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13, 957967

Spotlight
Vesicles as Vehicles
for Virulence
Monica R. Mugnier,1,2,*
F. Nina Papavasiliou,1,* and
Danae Schulz1,3,*
Immune
Parasites have long been known modulaon?
to inuence host responses
to infection through the secretion
of virulence factors. Extracellular
vesicles are emerging as impor-
tant mediators of these mani-
pulations, and a new study by
Szempruch et al. suggests they Figure 1. Extracellular Vesicles Could Mediate a Variety of Processes in Trypanosoma brucei
could play a crucial role in host Infection. Szempruch et al. demonstrate that Trypanosoma brucei-generated extracellular vesicles (EVs) have
the ability to transfer protein to other parasites and to host cells [3]. This could be important for modulating the
responses to African trypano- immune response to parasite infection both in the mammal and the y. EVs could also be the mechanism by
some infections. which repellants or other factors important for social motility are transferred between parasites in the y. Finally,
EVs could play a role in quorum sensing that mediates density-dependent differentiation from long slender to
Extracellular vesicles (EVs) are produced stumpy forms within the mammal.

by nearly every cell type, including most

parasites [1]. The transfer of their con-
tents, whether protein, lipid, or nucleic
acid, from one cell to the next can alter
the functioning of the recipient cell, making
these vesicles crucial mediators of cell
signaling with huge potential as therapeu-
tic and diagnostic tools (Figure 1). EVs
were recently reported in African trypano-
somes in Trypanosoma brucei gam-
biense, a form of T. brucei responsible
for chronic African sleeping sickness in
humans [2]. A new study by Szempruch
et al. identies EVs in an animal infective
form of the parasite, Trypanosoma brucei
brucei [3], which appear very similar to
those described in T. b. gambiense, at
least morphologically. The authors extend
upon the ndings in T. b. gambiense by
identifying parasite membrane nano-
tubes, which had been described in
T. brucei in the 1960s and referred to as
plasmanemes at the time [4]. The role of
plasmanemes was unclear then, but
Szempruch and colleagues suggest that
these nanotubes/plasmanemes may be
the origin of EVs in African trypanosomes.
They microscopically observe the forma-
tion of EVs during the dissociation of
membrane nanotubes, although it is not
clear if this is the exclusive mechanism of
EV formation in T. brucei. Interestingly,
membrane nanotubes appear to tran-
siently interact with neighboring parasites.
If functional, these structures might medi-
ate cell-to-cell communication.
One of the most intriguing aspects of EVs
in the context of infectious disease is their
potential to fuse with and alter the function
of host cells. Szempruch et al. show that,
indeed, parasite EVs fuse with host eryth-
rocytes, transferring parasite variant sur-
face glycoproteins (VSGs). The transfer of
VSGs to host erythrocytes has been pre-
viously observed [5], but the mechanism
behind it and its functional relevance
remains a mystery. Szempruch et al. dem-
onstrate that fusion of EVs with host eryth-
rocytes affects erythrocyte rigidity and size

