Immunopathogenic mechanisms of non-healing cutaneous leishmaniasis caused by Leishmania amazonensis infection

The objective of my dissertation project is to understand mechanisms employed by Leishmania amazonensis to evade host immune components, particularly B cells and interferon-gamma. Our data have shown that L. amazonensis infection induces B cell activation, leading to enhanced lesion development. In the absence of B cells, L. amazonensis-infected mice developed a delayed onset of disease, correlating with an impaired activation of antigen-specific pathogenic CD4+ T cells. Flow cytometry and immunohistochemical studies suggest that B cells may provide secondary signals for activating T helper cells and recruiting leukocytes to the site of infection. The pathogenic role of B cells was suggested to be partly due to the presence of antibodies, which induced dendritic cell activation and promoted efficient priming of parasite-specific T cells to produce high levels of IL-10. The investigation of the role of IFN-g in L. amazonensis infection revealed that IFN-g alone could promote parasite growth within macrophages (MFs) by inducing the expression of mouse cationic amino acid transporter-2B (mCAT-2B), a key transporter for L-arginine. Although a clear upregulation of mCAT-2B and L-arginine transport was detected, no measurable iNOS or arginase activities were observed in IFN-g-treated, infected MFs. These data suggest an involvement of a novel L-arginine usage independent of iNOS and arginase activities during IFN-g-mediated parasite growth enhancement. The ability to scavenge available L-arginine directly by the parasites is proposed. In addition to inducing pathogenic B cells and interfering with L-arginine pathways, these parasites were found to express molecules similar to the mammalian chemokine receptor, CCR5. Although the function of a parasite-derived CCR5-like molecule remains unclear, it may help the parasites to find immature “safe target” cells. Together, this project provides new insights into the complex interactions between the parasite and host immune system and indicates the challenges we will face in the control of non-healing cutaneous leishmaniasis.

Name thesis:degree_name

PhD

Level thesis:degree_level

Doctoral

Grantor

The University of Texas Medical Branch

Year dc:date.issued

2007

Author dc:creator

• Nanchaya Wanasen

Advisor dc:contributor.advisor

• Lynn Soong

Committee members dc:contributor.committeemember

• Victor E Reyes
• Richard G Titus
• Gary R Klimpel
• Allan R Brasier

• Leishmania amazonensis
• interferon gamma
• CCR5
• B cells

Statement dc:rights

• Copyright © is held by the author. Presentation of this material on the TDL web site by The University of Texas Medical Branch at Galveston was made possible under a limited license grant from the author who has retained all copyrights in the works.

Language dc:language.iso

eng

Dc Identifier Other

etd-04262007-150805

OAI identifier oai:identifier

oai:utmb-ir.tdl.org:2152.3/101