COMMENTARY
Recent buzz in malaria research
Emily J. Chenette
The FEBS Journal, Editorial Office, Cambridge, UK
Introduction
Malaria is an urgent public health problem. There
were an estimated 296 million cases of malaria in 2015
[1], with 730 500 deaths [2]; it is a leading cause of
death worldwide in children under the age of 5. Most
deadly cases of malaria are caused by the Plasmod-
ium falciparum parasite. Plasmodium species have a
complicated life cycle that requires both mosquito and
vertebrate hosts. A simplified overview: during a bite
from an infected mosquito, Plasmodium sporozoites
leave the mosquito salivary gland and enter the host
bloodstream, traversing several cell types before even-
tually invading hepatocytes. The parasites multiply,
and eventually the infected hepatocytes burst and
release merozoites into the bloodstream. Merozoites
then invade host erythrocytes, where they continue
multiplying inside a specialised vacuole, leading to ery-
throcyte rupture and further dissemination of mero-
zoites. These merozoites go on to invade, infect and
lyse additional erythrocytes in a cycle that has devas-
tating effects on the host. However, when inside ery-
throcyte vacuoles, the parasites can also form
gametocytes that escape the erythrocyte vacuole, circu-
late in the bloodstream, and are then taken up again
by a mosquito as it bites. The gametes combine in the
mosquito midgut, eventually forming sporozoites that
migrate to the mosquito salivary gland, and the deadly
cycle repeats (Fig. 1).
This Special Issue of The FEBS Journal brings
together reviews and primary research highlighting the
latest advances in malaria research. However, the
breadth of the field and the enormity of the conse-
quences to human health warrant additional discussion
of the most active areas in malaria research. In this
Commentary, we review the latest findings in three
areas of malaria research: Plasmodium biology, host
response and drug discovery.
The notoriously complex Plasmodium life cycle has
been intensively studied, yet certain aspects are still not
well understood. We highlight recent research on sporo-
zoite cell traversal and gametocyte egress that reinforce
the essential, if still somewhat mysterious, nature of
these processes in the Plasmodium life cycle. Plasmodium
parasites are involved in an escalating arms race to
evade detection by the host immune system, and we
2556 The FEBS Journal 284 (2017) 2556–2559 ª 2017 Federation of European Biochemical Societies
discuss recent studies on mechanisms by which Plasmod-
ium infection suppresses T-cell responses. However, the
host is no passive bystander to this onslaught. Exciting
research reveals a link between host metabolism and
Plasmodium infectivity, and suggests that the composi-
tion of the gut microbiome might inform the severity of
malaria. Moreover, as new insights are gleaned into
Plasmodium life cycle and biology, scientists are able to
develop effective targeted therapies that block invasion
and replication, as well as new strategies for the control
and prevention of malaria.
Plasmodium biology
The complicated lifecycle of Plasmodium opens the
parasite to therapeutic intervention at several different
stages. Indeed, two recent reports suggest an important
role for cell traversal, which occurs prior to hepatocyte
invasion, in eventual infection. Justin Boddey and col-
leagues generated P. falciparum mutants that lack
sporozoite microneme protein essential for cell traver-
sal (SPECT) and perforin-like protein 1 (PLP-1) and
showed that these genes are dispensable for erythro-
cyte egress and hepatocyte infection, and are not
required for sporozoite formation in the mosquito.
However, SPECT and PLP-1 were necessary for P. fal-
ciparum traversal across macrophages and hepatocytes
in vitro, and were also required for liver infection
in vivo in a humanised mouse model [3]. Marcelo
Jacobs-Lorena and colleagues report that GAPDH on
the sporozoite surface interacts with the cell surface
protein CD68 on Kupffer cells, which might facilitate
Kupffer cell traversal. Blocking this interaction with
an anti-GAPDH antibody inhibited Plasmod-
ium berghei macrophage entry and decreased liver
infection in mice [4]. These studies point to an impor-
tant role for traversal in eventual infection and suggest
several new targets for drug discovery.
