Chloroquine Has a Cytotoxic Effect on Acanthamoeba Encystation through Modulation of Autophagy

Jha, Bijay Kumar; Jung, Hui-Jung; Seo, Incheol; Kim, Hyun Ah; Suh, Seong-Il; Suh, Min-Ho; Baek, Won-Ki

doi:10.1128/aac.03164-14

Cited by 19 publications

(10 citation statements)

References 52 publications

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“…autophagy 18,19 , serine and cysteine proteases and cellulose biosynthesis 20,21 . This causes Acanthamoeba to persist long enough as the vulnerable trophozoites 22,23 and to allow a second cytotoxic agent to exert its effect 24 . The combination of different administration routes has also provided positive outcomes, for example topical and systemic administration using topical chlorhexidine 0.06% and propamidine isetionate 0.1% and the zwitterionic alkylphosphocholine (APC) called miltefosine 25,26 .…”

mentioning

confidence: 99%

Alkyl-carbon chain length of two distinct compounds and derivatives are key determinants of their anti-Acanthamoeba activities

Mooney

Masala

Martial

et al. 2020

Sci Rep

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the opportunistic pathogen, Acanthamoeba castellanii is the causative agent for the sight threatening infection Acanthamoeba keratitis (AK). it is commonly associated with contact lens wearers, and prevalence is increasing at an alarming rate due to an inadequate preventive strategy to protect the lens from this protist. This problem is compounded by the lack of an effective acanthamoebocide, particularly with cysticidal activity in the contact lens solutions. We have used cytotoxicity assays and a variety of biophysical approaches to show that two molecules with tails made of alkyl carbon, alkylphosphocholines (APCs) and quaternary ammonium compounds (QACs) had significant chain-length dependent efficacy against A. castellanii trophozoites, the latter producing death via permeabilization, and DNA complexing. QACs were more effective than APCs and had activity against cysts. Conversely, the QAC with 12 alkyl carbon chain, was non toxic, its presence increased A. castellanii trophozoites biomass and delayed encystation by 96 h. Interestingly, it was unable to induce excystation and increased trophozoite sensitivity to APC16. These results present a mono-and multi-inhibitor management strategy effective against trophozoites and cysts that may be useful for formulating into contact lense cleaning solutions and reducing AK incidence. Acanthamoeba are free-living protists, existing as active trophozoites and non-replicative cysts characterised by double cellulose cell walls 1. They have opportunistic tendencies and can cause the diseases, Acanthamoeba keratitis (AK), cutaneous acanthamoebiasis (CA) and granulomatous amoebic encephalitis (GAE) 2,3. Whilst CA and GAE are lethal but rare and affect the skin and CNS, respectively, the non-lethal AK causes severe infection in the cornea, threatening sight loss and causing emotional and psychological trauma, described as life-changing in patients 4. Trophozoites to cysts interconversion and vice versa (encystation and excystation) is induced by external environmental cues 5,6 and poses significant challenges for curative treatment particularly causing AK resurgences and relapses 7. AK cases are increasing and prevalence is high amongst contact lens users 8,9. Cases of AK within the UK have risen drastically within the last 20 years and continue to do so 10. The reason for this upsurge in incidence rates does not appear to be as a result of increased lens wearers but is as of yet unknown, likely the result of multiple factors 10. Spatial geographic differences are common with 15 times more cases reported in the UK than the USA 11,12 , and 8 times more in Scotland than England 13. These differences are strongly linked with water supply, quality and usage 12. Indeed, the incidence of AK in contact lens users is believed to be due to rinsing of contact lenses with domestic tap water 14. Further, the lack of anti-acanthamoebocides in cleaning solutions is another issue. Despite the presence of preservative compounds such as polyhexamethylene biguanide used in existing solutions,...

