impaginato piccolo - Società Italiana di Parassitologia (SoIPa)

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geographic distribution in sub-Saharan Africa and Asia
(Pagnier et al., 1984), whereas HbC, which has no
obvious CC segregational load, occurs only in a small
area of central West-Africa. To address this apparent
paradox, we adopted two partially independent haplotypic
approaches in the Mossi population of Burkina
Faso where both the local S (SBenin) and the C alleles
are common (0.05 and 0.13). We showed that C has
accumulated a 4-fold higher recombinational and DNA
slippage haplotypic variability than the SBenin allele (P
= 0.003) implying higher antiquity. These results, consistently
with epidemiological evidences, imply that the
C allele has been accumulated mainly through a recessive
rather than a semidominant mechanism of selection.
This evidence explains the apparent paradox of
the uni-epicentric geographic distribution of HbC, representing
a ‘slow but gratis’ genetic adaptation to
malaria through a transient and long-lagged polymorphism,
compared to the polycentric ‘quick but costly’
adaptation through balanced polymorphism of HbS.
The demonstration that the selection of the C allele
occurred mainly through homozygosis has obvious
implications when studying the possible protective
mechanisms (Fairhurst et al., 2005).
Interethnic differences in the susceptibility to malaria:
the role of T regulatory cells (Torcia et al., 2008)
Previous inter-ethnic comparative studies on the susceptibility
to malaria performed in West Africa showed
that Fulani are more resistant to Plasmodium falciparum
malaria than sympatric ethnic groups (Modiano
et al., 1996; Dolo et al., 2006) with different genetic
background Modiano et al., 2001b). This resistance
was not associated to classic malaria resistance genes
(Modiano et al., 2001c) and the analysis of the antibody
response to P. falciparum antigens revealed higher
immune reactivity in the Fulani (Modiano et al.,
1996; 1998; 1999). The hypothesis of a stronger activation
of the immune system in this ethnic group is also
suggested by the higher frequency of the tropical
splenomegaly syndrome reported in this population
(Greenwood et al., 1987). In this context, the analysis
of the expression, in selected cellular populations of the
immune system, of a large panel of genes involved in
the immune response by Microarray and Real-Time
PCR techniques might be helpful in the identification
of genes for genetic susceptibility studies. We analyzed,
in peripheral blood mononuclear cells (PBMC) from
Fulani and sympatric Mossi, the expression profile of a
large panel of genes involved in the immune response
and obtained evidences suggesting a functional deficit
of the mechanisms of immune regulation in Fulani:
they showed an increased expression of genes related to
TH1 or TH2 function, together with a reduced expression
of CTLA4 and FOXP3, two genes involved in the
immune modulation operated by T cells. Microarray
analysis on RNA purified from peripheral blood
CD4+CD25+ T-regulatory cells (Treg), showed great
differences between the two ethnic groups, with impor-
F. Verra et al. - Genetic susceptibility to malaria
tant genes such as TGFβ, TGFβRs, CTLA4, and
FOXP3, being less expressed in Fulani compared to
Mossi, as well as to European donors not living in
malaria endemic areas. The reduced expression of
genes related to suppressive activity seriously affected
the ability of T reg cells to suppress P. falciparuminduced
cell proliferation in Fulani. In fact depletion of
these cells did not significantly increase the proliferation
of PBMC to P. falciparum antigens in this group,
while it restored an optimal response to the same antigens
in the sympatric Mossi.
Overall, these results suggested that a functional deficit
of T-regulatory cells in Fulani could be involved in the
lower susceptibility to malaria of this ethnic group.
This study highligthed the existence of clear-cut differences
in strategic pathways of the immunoregulatory
network between sympatric populations differing in
their genetic background and degree of susceptibility to
malaria. The functional deficit of Treg here reported in
Fulani is consistent with their higher susceptibility to
diseases with autoimmune pathogenesis such as diabete
mellitus (Fisch et al., 1987), pemphigus (Mahe et al.,
1996) and onchocercal skin disease (Brieger et al.,
1997). A higher resistance against infectious diseases
like P. falciparum malaria could have been the driving
selective force of this disorder. The definition of the
genes involved could have important implications in
the understanding of host-parasite relationships and in
the development of anti-malaria vaccines.
Interferon Regulator Factor-1 polymorphisms are
associated with the control of Plasmodium falciparum
infection (Mangano et al., 2008).
Interferon Regulatory Factor 1 (IRF-1) is a transcription
factor that regulates the expression of a number of
genes whose products play crucial roles in innate as
well as adaptive immunity (Kroger et al., 2002). IFNgamma
is the strongest IRF-1 inducer known and IRF-
1 promotes transcription of a number of genes, acting
as an important mediator of IFN-gamma activity. IRF-1
activity is essential for recognition of micro-organisms
and antigen presentation, as it regulates the expression
of genes such as Toll-like Receptor 9, MHC class I and
class II genes. IRF-1 locus lies in the 5q31 human
genome region previously shown to be linked to
Plasmodium falciparum infection (Rihet et al., 1998).
To determine whether genetic variation at the IRF-1
locus affects resistance to malaria infection in humans,
and might therefore underlie the P. falciparum infection-level
locus, we studied IRF-1 genetic diversity in
two West African ethnic groups that show striking differences
in their susceptibility and immune response to
malaria, and conducted a candidate gene association
study with carriage of P. falciparum infection. In order
to evaluate the effect of IRF-1 polymorphisms on disease
severity, we also conducted a classical intra-ethnic
case-control study where we compared the allele frequency
of three haplotype-tagging SNPs (htSNPs)
between healthy population controls, mild malaria