The Chemokines CXCL9 and CXCL10 Promote a Protective Immune Response but Do Not Contribute to Cardiac Inflammation following Infection with<i>Trypanosoma cruzi</i>

Hardison, Jenny L.; Wrightsman, Ruth A.; Carpenter, Philip M.; Lane, Thomas E.; Manning, Jerry E.

doi:10.1128/iai.74.1.125-134.2006

Cited by 56 publications

(59 citation statements)

References 43 publications

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“…Chemokine genes are expressed within the hearts of T. cruzi-infected mice, suggesting that these molecules may have a role in defense and/or disease (3,8,44). In support of this idea, we and others have determined that the T-cell and macrophage chemoattractant chemokine ligands CXCL9, CXCL10, and CCL5 are detected within the heart during both acute and chronic disease (17,44). Treatment of mice with neutralizing antibodies specific for CXCL9 and CXCL10 resulted in increased parasitemia, indicating an important role in generating a protective immune response.…”

supporting

confidence: 54%

The CC Chemokine Receptor 5 Is Important in Control of Parasite Replication and Acute Cardiac Inflammation following Infection withTrypanosoma cruzi

Hardison¹,

Wrightsman²,

Carpenter

et al. 2006

Infect Immun

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Infection of susceptible mice with the Colombiana strain of Trypanosoma cruzi results in an orchestrated expression of chemokines and chemokine receptors within the heart that coincides with parasite burden and cellular infiltration. CC chemokine receptor 5 (CCR5) is prominently expressed during both acute and chronic disease, suggesting a role in regulating leukocyte trafficking and accumulation within the heart following T. cruzi infection. To better understand the functional role of CCR5 and its ligands with regard to both host defense and/or disease, CCR5؊/؊ mice were infected with T. cruzi, and the disease severity was evaluated. Infected CCR5؊/؊ mice develop significantly higher levels of parasitemia (P < 0.05) and cardiac parasitism (P < 0.01) during acute infection that correlated with reduced survival. Further, we show that CCR5 is essential for directing the migration of macrophages and T cells to the heart early in acute infection with T. cruzi. In addition, data are provided demonstrating that CCR5 does not play an essential role in maintaining inflammation in the heart during chronic infection. Collectively, these studies clearly demonstrate that CCR5 contributes to the control of parasite replication and the development of a protective immune response during acute infection but does not ultimately participate in maintaining a chronic inflammatory response within the heart.

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confidence: 54%

The CC Chemokine Receptor 5 Is Important in Control of Parasite Replication and Acute Cardiac Inflammation following Infection withTrypanosoma cruzi

Hardison¹,

Wrightsman²,

Carpenter

et al. 2006

Infect Immun

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“…Thus, CD11b + HI MDSCs may regulate the excessive T cell-dependent inflammation in the heart at the onset of infection, which could much later determine the severity of cardiomyopathy. Among the genes expressed by CD11b + HI cells are the chemokines Ccl2, Ccl5, Cxcl9, and Cxcl10 that were previously shown to be expressed in the hearts of T. cruzi-infected mice during the acute phase, and they play a protective role in T. cruzi infection but not in association with the heart inflammatory phenotype (23,25). This indirectly would suggest a protective role of CD11b + HI cells in T. cruzi-induced myocarditis.…”

Section: Ly6gmentioning

confidence: 95%

Myeloid-Derived Suppressor Cells Infiltrate the Heart in Acute Trypanosoma cruzi Infection

