<i>Leishmania major</i>Phosphoglycans Influence the Host Early Immune Response by Modulating Dendritic Cell Functions

Liu, Dong; Kébaïer, Chahnaz; Pakpour, Nazzy; Capul, Althea A.; Beverley, Stephen M.; Scott, Phillip; Uzonna, Jude E.

doi:10.1128/iai.01447-08

Cited by 38 publications

(38 citation statements)

References 56 publications

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“…Modest differences were seen with a few markers (CD206 transiently, Arg1, and CD11c; Fig. S5), which may reflect the absence of phosphoglycans or other metabolites in the lpg2 − and could contribute to the immune response and ability to vaccinate (25,27,55). Overall, these data support the continued use of lpg2-parasites as a model of Leishmania persistence and vaccination.…”

Section: Lpg2mentioning

confidence: 57%

Continual renewal and replication of persistentLeishmania majorparasites in concomitantly immune hosts

Mandell

Beverley

2017

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

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In most natural infections or after recovery, small numbers of Leishmania parasites remain indefinitely in the host. Persistent parasites play a vital role in protective immunity against disease pathology upon reinfection through the process of concomitant immunity, as well as in transmission and reactivation, yet are poorly understood. A key question is whether persistent parasites undergo replication, and we devised several approaches to probe the small numbers in persistent infections. We find two populations of persistent Leishmania major: one rapidly replicating, similar to parasites in acute infections, and another showing little evidence of replication. Persistent Leishmania were not found in "safe" immunoprivileged cell types, instead residing in macrophages and DCs, ∼60% of which expressed inducible nitric oxide synthase (iNOS). Remarkably, parasites within iNOS + cells showed normal morphology and genome integrity and labeled comparably with BrdU to parasites within iNOS − cells, suggesting that these parasites may be unexpectedly resistant to NO. Nonetheless, because persistent parasite numbers remain roughly constant over time, their replication implies that ongoing destruction likewise occurs. Similar results were obtained with the attenuated lpg2 − mutant, a convenient model that rapidly enters a persistent state without inducing pathology due to loss of the Golgi GDP mannose transporter. These data shed light on Leishmania persistence and concomitant immunity, suggesting a model wherein a parasite reservoir repopulates itself indefinitely, whereas some progeny are terminated in antigen-presenting cells, thereby stimulating immunity. This model may be relevant to understanding immunity to other persistent pathogen infections.latency | quiescence | trypanosomatid protozoan parasite | vaccination | stem cell-like

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Section: Lpg2mentioning

confidence: 57%

Continual renewal and replication of persistentLeishmania majorparasites in concomitantly immune hosts

Mandell

Beverley

2017

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

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101

100

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“…We previously reported that L. major parasites lacking the phosphoglycan coats (termed lpg2 − L. major ) are attenuated in vitro , persist indefinitely (56) and protect against virulent L. major challenge (57). The attenuation in virulence of phosphoglycan deficient parasites is related in part to the induction of skewed early IFN-γ and a concomitant blunted IL-4 and IL-10 responses when compared to WT infection (57, 58). Although infection with arg − L. major results in attenuated pathology, the early immune response was significantly reduced compared to WT-infection.…”

Section: Discussionmentioning

confidence: 99%

Parasite-Derived Arginase Influences Secondary Anti-LeishmaniaImmunity by Regulating Programmed Cell Death-1–Mediated CD4+ T Cell Exhaustion

Mou

Muleme

Liu

et al. 2013

The Journal of Immunology

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The breakdown of L-arginine to ornithine and urea by host arginase supports Leishmania proliferation in macrophages. Studies using arginase-null mutants show that Leishmania-derived arginase plays an important role in disease pathogenesis. We investigated the role of parasite-derived arginase in secondary (memory) anti-Leishmania immunity in the resistant C57BL/6 mice. We found that C57BL/6 mice infected with arginase deficient (arg−) L. major failed to completely resolve their lesion and maintained chronic pathology after 16 weeks, a time when the lesion induced by wild type (WT) L. major is completely resolved. This chronic disease was associated with impaired antigen-specific proliferation and IFN-γ production, a concomitant increase in programmed cell death-1 (PD-1) expression on CD4+ T cells and failure to induce protection against secondary L. major challenge. Treatment with anti-PD-1 monoclonal antibody restored T cell proliferation and IFN-γ production in vitro and led to complete resolution of chronic lesion in arg− L. major-infected mice. These results show that infection with arg− L. major results in chronic disease due in part to PD-1-mediated clonal exhaustion of T cells, suggesting that parasite-derived arginase contributes to the overall quality of the host immune response and subsequent disease outcome in L. major-infected mice. They also indicate that persistent parasites alone do not regulate the quality of secondary anti-Leishmania immunity in mice and that the quality of the primary immune response may be playing a hitherto unrecognized dominant role in this process.

