Research Group Heussler (Malaria I) - Bernhard-Nocht-Institut für ...

Medical Microbiology Section
Immunpathways in filarial infection in mice:
old Acquaintances and Surprises
Zusammenfassung:
Verschiedene immunologische Parameter sind für
die Abwehr von Filarienematoden von großer Bedeutung.
Das Zusammenspiel dieser Parameter wurde
in Studien an gentechnisch veränderten Mäusen
durchgeführt, die zum Teil einen doppelten Defekt in
zwei Genen aufwiesen. Es zeigte sich, dass Zytokine
synergistisch zusammenwirken, die bisher allgemein
nicht im Verdacht standen Synergien miteinander zu
bilden. Auch Immunzellen, von denen bekannt war,
dass sie gegen Viren, Bakterien und Protozoen
wirken, wurden in Zusammenhang mit der Abwehr
von Filarien gebracht. Wichtige Erkenntnisse wurden
über die Rolle der Wolbachien und deren freigesetzte
LPS-ähnliche Produkte für den Verlauf der
Immunabwehr gewonnen.
Summary
Different immunological parameters are of great importance
for the defence against filarial infections. The interaction
of these parameters was analysed in studies
with genetic deficient mice. It was shown that cytokines
that were thought to be antagonistic in the mode of action,
rather interact synergistically with each other. Also
immune cells, which are known to be involved in the defence
against viruses, bacteria and protozoa were
demonstrated to be important for defence against filarial
infections. Important results were collected about
Wolbachia and their released LPS-like products for the
immune reaction.
Introduction
Filarial infections are a great problem in tropical countries.
Over 180 million persons are infected with filarial
worms. The immunological defence mechanisms are
not understood in detail, which leads to the survival of
worms for more than 20 years in the host. Our studies
focus on the better understanding of these immune reactions.
Experiments were done with mice which had a
double deficiency of IL-5 and interferon-γ. These mice
were analysed to see if this double deficiency had a
synergistic or antagonistic effect on the course of the
immune reaction. The role of IL-4, IL-4 receptor-α and
IL-5 was analysed in knockout mice in the course of a filarial
infection. Further studies of our group focused on
the role of NK cells, as no role for NK cells was yet
known in the defence against helminth infections. The
important role of endosymbiotic Wolbachia bacteria for
the defence against filarial infections was shown in animal
models.
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Project Description and Results
Natural killer cells are known to be important for the defence
against virus, bacteria and protozoa. In vivo depletion
of NK cells led to a significantly higher worm
load in mice. These data demonstrated for the first time
that NK cells were involved in the defence mechanism
against helminth parasites (Korten et al., 2002).
Comparison of the immune reaction in IL-4, IL-4 receptor-α
and IL-5 deficient mice demonstrated that IL-5 in
contrast to IL-4 is important for the defence against
adult worms. Only IL-5 KO mice had up to 200 times
more adult worms and a longer persistence of worms
during the chronic phase of the infection. In contrast,
no significant differences in adult worm survival were
observed between IL-4, IL-4 receptor-α and BALB/c
wild-type mice. Both IL-5 and IL-4 knockout mice show
a greatly enhanced microfilaremia and prolonged susceptibility.
These data demonstrate that IL-5 and IL-4 effector
pathways act against different stages of filarial
worms. Deficiency of IL-5 results in effects on the adult
worms and microfilariae, while deficiency of IL-4 and IL-
4 receptor-α has only effects on the microfilariae (Volkmann
et al., 2003).
A prevailing perception is that Th1 and Th2 immune
reactions induce antagonistic immune effector mechanisms.
IL-5 and IFN-γ knockout mice both show a
higher worm load compared to the wild-type. The question
was if IFN-γ/IL-5 double knockout mice have a significantly
higher worm load compared to each single
knockout mice. The results indicate that double deficiency
of IFN-γ and IL-5 act synergistically and leads to
a higher worm load compared to each single knockout.
Our results show that these synergistic effects of these
two cytokines were mediated in part by neutrophils.
Neutrophils are important cells for the containment and
encapsulation process of the worms. An important cytokine
for neurophil activation is TNF-α, which was reduced
in macrophages of KO mice. Furthermore, neutrophils
of IL-5 KO, IFN-γ KO and double deficient mice
were significantly decreased in their chemotactic activity
compared to controls and double deficient mice
show the lowest phagocytic activity (Saeftel et al.,
2003).
Wolbachia are intracellular endobacteria of filarial
worms and their released LPS-like molecules might
play a role in the induction of immune response. By using
the LPS-nonresponsive C3H/HeJ mouse strain it
was shown that these mice develop a higher fertility of
adult worms. This experiment indicates that TLR4 signaling
is involved in the immune reaction that controls
worm fertility and embryogenesis (Pfarr et al., 2003).