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Microbiology: Current Research | Volume 3
May 20-21, 2019 | Vienna, Austria
Medical Microbiology
4
th
International Conference on
Infection of mammalian liver by the malaria parasites relies of a network of
parasite kinases
Purnima Bhanot
Rutgers University, USA
T
here are 240 million cases of malaria leading to nearly
400,000 deaths each year. It is caused by five species of the
protozoan parasite,
Plasmodium
, transmitted to humans by
mosquitoes, in the form of ‘sporozoites’. Sporozoites invade
hepatocytes where they develop intracellularly into ‘liver
stages’. Liver stages exit the hepatocytes inmembrane-bound
vesicles, termed ‘merosomes’, that disintegrate in the blood-
stream. There, liver stages infect erythrocytes and initiate
the symptomatic step of malaria. Blocking
Plasmodium’s
liver cycle could prevent disease and a better understanding
of the key pathways at this step can identify drug targets for
malaria chemoprophylaxis. We report that sporozoite entry
into hepatocytes requires the parasite’s cGMP-dependent
protein kinase (PKG) and Calcium-Dependent Protein Kinases
1, 4 and 5 (CDPK1, CDPK4 and CDPK5). PKG and CDPK5 are
also required for the parasite’s egress from the hepatocyte.
Chemical inhibition of
Plasmodium
PKG abolishes sporozoite
motility by preventing secretion of proteins that enable
adhesion of sporozoites to the extracellular matrix. Depletion
of CDPK1, 4 and 5 also decreases sporozoite motility, but
without significantly affecting their adhesion to the substrate.
Since motility is required for sporozoites to a) disseminate
from the site of deposition in the dermis, migrate through
cell- and tissue-layers to enter the blood stream and c) enter
a hepatocyte, its inhibition significantly decreases sporozoite
infectivity. Chemical inhibition or knockdown of PKG and
CDPK5 has a second effect – inhibiting either the formation
or release of merosomes. Mice treated with a PKG inhibitor
are significantly less susceptible to infection by sporozoites,
providing preliminary evidence that chemical inhibition of
parasite PKG can block infection in animals. By revealing the
requirement for PKG, CDPK1, 4 and 5 in
Plasmodium
invasion
of and egress from hepatocytes, our work provides biological
and chemical validation for targeting these
Plasmodium
kinases for chemoprotection against malaria.
e
:
bhanotpu@njms.rutgers.eduMicrobiol Curr Res, Volume 3
DOI: 10.4066/2591-8036-C1-006