Acute lipid profile changes in malaria patients - a gateway towards novel antimalarial drug class identification?

In industrialized countries, malaria remains the most important, potentially
live-threatening infectious disease imported by travelers from endemic regions.
From 2001 to 2011, it accounted for an estimated 6,000-16,000 imported cases in
Europe annually [1-6]. Recently, progress in malaria control has been made and
elimination, if not eradication, appears again on the international agenda as a
long-term goal seriously to be considered [7]. However, there is still a long
way to go, from better understanding of malaria patho-physiology to the
identification and exploitation of routes towards new and improved control
tools, including novel drugs. Alterations in plasma lipid profiles in the acute
phase of infectious diseases are well-known since long and possibly owed to a
whole range of at least in part disease-specific mechanisms. With regard to
malaria, a characteristic pattern consisting of low overall cholesterol,
high-density lipoprotein cholesterol (HDL), apolipoprotein a, low-density
lipoprotein cholesterol (LDL), very low-density lipoprotein (VLDL) and high
triglycerides has been reported before in returned travelers by various groups
[8-11], and a correlation with parasitaemia [9] but not with overall disease
severity [10] was noted. However, apart from a suggestion made that these
transient changes related to the parasitaemic phase may be a potential adjuvant
diagnostic tool [9,10], little attention has been paid up to date to exploit
this phenomenon any further.
Hemozoin (Hz; *malaria pigment*) is the plasmodial end product of haem
metabolism and detoxification, and interference with its intraplasmodial
formation and storage in one way or another is the prime target of most of our
antimalarial drugs to date [12]. Its detection is utilized as adjuvant
diagnostic and prognostic tool, and its role as influential host immunity
modulator has been recognized clearly [12], yet the underlying mechanisms are
still to be fully elucidated. Host plasma lipids have been found to be
implicated in hemozoin formation in vivo [13,14]. It has been shown that
hemozoin is formed at the interface of the aequeous medium of the parasite*s
food vacuole and lipid nanospheres [15]; and the *lipid hypothesis* postulates
that hemozoin formation occurs most rapidly at lipid-water interfaces [16].
Moreover, not only does the Hz production requires host lipids, but it appears
also that the inhibition of host monocyte functions as one of the eminent
immune-modulating Hz effects are hydroxy fatty acids, generated by plasmodia in
large amounts in the human host .
If a link between human host serum lipid alterations and the above outlined
mechanisms can be demonstrated, further studies to elucidate the precise
pathways are thinkable - moreover - novel treatment approaches could be
explored (first in vitro, and e.g. by experiments subjecting P. falciparum to
lipid metabolism-regulating drugs).

Hypotheses:
(i) The lipid profile of acute malaria exhibits characteristic changes,
including low overall cholesterol, low HDL and apolipoprotein a, low LDL and
VLDL and high triglycerides.
(ii) These changes are characteristic for the malaria-specific pathogen-host
interplay and are directly proportional to the amount of hemozoin produced by
human-pathogenic plasmodia, thus opening up avenues to explore novel
antiparasitic interventions.

In order to confirm previous observations and to increase our understanding of
the patho-physiologic mechanism of the plasma lipid changes; in this study, we
will prospectively measure the blood lipid profile of approx. 120 malaria
patients and an equal number of matched healthy controls over time during acute
disease and following recovery. This is best done in travelers representing a
wide range of strains and hosts rather than one particular strain group and a
homogenous human ethnicity, as typical for field studies:
(A) To test hypothesis (i) the plasma lipid spectrum (total cholesterol, HDL,
apolipoprotein A1, LDL, VLDL and triglycerides) in 120 acute malaria cases will
be assessed.
(B) To test hypothesis (ii) the amount of circulating malaria pigment in
parasites and macrophages will be quantified and correlated both with light
microscopy and laser flow-cytometric detection.

We propose a prospective observational cohort study including suitable controls
and malaria patients

In this study, 12 mL of blood shall be drawn for study purposes from each
participant at three time points (additional volume, yet only one additional
venipuncture required as blood draws at least at D0, D3 will be obtained for
routine care in any case). In volunteers, one single blood draw of 12 mL is
required. To that end, risk of study-related physical harm will be limited, yet
personal risks and benefits for participating in the study shall be explained
in detail.