Daniel Bargieri and colleagues [5] investigate the
process of gametocyte egress from erythrocytes, and
find a key role for Plasmodium merozoite throm-
bospondin-related anonymous protein (MTRAP) in
this process. Knocking out MTRAP in P. berghei
blocked transmission from infected mice to mosquitos,
 Commentary

Fig. 1. Plasmodium lifecycle. Propagation of the malaria parasite requires two different hosts (here, mosquito and human). Image credit:
CDC – DPDx/Alexander J. da Silva, PhD, Melanie Moser. CDC Public Health Image Library identification number 3405.

indicating a defect in gametocyte development. Indeed,
P. berghei and P. falciparum gametocytes that lacked
MTRAP were unable to egress from the vacuole [5]. A
different approach by Kehrer, Frischknecht and Mair
[6] independently identified the importance of MTRAP
in gametocyte egress and transmission. Although the
precise function of MTRAP in egress remains to be
elucidated, the known role for TRAP family proteins
in parasite gliding motility and host cell invasion support
an intriguing role for actin dynamics in vacuole egress.
Host response
Plasmodium parasites spend much of their lifecycle
ensconced in parasitic vacuoles, relatively protected
from the innate immune system. But how do sporo-
zoites avoid triggering an innate immune response
immediately after infection? A report from James
McCarthy, Christian Engwerda and colleagues high-
lights an inhibitory role for type I interferons (IFNs)
in anti-Plasmodium immunity. They found increased
production of type I IFNs after P. falciparum infec-
tion, which suppressed IFNc production by CD4+ T
cells, decreased IL-6 production by monocytes and
increased IL-10 levels in human volunteers. This sug-
gests that type I IFNs suppress infection-induced
inflammation, although a clear link between type I
IFNs and parasite burden was not identified in this
study [7]. Katsuyuki Yui and colleagues find that a
subset of CD4+ T cells from P. berghei-infected mice
produce IL-27, which suppresses IL-2 production and
inhibits clonal expansion of CD4+ T cells [8]. The
development of targeted therapies that specifically pro-
mote T-cell proliferation and IFNc production might
represent a useful strategy in early stages of Plasmod-
ium infection.

The FEBS Journal 284 (2017) 2556–2559 ª 2017 Federation of European Biochemical Societies 2557
Commentary
Although the innate immune system receives much
of the attention in studying the response to Plasmod-
ium infection, research fronts in other systems are
yielding exciting findings as well. A report from Maria
Mota, Liliana Mancio-Silva and colleagues found that
P. berghei infection decreased hepatic activation of the
key metabolic enzyme AMPK in vitro. Intriguingly,
expression of constitutively active AMPK mutants lim-
ited hepatic schizont size in vitro. Moreover, AMPK
agonists decreased merozoite release and reduced para-
site burden in the liver in vivo, supporting the develop-
ment of AMPK agonists as potential prophylactic
drugs [9]. Furthermore, Nathan Schmidt and collea-
gues report that the composition of the gut micro-
biome might modulate the severity of malaria in
mouse models. The authors observed that mice
obtained from different vendors showed different
malaria parasite burdens after Plasmodium yoelii or
P. berghei infection. They also noted differences in
cecal bacterial communities in mice from each vendor,
suggesting that gut microbiota might have a role in
this phenotype. Intriguingly, feeding mice yogurt sup-
plemented with Lactobacillus and Bifidobacterium
decreased parasite burden and morbidity, possibly via
modulating the host immune response [10]. These
reports highlight exciting new avenues for future inves-
tigation.
Drug discovery
The recent advances in understanding Plasmodium
biology and the host response to infection should
usher in a new era of drug development, and indeed
exciting progress is being made in this area. Plasmod-
ium is evolving resistance to commonly used anti-
malarial compounds including artemisinin (ART),
chloroquine and related drugs. However, increased
resistance towards one drug correlates with increased
sensitivity to other cellular perturbations. Rowena
Martin and colleagues now provide insight into how
this occurs. They show that mutations in the P. falci-
parum chloroquine resistance transporter (CRT) that
confer resistance to chloroquine, sensitise it to quinine,
which blocks CRT function and kills the parasite. The
authors also found that mutant CRT is better able to
transport the antiviral compound amantadine to the
cytoplasm, causing the parasite to be hypersensitive to
amantadine [11]. Paula da Fonseca, Matthew Bogyo
and colleagues use a structure–function approach to
develop an inhibitor of the P. falciparum 20S protea-
some that reduces parasite burden in vivo in mice.
