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Dr Nishith Gupta is working towards understanding
intracellular parasitism and developing therapeutic
strategies for the inhibition of parasites. Here, he discusses
the field, his daily challenges, the importance of technology
and collaboration, and of an interdisciplinary approach
Why parasite-host interactions?
Intracellular parasites reprogramme their host
cells to create a safe haven for their survival.
Conversely, triggers from the host cell can
influence these pathogens to replicate, die,
differentiate, or undergo dormancy and sexual
reproduction. A successful parasitism requires
efficient access and allocation of host resources.
We would like to know how different parasites
manipulate their host cells to eventually win
the Armageddon.
What are the primary objectives of your
research?
Most protozoan parasites have adapted to
highly convertible life styles, which often
comprise development in more than one type
of host or tissue, switching between fast-
replicating (acute) and quiescent (dormant)
modes, and asexual-sexual conversion. We
endeavour to delineate the impact of host-
parasite metabolism on parasite growth and
differentiation. In a nutshell, our studies
explore the metabolic basis of parasitism, host
cell tropism and stage switching. We have
selected three complementary parasite models
based on solicited questions, experimental
feasibility and their comparative value.
Toxoplasma and Plasmodium species have
proven useful to examine the pathogen-host
interactions occurring during the asexual
phase. Eimeria falciformis, a monoxenous
parasite with a short life cycle in the mouse
(an established research model), has been
pivotal in identifying host determinants of the
parasite’s sexual development and to study in
vivo parasite-host interactions.
Could you elaborate on the basic research
being carried out in this area?
One key process is the transaction of host- and
parasite-derived metabolites across biological
membranes and macromolecular biogenesis
within the parasite. To reproduce, a parasite
must generate a significant amount of biomass
(proteins, nucleotides and lipids) and energy.
Moreover, when a parasite switches between the
proliferating and quiescent modes, it must rewire
metabolism to accommodate cell division or
dormancy. Equally, metabolic cues can influence
the gene expression and stage switch. Our work
strives to appreciate the evolutionary framework
and regulation of carbon metabolism, and its
impact on the parasite growth, pathogenesis and
nutritional adaptations in discrete host niches.
What are the advantages of studying mutual
interactions in addition to just the parasite
and host cell individually?
Because the parasites we study are not able to
survive without their host cells, it is important
to address both partners to understand the
underlying concepts of intracellular parasitism
and to develop drugs. Studying the pathogen,
host and their interactions provides a prevailing
insight into their coevolution, and identifies drug
targets at different cellular levels. I have also
been amazed to discern quite a few analogies
between our laboratory studies on the parasite-
host relationships, and the binary interactions
we face in our daily life.
How does technology help advance your
investigations?
Our work uses a combination of classical and
state-of-the-art methods on three singular
parasites to study both facets of pathogen-host
interactions in an integrated manner. More
recently, we have begun exploring the metabolic
basis and control of epigenetic modifications
during parasite differentiation. This involves a
combination of contemporary transcriptomics,
metabolomics and epigenetics experiments
along with more conventional methods of
molecular genetics, biochemistry and cell
biology. We have also been pioneering the use
of optogenetic tools in infection research to
modulate the parasite or host processes in a
specific, dynamic and spatiotemporal fashion.
What are your daily activities and challenges?
Most of my activities are scientific, such as
managing and mentoring the laboratory,
experimental troubleshooting, writing and
reviewing grants and publications, presenting
our research, and teaching and training
students. Infection research, particularly with
the human pathogens and animal models,
must overcome numerous ethical and practical
issues. This includes obtaining appropriate
work permissions, setting up the laboratories
and techniques, recruiting the right workforce,
ensuring their safety and finding suitable
cooperation partners. This is what I admire
about science though; taking up intellectual
challenges and resolving them fruitfully. I see
problems as precious opportunities to improve
my workforce and myself. Every single day feels
different and rewarding in terms of the work
we do.
How important is an interdisciplinary,
collaborative approach to your research?
Our interdisciplinary work has been a
prerequisite to ask and answer appropriate
questions while ensuring a competitive
advantage. Of late, our wet-lab work has
amalgamated with theoretical biology to
systematically model conjoined cellular
networks of the parasite and its host cell.
We have benefited immensely from our
diverse cooperation partners. I believe that a
collaborative approach has become the lynchpin
of modern science, research and technology.
