impaginato piccolo - Società Italiana di Parassitologia (SoIPa)

Parassitologia 50: 147-150, 2008
Genetic epidemiology of susceptibility to malaria: not only
academic exercises
F. Verra, P. Avellino, G. Bancone, V. Mangano, D. Modiano
Malaria Epidemiology Group, Department of Public Health Sciences, University of Rome “La Sapienza”
Abstract. Descriptive genetic epidemiology represents the initial step of a logical procedure of linked and
consequential phases spanning from the identification of genes involved in the resistance/susceptibility to
diseases, to the determination of the underlying mechanisms and finally to the possible translation of the
acquired knowledge in new control tools. In malaria, the rational development and potential of this pathway
is based on complementary interactions of heterogeneus disciplines going from epidemiology (the transmission,
the infection, the disease) to vaccinology passing through genetics, pathogenesis, and immunology.
Several epidemiological approaches can be applied in the study of the genetic susceptibility to
Plasmodium falciparum malaria: intra-ethnic case-control studies comparing genetic candidates of resistance/susceptibility
between subjects with different presentation of malaria (from severe disease to asymptomatic
infection) and the general healthy population is the classic approach; inter-ethnic comparative
analyses among populations with different genetic backgrounds, exposed to the same epidemiological
context and showing different susceptibility to the disease is a further, complementary, strategy.
Key words: Malaria, hemoglobin, T regulatory cells, IRF-1
Plasmodium falciparum malaria represents one of the
most selective forces for the human genome
(Kwiatkowski DP, 2005). Even today in rural areas of
sub-Saharan Africa entomological inoculation rates are
often in the order of hundreds infective bites per person
per year (Rogers DJ et al., 2002) meaning that each
individual in these areas is exposed to a potentially
lethal infection more than once per day. This stable and
perennial degree of selective pressure has contributed
to the progressive accumulation of genetic conditions
that decrease the susceptibility of human populations
to malaria (Kwiatkowski DP, 2005). The study of this
field of evolutionary biology, aims in the initial phase at
the identification of genes involved in the
resistance/susceptibility to the disease, then at the
determination of the underlying protective mechanisms
and finally at the possible translation of the acquired
knowledge in new control tools.
A brief overview of recent achievements in this field by
our group is presented.
Hemoglobin C and S role in acquired immunity
against Plasmodium falciparum malaria (Verra et
al., 2007)
Conclusive evidence exists on the protective role of
Haemoglobin C (HbC; β6Glu→Lys) against clinical
Plasmodium falciparum malaria as well as of HbS
(β6Glu→Val), both occurring in sub-Saharan Africa
(Allison, A.C. 1954; Modiano et al., 2001a). However,
the mechanism/s of the protection exerted remain/s
Correspondence: David Modiano, Dipartimento di Scienze di
Sanità Pubblica, Università “La Sapienza”, Piazzale Aldo Moro 5,
00185 Rome, Italy
e-mail: david.modiano@uniroma1.it
debated for both haemoglobin variants, HbC and HbS.
Recently, an abnormal display of PfEMP1, an antigen
involved in malaria pathogenesis, was reported on
HbAC and HbCC infected erythrocytes that showed
reduced cytoadhesion and impaired rosetting in vitro
(Fairhurst et al., 2005). On this basis it has been proposed
that HbC protection might be attributed to the
reduced PfEMP1-mediated adherence of parasitized
erythrocytes in the microvasculature. Furthermore,
impaired cytoadherence was observed in HbS carriers
suggesting for the first time a convergence in the protection
mechanism of these two haemoglobin variants
(Cholera R., et al., 2008). We investigated the impact
of this hypothesis on the development of acquired
immunity against Plasmodium falciparum variant surface
antigens (VSA) encoding PfEMP1 in HbC and
HbS carriers in comparison with HbA of Burkina Faso.
Higher immune response against a VSA panel and several
malaria antigens were observed in all adaptive
genotypes containing at least one allelic variant HbC or
HbS in the low transmission urban area whereas no differences
were detected in the high transmission rural
area. In both contexts the response against tetanus toxoid
was not influenced by the β-globin genotype. Thus,
these findings suggested that both HbC and HbS affect
the early development of naturally acquired immunity
against malaria.
Quick but “costly” versus “slow but gratis” genetic
adaptations to Plasmodium falciparum malaria
(Modiano et al., 2008)
Hemoglobin S (HbS; β6Glu→Val) and Hemoglobin C
(HbC; β6Glu→Lys) strongly protect against clinical
Plasmodium falciparum malaria (Allison, A.C. 1954;
Modiano et al., 2001a). HbS, which is lethal in
homozygosity, has a multi-foci origin and a widespread