Trends in Parasitology, June 2016, Vol. 32, No. 6 435

and postulate that this results in preferen-
tial clearance by host myeloid cells [6],
although this is not tested directly. Con-
sistent with this model, the intravenous
injection of parasite EVs into nave mice
results in a 510% decrease in the number
of host erythrocytes within 1 h, demon-
strating a potential role for parasite EVs
in infection-associated anemia. The trans-
fer of VSGs from the parasite surface to
the recipient erythrocyte raises the possi-
bility that erythrocytes could become tar-
gets of antibody responses directed
against parasite VSGs, which might also
be expected to cause increased erythro-
cyte clearance, although Stijlemans et al.
show preferential clearance of trypano-
some-altered erythrocytes even in unin-
fected mice [6]. It remains to be seen
whether T. brucei EVs fuse with other host
cell types, and what, if any, modulatory
effect they have.
In addition to the interaction between EVs
and erythrocytes, Szempruch and col-
leagues demonstrated that African try-
panosome EVs were able to transfer
virulence factors from one parasite to
another. One such factor is the serum
resistance-associated (SRA) gene prod-
uct, which allows Trypanosoma brucei
rhodesiense to escape lysis by blocking
the action of the trypanosome lytic
factor (TLF) found in human blood [7].
T. b. brucei lacks the SRA gene and is
thus usually susceptible to lysis by TLF. In
an elegant series of experiments, the
authors demonstrated that co-culturing
T. b. brucei in transwells with either
T. b. rhodesiense or with T. b. brucei
carrying an SRA transgene conferred resis-
tance to killing by TLF. They went on to
show that resistance to TLF could be con-
ferred through the addition of EVs alone,
provided that they were harvested from
either SRA transgenic T. b. brucei or from
T. b. rhodesiense. The authors also dem-
onstrated that SRA and other vesicular
membrane proteins from EVs enter the
endocytic pathway at the agellar pocket
of the recipient parasite, with no evidence
436 Trends in Parasitology, June 2016, Vol. 32, No. 6
for receptor-mediated internalization. parasitemia within the mammal could lead
This raises interesting questions as to to increased nanotube formation, followed
whether co-infections with T. b. brucei by delivery of SIF via EVs, culminating in
and T. b. rhodesiense could lead to differentiation from long slender to short
enhanced ability of T. b. brucei to survive stumpy parasites that are preadapted for
within a primate reservoir. survival within the y midgut. The involve-
ment of EVs as carriers of signals for differ-
In all scenarios tested by Szempruch and entiation to stumpy forms or for social
colleagues, the EV-mediated interaction motility is now an open and exciting area
between trypanosomes, or between try- of inquiry.
panosomes and host cells, leads to the
transfer of proteins. Thus, the question This work ties together the mysterious
remains open as to whether EVs also carry observations of plasmanemes and para-
DNA or RNA cargo, the delivery of which site-to-host transfer of VSGs, while at the
could effectively reprogram the recipient same time suggesting new mechanisms for
cell, as happens with Plasmodium falcipa- parasite communication. With these nd-
rum [1]. This type of reprogramming could ings, T. brucei joins the ranks of the numer-
lead to immune modulation in the host, ous parasites that use these unique
which has been demonstrated in a num- structures as mediators of cell-to-cell com-
ber of other parasitic systems [1]. munication, both between parasites and
with their intimately associated hosts [1].
Additionally, it remains to be seen whether 1
Laboratory of Lymphocyte Biology, The Rockefeller
T. brucei EVs contain cargo that mediate University, 1230 York Avenue, New York, NY 10065, USA
communication or quorum sensing. While 2The Rockefeller Graduate Program, The Rockefeller
trypanosomes are single-celled eukar- 3University, 1230 York Avenue, New York, NY 10065, USA
Current address: Department of Biology, Harvey Mudd
yotes, their behavior within their insect College, 301 Platt Bvd, Claremont, CA 91711, USA
and mammalian hosts suggests that they
communicate with one another, and the *Correspondence: mmugnier@rockefeller.edu
(M.R. Mugnier), papavasiliou@rockefeller.edu
means by which this occurs has been a (F.N. Papavasiliou), dschulz@rockefeller.edu (D. Schulz).
long-standing mystery in the eld. In the http://dx.doi.org/10.1016/j.pt.2016.03.001
insect form, T. brucei exhibits social motil-
ity, which has been shown to be important References
1. Coakley, G. et al. (2015) Exosomes and other extracellular
for colonization of the y midgut [8]. Colo- vesicles: the new communicators in parasite infections.
Trends Parasitol. 31, 477489
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2. Geiger, A. et al. (2010) Exocytosis and protein secretion in
another, but the nature and function of Trypanosoma. BMC Microbiol. 10, 20
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Trypanosoma brucei mediate virulence factor transfer and
mammal, T. brucei appears to possess cause host anemia. Cell 164, 246257
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in density-dependent differentiation from able antigens in the surface coat of Trypanosoma brucei
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Mony, B.M. and Matthews, K.R. (2015) Assembling the
EVs, one could imagine a scenario where 9. components of the quorum sensing pathway in African try-
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