Unravelling the unsolved paradoxes of cytokine families in host resistance and susceptibility to Leishmania infection

Osero, Bernard; Aruleba, Raphael Taiwo; Brombacher, Frank; Hurdayal, Ramona

doi:10.1016/j.cytox.2020.100043

Cited by 16 publications

(11 citation statements)

References 105 publications

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“…Moreover, we observed a significantly decreased expression of tumor necrosis factor-α ( TNF-α ) ( Figure 4 ). This cytokine is an essential component of the Th1 response, as it contributes to trigger nitric oxide production in activated macrophages, and therefore, its deficit may increase the severity of leishmaniosis ( 77 ). However, a significant increase in the expression of IFN-γ , the canonical Th1 cytokine, was found in the CanL group ( Figure 4 ).…”

Section: Discussionmentioning

confidence: 99%

Modulation of Host Immune Response during Leishmania infantum Natural Infection: A Whole-Transcriptome Analysis of the Popliteal Lymph Nodes in Dogs

et al. 2022

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Leishmania infantum, the etiological agent of canine leishmaniosis (CanL) in Europe, was responsible of the largest outbreak of human leishmaniosis in Spain. The parasite infects and survives within myeloid lineage cells, causing a potentially fatal disease if left untreated. The only treatment option relies on chemotherapy, although immunotherapy strategies are being considered as novel approaches to prevent progression of the disease. To this aim, a deeper characterization of the molecular mechanisms behind the immunopathogenesis of leishmaniosis is necessary. Thus, we evaluated, for the first time, the host immune response during L. infantum infection through transcriptome sequencing of the popliteal lymph nodes aspirates of dogs with CanL. Differential expression and weighted gene co-expression network analyses were performed, resulting in the identification of 5,461 differentially expressed genes (DEGs) and four key modules in sick dogs, compared to controls. As expected, defense response was the highest enriched biological process in the DEGs, with six genes related to immune response against pathogens (CHI3L1, SLPI, ACOD1, CCL5, MPO, BPI) included among the ten most expressed genes; and two of the key co-expression modules were associated with regulation of immune response, which also positively correlated with clinical stage and blood monocyte concentration. In particular, sick dogs displayed significant changes in the expression of Th1, Th2, Th17 and Tr1 cytokines (e. g. TNF-α, IFN-γ, IL-21, IL-17, IL-15), markers of T cell and NK cell exhaustion (e. g. LAG3, CD244, Blimp-1, JUN), and B cell, monocyte and macrophage disrupted functionality (e. g. CD40LG, MAPK4, IL-1R, NLRP3, BCMA). In addition, we found an overexpression of XBP1 and some other genes involved in endoplasmic reticulum stress and the IRE1 branch of the unfolded protein response, as well as one co-expression module associated with these processes, which could be induced by L. infantum to prevent host cell apoptosis and modulate inflammation-induced lymphangiogenesis at lymph nodes. Moreover, 21 lncRNAs were differentially expressed in sick dogs, and one key co-expression module was associated with chromatin organization, suggesting that epigenetic mechanisms could also contribute to dampening host immune response during natural L. infantum infection in the lymph nodes of dogs suffering from clinical leishmaniosis.

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Section: Discussionmentioning

confidence: 99%

Modulation of Host Immune Response during Leishmania infantum Natural Infection: A Whole-Transcriptome Analysis of the Popliteal Lymph Nodes in Dogs

et al. 2022

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“…IFN-g is unambiguously a host-protector in CL (33). Indeed, studies have shown evidence that IFN-g secretion by macrophages and DCs fuel a rapid escalation of nitric oxide (NO) production that induces parasite killing (68,69).…”

Section: Discussionmentioning

confidence: 99%

“…Type 2 Cytokine Responses Are Increased in CD11c cre IL-4Ra -/lox but Did Not Confer Hyper-Susceptibility Over Littermate IL-4Ra -/lox Mice Susceptibility and resistance to CL in mice are dependent on Th1/Th2 immune responses (33). Therefore, we investigated the role of IL-4Ra signaling on DCs in the cellular response to L. mexicana infection by evaluating the cytokine profile (IFN-g, IL-4, and IL-13) in infected mice by ELISA.…”

