal activity of human or bovine LF (hLF or bLF) has been associated with the N-terminal region of the mature LF - lactoferricin (LFcin). LFcin is produced by pepsin cleavage of the native protein in vitro and likely in vivo. In this work, we analyse the participation of the endocytic machinery of G. lamblia in the internalization of bLF and bLFcin and their effects on cell homeostasis. Our results show that, when bLF or bLFcin are internalized by receptor-mediated endocytosis, cell growth stops, and morphological changes are produced in the trophozoites, which ultimately will produce immature cysts. Our findings contribute to disclose the fine mechanism by which bLF and bLFcin may function as an antigiardial molecule and why they have therapeutic potential to eradicate giardiasis.
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