Interestingly, this compound was more efficient in
killing ART-resistant P. falciparum parasites than
2558 The FEBS Journal 284 (2017) 2556–2559 ª 2017 Federation of European Biochemical Societies
ART-sensitive parasites, perhaps because of the sensi-
tising effect of drug resistance [12].
The utility of high-throughput approaches in devel-
oping new malaria targets is exemplified by research
from Janet Hemingway, Stephen Ward and colleagues
who use click chemistry-compatible activity-based
probes to develop a catalogue of ART targets. Their
work not only uncovers new pathways through which
ART might exert its antimalarial effect, but also pro-
vides insight into how resistance to this compound
might be avoided [13]. Two other recent studies have
taken a large-scale approach to drug development.
The Saponin-lysis Sexual Stage Assay (SaLSSA),
developed by Elizabeth Winzeler and colleagues identi-
fies small molecules that block transmission of gameto-
cytes [14]. Approaches such as this could yield new
compounds that will be useful in stopping the spread
of malaria. In an inspiring collaborative effort, the
Medicines for Malaria Venture distributed a ‘Malaria
Box’ of 400 representative compounds that kill P. fal-
ciparum to labs around the world. In the resulting
study, 55 groups reported the results of over 290
assays on the Malaria Box compounds, revealing new
pharmacokinetic data and mechanisms of action for
many of the compounds [15]. Bold efforts such as
these should be commended for injecting enthusiasm
and a spirit of collaboration into a research area that
has the potential to save hundreds of thousands of
lives annually.
The impressive advances in drug discovery are bol-
stered by research programmes that aim to eradicate
malaria. Nikolai Windbichler, Andrea Crisanti, Tony
Nolan and colleagues developed CRISPR-Cas9 con-
structs that disrupt fertility in female mosquitoes,
which could deplete this key vector for Plasmodium
transmission [16]. In complementary work, Philip
Eckhoff and colleagues use epidemiological modelling
to identify a gene drive approach with the best chance
of success. Their model considers environmental as
well as biological factors and will be an important
resource for malaria eradication projects [17].
This diverse collection of papers highlights new dis-
coveries in different areas of malaria research and sup-
ports new therapeutic initiatives that could reduce the
morbidity and mortality associated with Plasmodium
infection. These fundamental observations into Plas-
modium biology support the development of drugs that
target specific aspects of its complicated life cycle,
whereas research into how the host response is com-
promised to facilitate Plasmodium replication could
yield strategies to circumvent or curtail infection. Phar-
maceutical approaches that exploit the side effects of
drug resistance provide some hope that drug-resistant
 Commentary

Plasmodium will not have as dire an effect as feared. 8 Kimura D, Miyakoda M, Kimura K, Honma K,
Finally, high-tech, high-throughput and collaborative Hara H, Yoshida H & Yui K (2016) Interleukin-
strategies are uncovering compounds that could eventu- 27-producing CD4+ T cells regulate protective
ally lead to the eradication of malaria. We hope you immunity during malaria parasite infection. Immunity
enjoyed this snapshot of research reported elsewhere, 44, 672–682.
and please keep reading this Special Issue for other 9 Grilo Ruivo MT, Vera IM, Sales-Dias J, Meireles P,
inspiring reviews and primary research in this active Gural N, Bhatia SN, Mota MM & Mancio-Silva L
field. (2016) Host AMPK is a modulator of Plasmodium liver
infection. Cell Rep 16, 2539–2545.
10 Villarino NF, LeCleir GR, Denny JE, Dearth SP,
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