Cuervo

Guerrero

Carbajosa

et al. 2011

The Journal of Immunology

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Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, affects several million people in Latin America. Myocarditis, observed in the acute and chronic phases of the disease, is characterized by a mononuclear cell inflammatory infiltrate. We previously identified a myeloid cell population in the inflammatory heart infiltrate of infected mice that expressed arginase I. In this study, we purified CD11b+ myeloid cells from the heart and analyzed their phenotype and function. Those CD11b+ cells were ∼70% Ly6G−Ly6C+ and 25% Ly6G+Ly6C+. Moreover, purified CD11b+Ly6G− cells, but not Ly6G+ cells, showed a predominant monocytic phenotype, expressed arginase I and inducible NO synthase, and suppressed anti-CD3/anti-CD28 Ab-induced T cell proliferation in vitro by an NO-dependent mechanism, activity that best defines myeloid-derived suppressor cells (MDSCs). Contrarily, CD11b+Ly6G+ cells, but not CD11b+Ly6G− cells, expressed S100A8 and S100A9, proteins known to promote recruitment and differentiation of MDSCs. Together, our results suggest that inducible NO synthase/arginase I-expressing CD11b+Ly6G− myeloid cells in the hearts of T. cruzi-infected mice are MDSCs. Finally, we found plasma l-arginine depletion in the acute phase of infection that was coincident in time with the appearance of MDSCs, suggesting that in vivo arginase I could be contributing to l-arginine depletion and systemic immunosuppression. Notably, l-arginine supplementation decreased heart tissue parasite load, suggesting that sustained arginase expression through the acute infection is detrimental for the host. This is, to our knowledge, the first time that MDSCs have been found in the heart in the context of myocarditis and also in infection by T. cruzi.

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“…Because macrophages are capable of producing many inflammatory chemokines, including CXCL9 and CXCL10 (58,59), it seemed likely that they might be responsible for the CXCR3-mediated NK-cell recruitment. Surprisingly, however, when we examined chemokine expression in the draining LN of mice treated with either control PBS-loaded liposomes or clodronate-loaded liposomes, we found no decrease in transcripts for Cxcl9 or Cxcl10 (Fig.…”

Section: Specific Chemokine Receptor-dependent Recruitment Of Nk Cellsmentioning

confidence: 99%

Interferon-γ mediates chemokine-dependent recruitment of natural killer cells during viral infection

Pak-Wittel¹,

Yang²,

Sojka³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Natural killer (NK) cells provide in vivo control of orthopoxvirus infections in association with their expansion in the draining lymph node (LN), where they are normally very rare. The mechanism of this expansion is unclear. Herein, we determined that NK-cell depletion results in enhanced infection following footpad inoculation of cowpox virus, a natural pathogen of rodents. Following cowpox virus infection in normal mice, NK cells were greatly expanded in the draining LN, were not replicating, and displayed markers similar to splenic NK cells, suggesting specific recruitment of splenic NK cells rather than in situ proliferation. Moreover, NK-cell expansion was abrogated by prior injection of clodronate-loaded liposomes, indicating a role for subcapsular sinus macrophages. Furthermore, recruitment of transferred splenic NK cells to the draining LN was pertussis toxin-sensitive, suggesting involvement of chemokine receptors. Comprehensive analysis of chemokine mRNA expression in the draining LN following infection suggested the selective involvement of CCR2, CCR5, and/or CXCR3. Mice deficient for CCR2 or CCR5 had normal NK-cell recruitment, whereas CXCR3-deficient mice displayed a major defect, which was NK cell-intrinsic. Interestingly, both induction of transcripts for CXCR3 ligands (Cxcl9 and Cxcl10) and NK-cell recruitment required IFN-γ. These data indicate that NK-cell recruitment is mediated by subcapsular sinus macrophages, IFN-γ, and CXCR3 during orthopoxvirus infection.

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The Chemokines CXCL9 and CXCL10 Promote a Protective Immune Response but Do Not Contribute to Cardiac Inflammation following Infection withTrypanosoma cruzi

Cited by 56 publications

References 43 publications

The CC Chemokine Receptor 5 Is Important in Control of Parasite Replication and Acute Cardiac Inflammation following Infection withTrypanosoma cruzi

The CC Chemokine Receptor 5 Is Important in Control of Parasite Replication and Acute Cardiac Inflammation following Infection withTrypanosoma cruzi

Myeloid-Derived Suppressor Cells Infiltrate the Heart in Acute Trypanosoma cruzi Infection

Interferon-γ mediates chemokine-dependent recruitment of natural killer cells during viral infection

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