Cell‐to‐cell transfer of<scp><i>L</i></scp><i>eishmania amazonensis</i>amastigotes is mediated by immunomodulatory<scp>LAMP</scp>‐rich parasitophorous extrusions

Real, Fernando; Florentino, Pilar Tavares Veras; Reis, Luiza Campos; Ramos-Sanchez, Eduardo Milton; Veras, Patrícia Sampaio Tavares; Goto, Hiro; Mortara, Renato Arruda

doi:10.1111/cmi.12311

Cited by 62 publications

(57 citation statements)

References 44 publications

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“…2I). Evidence of parasite extrusion has been substantiated by previous reports (36). Treatment of RAW 264.7 macrophages with Wnt5a after 4 h of infection with L. donovani also yielded a similar decrease (∼50-70%) in L. donovani-specific amastin and G6PDH gene expression within the first 6 h of treatment (Fig.…”

Section: Treatment Of Macrophages With Wnt5a Reduces Parasite Loadsupporting

confidence: 80%

Wnt5a Signaling Promotes Host Defense againstLeishmania donovaniInfection

Chakraborty

Kurati

Mahata

et al. 2017

The Journal of Immunology

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Leishmania donovani infects macrophages, disrupting immune homeostasis. The underlying mechanism that sustains infection remains unresolved. In view of the potential of Wnt5a signaling to support immune homeostasis, we evaluated the interrelationship of Wnt5a signaling and Leishmania donovani infection. Upon infecting macrophages separately with antimony drug–sensitive and –resistant L. donovani, we noted disruption in the steady-state level of Wnt5a. Moreover, inhibition of Wnt5a signaling by small interfering RNA transfection in vitro or by use of inhibitor of Wnt production in vivo led to an increase in cellular parasite load. In contrast, treatment of macrophages with recombinant Wnt5a caused a decrease in the load of antimony-sensitive and -resistant parasites, thus confirming that Wnt5a signaling antagonizes L. donovani infection. Using inhibitors of the Wnt5a signaling intermediates Rac1 and Rho kinase, we demonstrated that Wnt5a-mediated inhibition of parasite infection in macrophages is Rac1/Rho dependent. Furthermore, phalloidin staining and reactive oxygen species estimation of Wnt5a-treated macrophages suggested that a Wnt5a-Rac/Rho–mediated decrease in parasite load is associated with an increase in F- actin assembly and NADPH oxidase activity. Moreover, live microscopy of L. donovani–infected macrophages treated with Wnt5a demonstrated increased endosomal/lysosomal fusions with parasite-containing vacuoles (parasitophorous vacuoles [PV]). An increase in PV–endosomal/lysosomal fusion accompanied by augmented PV degradation in Wnt5a-treated macrophages was also apparent from transmission electron microscopy of infected cells. Our results suggest that, although L. donovani evades host immune response, at least in part through inhibition of Wnt5a signaling, revamping Wnt5a signaling can inhibit L. donovani infection, irrespective of drug sensitivity or resistance.

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Section: Treatment Of Macrophages With Wnt5a Reduces Parasite Loadsupporting

confidence: 80%

Wnt5a Signaling Promotes Host Defense againstLeishmania donovaniInfection

Chakraborty

Kurati

Mahata

et al. 2017

The Journal of Immunology

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“…The increased resistance delays cell death, allowing parasite transformation into amastigotes and replication. Lastly, Leishmania parasites exploits the apoptotic host cell to spread to neighboring macrophages, reducing the exposure to extracellular immune recognition system [44]. The mild UPR in infected cells could also contribute to explain many previous findings concerning manipulation of host cellular pathways, such as induction of antioxidant enzymes, translation repression, induction of autophagy, and also Akt phosphorylation, which is induced by ER stress in a PERK-dependent manner [45].…”

Section: Discussionmentioning

confidence: 99%

Leishmania infantum Induces Mild Unfolded Protein Response in Infected Macrophages

et al. 2016

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The Leishmaniases are a group of parasitic diseases caused by protozoa of the Leishmania genus affecting both humans and other vertebrates. Leishmania is an intracellular pathogen able to confer resistance to apoptosis in the early phase of macrophages infection by activation of host PI3K/Akt pathway and inhibition of caspase-3 activation. Intracellular pathogens hijack organelles such as ER to facilitate survival and replication, thus eliciting ER stress and activating/modulating the unfolded protein response (UPR) in the host cell. The UPR is aimed to mitigate ER stress, thereby promoting cell survival. However, prolonged ER stress will activate the apoptotic pathway. The aim of this study was to investigate the ER stress response in Leishmania-infected macrophages to gain insights about the mechanisms underlying the apoptosis resistance in parasitized cells. Macrophages differentiated from human monocytic cell lines (U937 and THP-1) and murine primary macrophages were infected with Leishmania infantum MHOM/TN/80/IPT1 (WHO international reference strain). Several ER stress/autophagy expression markers, as well as cell survival/apoptosis markers (phospho-Akt and cleaved caspase-3) were evaluated by qPCR and/or by western blotting. As ER stress positive control, cells were treated with tunicamycin or dithiothreitol (DTT). The gene expression analyses showed a mild but significant induction of the ER stress/autophagy markers. The western blot analyses revealed that the Leishmania infection induced Akt phosphorylation and significantly inhibited the induction of caspase-3 cleavage, eIF2α phosphorylation and DDIT3/CHOP expression in tunicamycin and DTT treated cells. The mild but significant increase in ER stress expression markers and the delay/attenuation of the effects of ER stress inducers in infected cells support the hypothesis that L. infantum could promote survival of host cells by inducing a mild ER stress response. The host ER stress response could be not only a common pathogenic mechanism among Leishmania species but also a target for development of new drugs.

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“…Again, as in healthy samples, the DMC of nucleus membrane is superior to the one from the rest of infected cell structure. The rise of average DMC in parasited samples in comparison with the healthy ones can be explained because apoptotic bodies (that typically contain nuclear material and actin cytoskeleton fragments) are shed within the cell , thus changing its DMC.…”

Section: Resultsmentioning

confidence: 99%

Label‐free bioanalysis of Leishmania infantum using refractive index tomography with partially coherent illumination

Soto

Mas

Rodrigo

et al. 2019

Journal of Biophotonics

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In this work, we report the use of refractive index (RI) tomography for quantitative analysis of unstained DH82 cell line infected with Leishmania infantum. The cell RI is reconstructed by using a modality of optical diffraction tomography technique that employs partially coherent illumination, thus enabling inherent compatibility with conventional wide‐field microscopes. The experimental results demonstrate that the cell dry mass concentration (DMC) obtained from the RI allows for reliable detection and quantitative characterization of the infection and its temporal evolution. The RI provides important insight for studying morphological changes, particularly membrane blebbing linked to an apoptosis (cell death) process induced by the disease. Moreover, the results evidence that infected DH82 cells exhibit a higher DMC than healthy samples. These findings open up promising perspectives for clinical diagnosis of Leishmania.

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Cell‐to‐cell transfer ofLeishmania amazonensisamastigotes is mediated by immunomodulatoryLAMP‐rich parasitophorous extrusions

Cited by 62 publications

References 44 publications

Wnt5a Signaling Promotes Host Defense againstLeishmania donovaniInfection

Wnt5a Signaling Promotes Host Defense againstLeishmania donovaniInfection

Leishmania infantum Induces Mild Unfolded Protein Response in Infected Macrophages

Label‐free bioanalysis of Leishmania infantum using refractive index tomography with partially coherent illumination

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