Mechanisms and consequences of persistence of intracellular pathogens: leishmaniasis as an example

Bogdan, Christian

doi:10.1111/j.1462-5822.2008.01146.x

Cited by 131 publications

(97 citation statements)

References 177 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Macrophages play a central role in the pathogenesis of Leishmania infection (36). We previously showed that while macrophages from both CL and ML patients exhibit predominantly proinflammatory profiles and secrete significantly more CXCL9, CXCL10, and TNF-␣ than do macrophages from SC subjects, macrophages from SC subjects have a greater ability to kill L. braziliensis than macrophages from CL or ML patients (37).…”

Section: Fig 6 Granzyme B Mediates Cd8mentioning

confidence: 99%

Protective and Pathological Functions of CD8⁺T Cells in Leishmania braziliensis Infection

et al. 2015

View full text Add to dashboard Cite

dCutaneous leishmaniasis (CL) caused by Leishmania braziliensis is characterized by a strong Th1 response that leads to skin lesion development. In areas where L. braziliensis transmission is endemic, up to 15% of healthy subjects have tested positive for delayed-type hypersensitivity to soluble leishmania antigen (SLA) and are considered to have subclinical (SC) infection. SC subjects produce less gamma interferon (IFN-␥) and tumor necrosis factor alpha (TNF-␣) than do CL patients, but they are able to control the infection. ؉ T cells was higher in CL than in SC cells. While the use of a granzyme B inhibitor decreased the number of apoptotic cells in the CL group, the use of z-VAD-FMK had no effect on the frequency of these cells. These results suggest that CL CD8 ؉ T cells are more cytotoxic and may be involved in pathology. L eishmaniasis is caused by infection with parasites of the genusLeishmania. Leishmaniasis is a neglected tropical disease; 214,000 new cases of cutaneous leishmaniasis (CL) are reported annually worldwide, and the estimated incidence of leishmaniasis is 690,000 to 1,200,000 cases. Approximately 67,000 cases are reported in South America, Central America, and the Caribbean (1). In mice, the majority of Leishmania-specific CD4 ϩ T cells differentiate into T-helper 1 (Th1) cells that secrete gamma interferon (IFN-␥) and contribute to the elimination of the parasite through the activation of macrophages (2, 3). Although protective immunity has predominantly been related to IFN-␥-producing CD4 ϩ T cells, infection with Leishmania also results in the activation and expansion of parasite-specific CD8 ϩ T cells (4, 5). Human CL caused by Leishmania braziliensis is characterized by a strong Th1 response with the production of high levels of IFN-␥ and tumor necrosis factor alpha (TNF-␣) (6, 7). This exaggerated Th1 response is associated with the development of lesions and the severity of the disease (6, 8-10). In patients with CL caused by L. braziliensis, there are more CD4 ϩ than CD8 ϩ T cells, but this ratio reaches an equilibrium due to the increase in CD8 ϩ T cells that occurs during the healing process (11). The enrichment of Leishmania-reactive CD8 ϩ T cells in older lesions suggests that these cells may play a role in the healing process (12). In contrast, other studies have associated CD8ϩ T cell functions with pathology. For example, the cytotoxicity mediated by CD8 ϩ T cells is greater in mucosal leishmaniasis (ML), a more severe form of L. braziliensis infection, than in CL (13,14). More recently, it was shown that the frequency with which CD8 ϩ T cells express granzyme in the lesions of CL patients is greater than that in patients in the early phase of CL (i.e., before the ulcer has developed) and that the frequency with which CD8 ϩ T cells express granzyme is directly associated with the intensity of the inflammatory reaction observed in CL ulcers (15,16). This controversy regarding the role of cytotoxicity in the pathogenesis of human leishmaniasis indicates that the functions of CD...

