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Are Overcome to Control Infection with Leishmania donovani in CC Chemokine Receptor (CCR) 5-, Macrophage Inflammatory Protein-1
-, or CCR2-Deficient Mice1







*
South Texas Veterans Health Care System, Audie L. Murphy Division, Departments of
Medicine and
Pathology, University of Texas Health Science Center, San Antonio, TX 78229;
§
Section of Molecular Genetics and Microbiology and
¶
Institute of Cellular and Molecular Biology, University of Texas, Austin, TX 78712; and
||
Department of Pathology and Laboratory Medicine, University of North Carolina Medical School, Chapel Hill, NC 27599
We investigated the immune responses in mice lacking CCR2, CCR5, or
macrophage inflammatory protein-1
(MIP-1
), a ligand for CCR5, in
two situations: following T cell stimulation or after challenge with
Leishmania donovani, an intracellular microbe whose
control is dependent on a Th1 immune response. Mice deficient in CCR5,
MIP-1
, or CCR2 had reduced IFN-
responses following ligation of
the TCR. Reduced IFN-
responses following PMA and ionomycin were
also observed in CD8+ T cells of CCR5-/- and
CCR2-/- mice. During the early phases of infection, all
three knockout mice had low Ag-specific IFN-
responses. However,
this reduced IFN-
response was overcome during a state of persistent
Ag stimulation (chronic infection), and was not associated with an
adverse parasitologic outcome in any of the gene-targeted mouse
strains. To the contrary, during the late phase of infection, an
exaggerated Ag-specific IFN-
response was evident in
CCR5-/- and MIP-1
-/- mice, and this
correlated with an enhanced control of parasite replication. Although
granuloma formation was abnormal in each of the knockout mice, there
was no correlation between the number or architecture of the granulomas
and parasite burden. Collectively, these findings indicate
an important role for CCR5, MIP-1
, and CCR2 in granulomatous
inflammation, and that CCR5 and MIP-1
, possibly acting through CCR5,
might play a deleterious role in the outcome of chronic L.
donovani infection. Our data also suggest that there might be
cross-talk between TCR and chemokine receptor signaling
pathways.
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