Modulation of host immune status by cryptococcus co-infection during HIV-1 pathogenesis and its impact on CD+4 cell and cytokines environment

Li, Linyu; Abuderman, Abdul Wahab Ali; Muzaheed, .; Acharya, Sadananda; Divakar, Darshan Devang

doi:10.1016/j.micpath.2019.103864

Cited by 5 publications

(4 citation statements)

References 30 publications

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“…However, it should be noted that this immunoadjuvant requires T cell priming for control and protection as highlighted through our dual CD4 + and CD8 + T depletion and TCR β KO mice ( Figure 5E and Supplementary Figure S6 ), so pan T cell immunosuppression would be a limiting factor of our mutant from a clinical viewpoint. Nonetheless, because we show that either CD4 + or CD8 + T cells are required, C. neoformans Δ sgl1 still remains a viable option for the major risk factors during the opportunistic infection with C. neoformans since CD8 + T cells remain accessible during CD4-lymphopenia ( Collins et al., 2020 ; Akhtar et al., 2020 ; Linyu et al., 2020 ). We are also currently investigating subunit-based vaccination strategies that have the potential to surpass this limitation.…”

Section: Discussionmentioning

confidence: 94%

“…These SGs were believed to cause the significantly increased levels of Th1 cytokines, including IL-1α, TNFα, IL-17, and IFNγ, and decreased levels of Th2 cytokines, including IL-4 and IL-5 ( Figure 2 ) since they occurred over the same timeline as the SGs were measurable in vivo ( Figure 1C ). It is widely accepted that host protection against C. neoformans requires a pro-inflammatory type 1 immune response mediated by IFNγ ( Mourad and Perfect, 2018 ; Li et al., 2019 ; Linyu et al., 2020 ; Hester et al., 2020 ; Normile et al., 2020a ; Akhtar et al., 2020 ; Montoya et al., 2021 ). Interestingly, SGs have been shown to induce Th1 T cell polarization ( Bouic et al., 1996 ; Lee and Han, 2006 ; Lee et al., 2007 ), but these studies have used plant-based SGs, not fungal-derived SGs.…”

Section: Discussionmentioning

confidence: 99%

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Cryptococcus neoformans Δsgl1 Vaccination Requires Either CD4+ or CD8+ T Cells for Complete Host Protection

Normile

Rella

Poeta

2021

Front. Cell. Infect. Microbiol.

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Cryptococcus neoformans is a fungal pathogen causing life-threatening meningoencephalitis in susceptible individuals. Fungal vaccine development has been hampered by the fact that cryptococcosis occurs during immunodeficiency. We previously reported that a C. neoformans mutant (Δsgl1) accumulating sterylglucosides (SGs) is avirulent and provides complete protection to WT challenge, even under CD4+ T cell depletion, an immunodeficient condition commonly associated with cryptococcosis. We found high levels of SGs in the lungs post-immunization with Δsgl1 that decreased upon fungal clearance. Th1 cytokines increased whereas Th2 cytokines concurrently decreased, coinciding with a large recruitment of leukocytes to the lungs. Depletion of B or CD8+ T cells did not affect either Δsgl1 clearance or protection from WT challenge. Although CD4+ T cell depletion affected clearance, mice were still protected indicating that clearance of the mutant was not necessary for host protection. Protection was lost only when both CD4+ and CD8+ T cells were depleted, highlighting a previously unexplored role of fungal-derived SGs as an immunoadjuvant for host protection against cryptococcosis.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Cryptococcus neoformans Δsgl1 Vaccination Requires Either CD4+ or CD8+ T Cells for Complete Host Protection

Normile

Rella

Poeta

2021

Front. Cell. Infect. Microbiol.

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“…Type 1 polarized CD4 + T cells have been well-documented to be essential in orchestrating host protection against WT C. neoformans 59 – 63 . Given that HIV/AIDS patients are at high risk for cryptococcosis due to CD4 + T cell lymphopenia 3 , 64 , the role of type 1 CD4 + polarized T cells in mediating host protection is undeniable. Although we have reported that either T cell subset sufficiently provided complete protection with no extrapulmonary dissemination after C. neoformans Δ sgl1 vaccination 41 , we have now discovered that CD4 + T cells exhibit a more robust response compared to CD8 + T cells (Fig.…”