Section: Susceptibility To L Mexicana In Balb/c Mice Is Independent Of Il-4ra Signaling On Cd11c + Cellsmentioning

confidence: 99%

Interleukin-4 Responsive Dendritic Cells Are Dispensable to Host Resistance Against Leishmania mexicana Infection

et al. 2022

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IL-4 and IL-13 cytokines have been associated with a non-healing phenotype in murine leishmaniasis in L. mexicana -infected BALB/c mice as demonstrated in IL-4−/−, IL-13−/− and IL-4Rα-/- global knockout mouse studies. However, it is unclear from the studies which cell-type-specific IL-4/IL-13 signaling mediates protection to L. mexicana. Previous studies have ruled out a role for IL-4-mediated protection on CD4+ T cells during L. mexicana infections. A candidate for this role may be non-lymphocyte cells, particularly DCs, as was previously shown in L. major infections, where IL-4 production drives dendritic cell-IL-12 production thereby mediating a type 1 immune response. However, it is unclear if this IL-4-instruction of type 1 immunity also occurs in CL caused by L. mexicana, since the outcome of cutaneous leishmaniasis often depends on the infecting Leishmania species. Thus, BALB/c mice with cell-specific deletion of the IL-4Rα on CD11c+ DCs (CD11ccreIL-4Rα-/lox) were infected with L. mexicana promastigotes in the footpad and the clinical phenotype, humoral and cellular immune responses were investigated, compared to the littermate control. Our results show that CL disease progression in BALB/c mice is independent of IL-4Rα signaling on DCs as CD11ccreIL-4Rα-/lox mice had similar footpad lesion progression, parasite loads, humoral responses (IgE, IgG1, IgG 2a/b), and IFN-γ cytokine secretion in comparison to littermate controls. Despite this comparable phenotype, surprisingly, IL-4 production in CD11ccreIL-4Rα-/lox mice was significantly increased with an increasing trend of IL-13 when compared to littermate controls. Moreover, the absence of IL-4Rα signaling did not significantly alter the frequency of CD4 and CD8 lymphocytes nor their activation, or memory phenotype compared to littermate controls. However, these populations were significantly increased in CD11ccreIL-4Rα-/lox mice due to greater total cell infiltration into the lymph node. A similar trend was observed for B cells whereas the recruitment of myeloid populations (macrophages, DCs, neutrophils, and Mo-DCs) into LN was comparable to littermate IL-4Rα-/lox mice. Interestingly, IL-4Rα-deficient bone marrow-derived dendritic cells (BMDCs), stimulated with LPS or L. mexicana promastigotes in presence of IL-4, showed similar levels of IL-12p70 and IL-10 to littermate controls highlighting that IL-4-mediated DC instruction was not impaired in response to L. mexicana. Similarly, IL-4 stimulation did not affect the maturation or activation of IL-4Rα-deficient BMDCs during L. mexicana infection nor their effector functions in production of nitrite and arginine-derived metabolite (urea). Together, this study suggests that IL-4 Rα signaling on DCs is not key in the regulation of immune-mediated protection in mice against L. mexicana infection.

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“…While the species of Leishmania parasite plays a large role in determining disease manifestations, host immunity and genetics largely influence the severity of infection. The classic T helper 1/T helper 2 (T H 1/T H 2) model has been applied for many years to explain the disease severity and outcome, with CD4 + T H 1 cells mediating resistance to Leishmania and CD4 + T H 2 cells promoting host susceptibility [12]. However, this assumption is based primarily on an experimental Leishmania (L.) major model of infection in congenic mouse strains, which are not entirely relevant to human infections.…”

Section: Introductionmentioning

confidence: 99%

Protective and Pathogenic Immune Responses to Cutaneous Leishmaniasis

Panahi¹,

Stanisic²,

Peacock³

et al. 2022

Leishmaniasis - General Aspects of a Stigmatized Disease

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Leishmania (Kinetoplastida: Trypanosomatidae) parasites are known to cause a broad spectrum of clinical diseases in humans, collectively known as the leishmaniases. Cutaneous leishmaniasis is the most common clinical presentation with varying degrees of severity largely driven by host immune responses, specifically the interplay between innate and adaptive immune response. The establishment of a T lymphocyte driven cell-mediated immune response, leading to activated phagocytic cells, leading to Leishmania parasite killing and control of infection. Alternatively, the Leishmania parasite manipulates the host immune system, enabling parasite proliferation and clinical disease. Here we review how the cumulative interactions of different aspects of the host immune response determines disease outcome, severity, and immunity to re-infection.

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Unravelling the unsolved paradoxes of cytokine families in host resistance and susceptibility to Leishmania infection

Cited by 16 publications

References 105 publications

Modulation of Host Immune Response during Leishmania infantum Natural Infection: A Whole-Transcriptome Analysis of the Popliteal Lymph Nodes in Dogs

Modulation of Host Immune Response during Leishmania infantum Natural Infection: A Whole-Transcriptome Analysis of the Popliteal Lymph Nodes in Dogs

Interleukin-4 Responsive Dendritic Cells Are Dispensable to Host Resistance Against Leishmania mexicana Infection

Protective and Pathogenic Immune Responses to Cutaneous Leishmaniasis

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