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confidence: 99%

Alkyl-carbon chain length of two distinct compounds and derivatives are key determinants of their anti-Acanthamoeba activities

Mooney

Masala

Martial

et al. 2020

Sci Rep

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“…Acanthamoeba trophozoites can convert itself into highly resistant cyst form, which diminishes the effectiveness of available therapeutic agents [ 4 ]. For this reason, new and more efficacious treatment options against cysts have been proposed and are still being examined [ 5 – 8 ].…”

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confidence: 99%

Effect of 2, 6-Dichlorobenzonitrile on Amoebicidal Activity of Multipurpose Contact Lens Disinfecting Solutions

et al. 2018

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Multipurpose contact lens disinfecting solutions (MPDS) are widely used to cleanse and disinfect microorganisms. However, disinfection efficacy of these MPDS against Acanthamoeba cyst remain insufficient. 2, 6-dichlorobenzonitrile (DCB), a cellulose synthesis inhibitor, is capable of increasing the amoebical effect against Acanthamoeba by inhibiting its encystation. In this study, we investigated the possibility of DCB as a disinfecting agent to improve the amoebicidal activity of MPDS against Acanthamoeba cyst. Eight commercial MPDS (from a to h) were assessed, all of which displayed insufficient amoebicidal activity against the mature cysts. Solution e, f, and h showed strong amoebicidal effect on the immature cysts. Amoebicidal efficacy against mature cysts remained inadequate even when the 8 MPDS were combined with 100 μM DCB. However, 4 kinds of MPDS (solution d, e, f, and h) including 100 μM DCB demonstrated strong amoebicidal activity against the immature cysts. The amoebicidal activity of solution d was increased by addition of DCB. Cytotoxicity was absent in human corneal epithelial cells treated with either DCB or mixture of DCB with MPDS. These results suggested that DCB can enhance the amoebicical activity of MPDS against Acanthamoeba immature cyst in vitro.

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“…Phagosomal pH was determined using flow cytometer as described by Jha et al. [40]. Briefly, peritoneal macrophages (5 × 10 5 ) from C57BL/6 mice were cultured in 24‐well plate and treated with rPPE18 for 2 h. The cells were either infected with M. smegmatis at MOI of 1:10 for 4 h or incubated with OVA antigen for 3 h. After removing the medium, LysoTracker Red DND‐99 (Thermo Fisher Scientific) at 200 ng/mL was added and incubated for 15 min at 37°C.…”

Section: Methodsmentioning

confidence: 99%

“…Briefly, peritoneal macrophages (5 × 10 5 ) from C57BL/6 mice were cultured in 24‐well plate and treated with rPPE18 for 2 h. The cells were either infected with M. smegmatis at MOI of 1:10 for 4 h or incubated with OVA antigen for 3 h. After removing the medium, LysoTracker Red DND‐99 (Thermo Fisher Scientific) at 200 ng/mL was added and incubated for 15 min at 37°C. Cells were washed extensively with FACS buffer and fluorescence associated with LysoTracker Red DND‐99 was measured using a flow cytometer (BD FACS Aria III) [40,41].…”

Section: Methodsmentioning

confidence: 99%

Mycobacterium tuberculosis PPE18 protein inhibits MHC class II antigen presentation and B cell response in mice

2020

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PPE18 protein belongs to PE/PPE family of Mycobacterium tuberculosis. We reported earlier that PPE18 protein provides survival advantage to M. tuberculosis during infection. In the current study, we found that PPE18 inhibits MHC class II‐mediated antigen presentation by macrophages in a dose‐dependent manner without affecting the surface level of MHC class II or co‐stimulatory molecules. PPE18 does not affect antigen uptake or presentation of preprocessed peptide by macrophages. Antigen degradation was found to be inhibited by PPE18 protein due to perturbation in phagolysosomal acidification. PPE18‐mediated inhibition of MHC class II antigen presentation caused poorer activation of CD4 T cells. Mice infected with M. smegmatis expressing PPE18 exhibited reduced maturation and activation of B cells and had decreased Mycobacteria‐specific antibody titers. Thus M. tuberculosis probably utilizes PPE18 to inhibit MHC class II antigen presentation causing poorer activation of adaptive immune responses. This study may be useful in understanding host–pathogen interaction and open up directions of designing novel therapeutics targeting PPE18 to tackle this nefarious pathogen.

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Chloroquine Has a Cytotoxic Effect on Acanthamoeba Encystation through Modulation of Autophagy

Cited by 19 publications

References 52 publications

Alkyl-carbon chain length of two distinct compounds and derivatives are key determinants of their anti-Acanthamoeba activities

Alkyl-carbon chain length of two distinct compounds and derivatives are key determinants of their anti-Acanthamoeba activities

Effect of 2, 6-Dichlorobenzonitrile on Amoebicidal Activity of Multipurpose Contact Lens Disinfecting Solutions

Mycobacterium tuberculosis PPE18 protein inhibits MHC class II antigen presentation and B cell response in mice

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