All our ongoing projects have one to two
partner labs with a frequent exchange of ideas,
resources, technologies and personnel.
Parasite-host
interactions
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DR NISHITH GUPTA
Exploiting the host
Ongoing research at the Humboldt University, Berlin, seeks to understand the processes by which intracellular
parasites exploit their hosts, specifically looking at the metabolic interactions occurring during symbiosis
PARASITISM IS A non-mutual relationship
between two different organisms where a
parasite lives at the expense of its host instead
of seeking out its own resources. Parasites may
be facultative, whereby the organism is not
obliged to act as a parasite – it can also satisfy its
cellular needs by independent means. Obligate
parasites, on the other hand, have no choice but
to exploit their host to complete the processes
critical to their life cycle. Particularly relevant
and interesting parasites include intracellular
pathogens, which co-opt individual host cells
and utilise their cellular machinery to acquire
the necessary resources.
Obligate intracellular parasites infect a
wide range of hosts, including both wild and
domesticated animals and also humans.
Infection can either be asymptomatic or
elicit trivial symptoms, and it is often the
case that those infected are unaware of their
newly acquired parasites – indeed, remaining
undetected is a viable strategy for a parasite
and underlies its evolutionary success. In many
cases, however, parasites produce debilitating
symptoms, which can lead to fatality. There
is a sizeable yearly socioeconomic burden
attributable to parasites. It is therefore
imperative to build a complete understanding
of how they survive and reproduce in order to
develop treatments and to improve the lives of
those affected by parasitic infections.
PARASITES OF INTEREST
Dr Nishith Gupta of the Department of Molecular
Parasitology at the Humboldt University, Berlin,
works at the forefront of this field. He seeks
to identify the interplay between pathogen
and host metabolism to better understand
intracellular parasitism. In particular, he studies
three different parasite genera of the protozoan-
apicomplexa phylum, Toxoplasma, Plasmodium
and Eimeria.
Toxoplasma gondii is considered to be one of
the most successful pathogens on Earth due
to its infective diversity, and is found in nearly
all warm-blooded vertebrates. About one-
quarter of the world’s population is seropositive
to this parasite. The parasite infection is
generally asymptomatic or produces mild flu-
like symptoms, but in immuno-suppressed
individuals, such as those affected by HIV/
AIDS and ageing, or patients undergoing organ
transplants, it can lead to cerebral and ocular
toxoplasmosis and eventual death. It also causes
spontaneous abortion during pregnancy, and
cognitive defects in newborns. Eimeria species
inflict gastrointestinal diarrhoea (coccidiosis) in a
variety of animals including poultry. Plasmodium
is the culprit parasite responsible for malaria,
which kills about 1 million people annually.
WHAT CAN WE LEARN FROM
METABOLISM?
Intracellular parasites rewire host metabolism
for their reproduction. A successful parasite must
be able to access the host cell’s resources and
allocate them towards its own cellular demands,
which vary depending on the parasite’s phase.
This requires a crosstalk between the metabolic
networks of both organisms. Through study of
how they interact, and how parasites deal with
changes in host cell metabolism, one can learn
how to manipulate them and develop strategies
to inhibit parasite growth. Gupta’s work aims to
understand the functioning of intertwined host-
parasite networks in different parasitic infections.
Moreover, his group is studying metabolic
transformation and network interactions
occurring when a parasite switches between its
replicative and non-replicative stages.
DR NISHITH GUPTA
96 INTERNATIONAL INNOVATION
PARASITE EVOLUTION AND METABOLISM
Some parasites, such as Toxoplasma are highly
promiscuous, meaning that they are able to
infect a multitude of different vertebrate hosts
and survive in virtually any nucleated cell.
This contrasts with Plasmodium and Eimeria
species, which are highly tissue- and cell-specific
parasites. Through the course of evolution,
these parasites have gained or lost metabolic
pathways, optimising their life cycles with that
of their host cell. For example, Toxoplasma,
Plasmodium and Eimeria express about 400-700
metabolic enzymes. When compared to a typical
mammalian host cell expressing about 1,400
enzymes, the data implies multiple metabolic
dependencies of these parasites as well as their
unique adaptation to parasitism. Gupta’s research
group strives to clarify the relationship between
the parasites’ metabolic capacities and their
ability to infect different hosts. If appropriate
metabolites are not available in a host, then the
parasite will not be able to survive and reproduce
in that particular environment. This could provide
clues as to how the aforementioned parasites
are adapted specifically to different hosts and
tissues, and may suggest new drug targets.