show abstract

Section: Fig 6 Granzyme B Mediates Cd8mentioning

confidence: 99%

Protective and Pathological Functions of CD8⁺T Cells in Leishmania braziliensis Infection

et al. 2015

View full text Add to dashboard Cite

show abstract

“…The murine model of Old World leishmaniasis (Leishmania major) has been instrumental for the elaboration of the Th1/Th2 paradigm, inasmuch as the preferential action of Th1 (IFN-␥, IL-12) or Th2 cytokines (IL-4, IL-13) results in cure or progression of the disease, respectively (3,4). In New World human and murine leishmaniasis, this Th1/Th2 dichotomy is much less explicit for in vitro or ex vivo cytokine production (2,5). Patients with localized cutaneous leishmaniasis display a diminished Th1 response during the early phase of disease, which is reverted after treatment (6).…”

mentioning

confidence: 99%

IFN-β Impairs Superoxide-Dependent Parasite Killing in Human Macrophages: Evidence for a Deleterious Role of SOD1 in Cutaneous Leishmaniasis

Khouri¹,

Báfica

Silva³

et al. 2009

The Journal of Immunology

View full text Add to dashboard Cite

Type I IFNs (IFN-α/β) have only recently gained considerable attention as immunomodulators in nonviral infectious diseases. IFN-β has been shown to protect, in a NO-dependent manner, against murine Old World leishmaniasis caused by Leishmania major, but data in New World leishmaniasis are lacking. We found that IFN-β dose-dependently increases parasite burden in Leishmania amazonensis- as well as Leishmania braziliensis-infected human macrophages, independent of endogenous or exogenous NO. However, IFN-β significantly reduced superoxide release in Leishmania-infected as well as uninfected human macrophages. This decrease in superoxide production was paralleled by a significant IFN-β-mediated increase in superoxide dismutase 1 (SOD1) protein levels. Additionally, IFN-β inhibition of leishmanicidal activity was mimicked by SOD1 and antagonized by either pharmacological or small interfering RNA-mediated inhibition of SOD1. Finally, pronounced SOD1 expression in situ was demonstrated in biopsies from New World cutaneous leishmaniasis patients. These findings reveal a hitherto unknown IFN-β/SOD1 axis in Leishmania infection and suggest that inhibition of SOD-associated pathways could serve as strategy in the treatment of L. amazonensis as well as L. braziliensis infection, major human pathogens.

show abstract

“…Suppression of immune function in VL infection can compromise treatment efficacy (5). It is usually associated with a depression of Th1 cells and preferential expansion of Th2 cells, and accordingly, skewing of T helper cells toward a Th1 response is considered a promising therapeutic strategy.…”

mentioning

confidence: 99%

CpG Oligodeoxynucleotide 2006 and Miltefosine, a Potential Combination for Treatment of Experimental Visceral Leishmaniasis

Gupta

Sane

Shakya

et al. 2011

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Mechanisms and consequences of persistence of intracellular pathogens: leishmaniasis as an example

Cited by 131 publications

References 177 publications

Protective and Pathological Functions of CD8⁺T Cells in Leishmania braziliensis Infection

Protective and Pathological Functions of CD8⁺T Cells in Leishmania braziliensis Infection

IFN-β Impairs Superoxide-Dependent Parasite Killing in Human Macrophages: Evidence for a Deleterious Role of SOD1 in Cutaneous Leishmaniasis

CpG Oligodeoxynucleotide 2006 and Miltefosine, a Potential Combination for Treatment of Experimental Visceral Leishmaniasis

Contact Info

Product

Resources

About

Mechanisms and consequences of persistence of intracellular pathogens: leishmaniasis as an example

Cited by 131 publications

References 177 publications

Protective and Pathological Functions of CD8+T Cells in Leishmania braziliensis Infection

Protective and Pathological Functions of CD8+T Cells in Leishmania braziliensis Infection

IFN-β Impairs Superoxide-Dependent Parasite Killing in Human Macrophages: Evidence for a Deleterious Role of SOD1 in Cutaneous Leishmaniasis

CpG Oligodeoxynucleotide 2006 and Miltefosine, a Potential Combination for Treatment of Experimental Visceral Leishmaniasis

Contact Info

Product

Resources

About

Protective and Pathological Functions of CD8⁺T Cells in Leishmania braziliensis Infection

Protective and Pathological Functions of CD8⁺T Cells in Leishmania braziliensis Infection