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“…Studies with other Leishmania species have shown that L. braziliensis-infected DCs remained immature and secreted . L. major was also able to modulate DC function by influencing the balance between Th1 and Th2 responses [27,28]. Although much is known regarding the ability of Leishmania infection to interfere with DC maturation, activation and function, the underlying mechanisms are not completely understood.…”

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confidence: 99%

Leishmania amazonensis impairs DC function by inhibiting CD40 expression via A_2B adenosine receptor activation

et al. 2012

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Dendritic cells (DCs) play an essential role in the modulation of immune responses and several studies have evaluated the interactions between Leishmania parasites and DCs.While extracellular ATP exhibits proinflammatory properties, adenosine is an important anti-inflammatory mediator. Here we investigated the effects of Leishmania infection on DC responses and the participation of purinergic signalling in this process. Bone marrowderived dendritic cells (BMDCs) from C57BL/6J mice infected with Leishmania amazonensis, Leishmania braziliensis or Leishmania major metacyclic promastigotes showed decreased major histocompatibility complex (MHC) class II and CD86 expression and increased ectonucleotidase expression as compared with uninfected cells. In addition, L. amazonensis-infected DCs, which had lower CD40 expression, exhibited a decreased ability to induce T-cell proliferation. The presence of MRS1754, a highly selective A 2B adenosine receptor antagonist at the time of infection increased MHC class II, CD86 and CD40 expression in L. amazonensis-infected DCs and restored the ability of the infected DCs to induce T-cell proliferation. Similar results were obtained through the inhibition of extracellular ATP hydrolysis using suramin. In conclusion, we propose that A 2B receptor activation may be used by L. amazonensis to inhibit DC function and evade the immune response. Keywords: Adenosine receptors r CD40 r Dendritic cell r Ectonucleotidases r Leishmania amazonensis IntroductionLeishmaniasis is a group of diseases that are caused by obligate intracellular parasites of the genus Leishmania. Leishmania infections can result in a wide spectrum of clinical manifestations and disease outcome is determined both by the parasite species and by Correspondence: Dr. Luís C. C. Afonso e-mail: afonso@nupeb.ufop.br the host immune response. Leishmania amazonensis differs from other species because it is able to cause chronic non-healing lesions in mouse strains genuinely resistant to other Leishmania species, such as Leishmania braziliensis and Leishmania major [1][2][3]. In humans, L. amazonensis causes diffuse cutaneous leishmaniasis, a condition characterised by a lack of antigen-specific T-cell responses against the parasite [4].DCs play a critical role in orchestrating the innate and adaptive components of the immune system [5,6]. Immature DCs capture and process antigens located throughout the body. After contacting microorganisms or other inflammatory substances, C 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu1204 Amanda B. Figueiredo et al. Eur. J. Immunol. 2012. 42: 1203-1215 these cells initiate their maturation process. DC maturation is characterised by increased expression of major histocompatibility complex (MHC) class II (MHCII) and co-stimulatory molecules, such as CD40, CD80, CD86 and CD54; decreased phagocytic capacity; increased cytokine secretion and expression of different chemokine receptors [5,7]. Extracellular ATP, which is accumulated following cellular injury, has important inf...

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Leishmania majorPhosphoglycans Influence the Host Early Immune Response by Modulating Dendritic Cell Functions

Cited by 38 publications

References 56 publications

Continual renewal and replication of persistentLeishmania majorparasites in concomitantly immune hosts

Continual renewal and replication of persistentLeishmania majorparasites in concomitantly immune hosts

Parasite-Derived Arginase Influences Secondary Anti-LeishmaniaImmunity by Regulating Programmed Cell Death-1–Mediated CD4+ T Cell Exhaustion

Leishmania amazonensis impairs DC function by inhibiting CD40 expression via A_2B adenosine receptor activation

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Leishmania majorPhosphoglycans Influence the Host Early Immune Response by Modulating Dendritic Cell Functions

Cited by 38 publications

References 56 publications

Continual renewal and replication of persistentLeishmania majorparasites in concomitantly immune hosts

Continual renewal and replication of persistentLeishmania majorparasites in concomitantly immune hosts

Parasite-Derived Arginase Influences Secondary Anti-LeishmaniaImmunity by Regulating Programmed Cell Death-1–Mediated CD4+ T Cell Exhaustion

Leishmania amazonensis impairs DC function by inhibiting CD40 expression via A2B adenosine receptor activation

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Leishmania amazonensis impairs DC function by inhibiting CD40 expression via A_2B adenosine receptor activation