INITIAL FINDINGS AND THE IMPACT
Significant progress has already been made
in these research endeavours. Gupta and
colleagues have identified and characterised
quite a few metabolic enzymes required for
parasite growth. In particular, the team has
demonstrated that disrupted synthesis of
certain membrane lipids arrests Toxoplasma
reproduction and decreases parasite-induced
lysis of host cells. These findings could therefore
have important implications in designing novel
therapeutics. His group has also developed a
transgenic yeast (Saccharomyces cerevisiae)
model for screening potential antimalarial
drugs, and unearthed key metabolic strategies
of apicomplexan parasites. Of particular note
is the investigation and comparison of sugar
metabolism in Toxoplasma and Plasmodium. The
researchers have shown a divergence in their
carbon usage, with Toxoplasma demonstrating
an unprecedented level of nutrient flexibility,
which perhaps underlies its comparatively much
wider host range. Additionally, Toxoplasma has
also been shown to have a greater plasticity
in its membrane biogenesis that parallels to a
free-living metazoan cell. Such a versatile and
autonomous sugar and lipid metabolism might
ensure the survival and growth of Toxoplasma
in a variety of nutritional milieus encountered in
different host cells.
The research group’s engagement with Eimeria
has also identified several host factors regulating
parasite development. The work shows how this
parasite subverts a key immune and metabolic
pathway of the mouse host to promote its own
life cycle. Last but not least, similarities have
also emerged between the metabolic functioning
of replicating parasites and cancer cells. Thus,
Gupta’s research has the potential to bridge the
fields of parasitology and tumour biology – the
consequences of which have yet to be seen.
These findings help us understand
the intracellular parasitism and
pathogenesis, and, if applied
successfully, have the potential to
improve clinical intervention
PARASITOLOGY
OBJECTIVES
• To investigate the metabolic interactions
between the single-celled obligate
intracellular parasites (namely Toxoplasma,
Eimeria and Plasmodium) and their host cells
• To reveal the metabolic processes that
underlie a successful reproduction and stage
differentiation in these pathogens
PARTNERS
Richard Lucius; Andreas Herrmann; Peter
Hegemann; Humboldt University, Berlin •
Kai Matuschewski, Max-Planck Institute of
Infection Biology, Berlin • Hermann-Georg
Holzhuetter, Charité Medical School, Berlin •
Stefan Kempa, Max-Delbrueck Centre, Berlin
• Isabelle Coppens, John Hopkins School
of Public Health, USA • Scott Landfear,
Oregon Health & Sciences University, USA
• Dominique Soldati-Favre, University of
Geneva, Switzerland • Yongsheng Chang,
Beijing Medical College, China • Boris Striepen,
University of Georgia, USA • Thomas Günther-
Pomorski, University of Copenhagen, Denmark
• Bernd Helms, Utrecht University, The
Netherlands • Dennis Voelker, National Jewish
Medical and Research Centre, USA
FUNDING
German Research Foundation (DFG)
• Helmholtz Foundation, Germany •
National Institute of Health, USA • Novartis
Pharmaceuticals, Switzerland • European
Society of Clinical Microbiology and Infectious
Diseases (ESCMID) • European Molecular
Biology Organization (EMBO) • Boehringer
Ingelheim Foundation, Germany • German
Academic Exchange Service (DAAD)
CONTACT
Dr Nishith Gupta, PhD
Principal Investigator
Department of Molecular Parasitology
Institute of Biology, Humboldt University
Philippstrasse 13, House 14
10115, Berlin, Germany
T +49 30 2093 6404
E gupta.nishith@staff.hu-berlin.de
www.parasit.hu-berlin.de/Members/1680986
www.researchgate.net/profile/Nishith_Gupta
NISHITH GUPTA finished his MSc in
Biotechnology at the Banaras Hindu
University (India); PhD in Microbial
Biochemistry from the University of Leipzig
(Germany); and subsequent postdoctoral
training in Molecular Parasitology from the
National Jewish Medical and Research Centre
(Denver, USA), and Humboldt University
(Berlin, Germany). He currently works as
a research group leader at the Humboldt
University of Berlin.
BIOLOGY MEETS MATHEMATICS TO EXPLORE PARASITEHOST INTERACTIONS
INTELLIGENCE
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