Section: Discussionmentioning

confidence: 99%

Vaccine protection by Cryptococcus neoformans Δsgl1 is mediated by γδ T cells via TLR2 signaling

et al. 2022

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We previously reported that administration of Cryptococcus neoformans Δsgl1 mutant vaccine, accumulating sterylglucosides (SGs) and having normal capsule (GXM), protects mice from a subsequent infection even during CD4+ T cells deficiency, a condition commonly associated with cryptococcosis. Here, we studied the immune mechanism that confers host protection during CD4+T deficiency. Mice receiving Δsgl1 vaccine produce IFNγ and IL-17A during CD4+ T (or CD8+ T) deficiency, and protection was lost when either cytokine was neutralized. IFNγ and/or IL-17A are produced by γδ T cells, and mice lacking these cells are no longer protected. Interestingly, ex vivo γδ T cells are highly stimulated in producing IFNγ and/or IL-17A by Δsgl1 vaccine, but this production was significantly decreased when cells were incubated with C. neoformans Δcap59/Δsgl1 mutant, accumulating SGs but lacking GXM. GXM modulates toll-like receptors (TLRs), including TLR2. Importantly, neither Δsgl1 nor Δcap59/Δsgl1 stimulate IFNγ or IL-17A production by ex vivo γδ T cells from TLR2−/− mice. Finally, TLR2−/− animals do not produce IL-17A in response to Δsgl1 vaccine and were no longer protected from WT challenge. Our results suggest that SGs may act as adjuvants for GXM to stimulate γδ T cells in producing IFNγ and IL-17A via TLR2, a mechanism that is still preserved upon CD4+ T deficiency.

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“…Crohnʼs disease (CD) is a type of IBD (Morgan et al, 2019) that is characterized by the presence of mucosal ulcers and inflammation. Although the pathogenesis of CD is unknown and requires elucidation, it is thought to be associated with certain immune responses, environmental factors, genetic susceptibility and intestinal flora (Lin, Ali, Muzaheed, & Divakar, 2020). 2,4,6‐Trinitobenzene sulfonic acid (TNBS) and ethanol are the commonly used chemicals to induce colitis in rats, which is similar to CD in human beings (Gecse, Vegh, & Lakatos, 2016).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the effect of Dahuang–Mudan decoction on TNBS‐induced colitis using UPLC–QTOF/MS‐based metabolomic analysis

Nong

Luo

Liang

et al. 2020

Biomedical Chromatography

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Dahuang–Mudan decoction (DMD) is a formula that has been widely used as a complementary treatment for inflammatory bowel disease (IBD). However, the mechanism of action of DMD in IBD has not been clearly elucidated. Therefore, we developed a metabolomics‐based method to evaluate the effects and potential mechanisms of DMD in a 2,4,6‐trinitobenzene sulfonic acid (TNBS)‐induced colitis model. The ultra‐high‐performance liquid chromatography/quadrupole time‐of‐flight mass spectrometry (UPLC/QTOF–MS) method combined with multiple analysis approaches including principal component analysis, partial least square discriminant analysis and orthogonal partial least square discriminant analysis were used to investigate the different urinary metabolites. We identified 29 potential biomarkers of TNBS‐induced colitis that returned to normal conditions after DMD administration. Pathway analysis indicated that changes in these metabolites were associated with cysteine and methionine metabolism, citric acid cycle, glycolysis and glycolic regeneration, pyruvate metabolism, biosynthesis of valine, leucine and isoleucine, biosynthesis of primary bile acids, glycine, serine and threonine metabolism, caffeine metabolism, arginine and proline metabolism and phenylalanine metabolism. It is worth noting that DMD has potential therapeutic effects on TNBS‐induced colitis, which functions by restoring the balance of multiple disturbed pathways to a normal condition. This study suggests the reliability of metabolomics‐based approaches to identifying biomarkers and pathways, which facilitate further investigation of the potential mechanisms of DMD.

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Modulation of host immune status by cryptococcus co-infection during HIV-1 pathogenesis and its impact on CD+4 cell and cytokines environment

Cited by 5 publications

References 30 publications

Cryptococcus neoformans Δsgl1 Vaccination Requires Either CD4+ or CD8+ T Cells for Complete Host Protection

Cryptococcus neoformans Δsgl1 Vaccination Requires Either CD4+ or CD8+ T Cells for Complete Host Protection

Vaccine protection by Cryptococcus neoformans Δsgl1 is mediated by γδ T cells via TLR2 signaling

Evaluation of the effect of Dahuang–Mudan decoction on TNBS‐induced colitis using UPLC–QTOF/MS‐based metabolomic analysis

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