Probing the molecular mechanism of aggressive infection by antimony resistant Leishmania donovani

被引:15
作者
Mukherjee, Budhaditya [1 ,3 ]
Mukherjee, Kamalika [1 ]
Nanda, Piyush [3 ]
Mukhopadhayay, Rupkatha [1 ]
Ravichandiran, V. [2 ]
Bhattacharyya, Suvendra N. [1 ]
Roy, Syamal [1 ,2 ]
机构
[1] CSIR Indian Inst Chem Biol, Kolkata 700032, India
[2] Natl Inst Pharmaceut Educ & Res, Kolkata 700054, India
[3] Indian Inst Technol, Sch Med Sci & Technol, Kharagpur 721302, W Bengal, India
关键词
Cytokine; Antimony resistance; Leishmania; MicroRNA; HuR; PP2A; EXPERIMENTAL VISCERAL LEISHMANIASIS; IMMUNE-RESPONSE; MICRORNAS; REPRESSION; PHOSPHATASES; MACROPHAGES; PARASITES; PROFILES;
D O I
10.1016/j.cyto.2020.155245
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The disease visceral leishmaniasis (VL) or kala azar is caused by the protozoan parasite, Leishmania donovani (LD). For many decades the pentavalent antimonial drugs countered the successive epidemics of the disease in the Indian sub-continent and elsewhere. With time, antimony resistant LD (LDR) developed and the drug in turn lost its efficacy. Infection of mammals with LDR gives rise to aggressive infection as compared to its sensitive counterpart (LDS) coupled with higher surge of IL-10 and TGF-beta. The IL-10 causes upregulation of multidrug resistant protein-1 which causes efflux of antimonials from LDR infected cells. This is believed to be a key mechanism of antimony resistance. MicroRNAs (miRNAs) are tiny post-transcriptional regulators of gene expression in mammalian cells and in macrophage play a pivotal role in controlling the expression of cytokines involved in infection process. Therefore, a change in miRNA profiles of macrophages infected with LDS or LDR could explain the differential cytokine response observed. Interestingly, the outcome of LD infection is also governed by the critical balance of pro- and anti-inflammatory cytokines which is inturn regulated by miRNAAgo2 or miRNP complex and its antagonist RNA binding protein HuR. Here Ago2 plays the fulcrum whose phosphorylation and de-phosphorylation dictates the process; which in turn is controlled by PP2A and HuR. LDS and LDR upregulate PP2A and downregulate HuR at different magnitude leading to various levels of antiinflammatory to proinflammatory cytokine production and resulting pathology in the host. While ectopic HuR expression alone is sufficient to clear LDS infection, simultaneous upregulation of HuR and inhibition of PP2A is required to inhibit LDR mediated infection. Therefore, tampering with miRNA pathway could be a new strategy to control infection caused by LDR parasite.
引用
收藏
页数:8
相关论文
共 46 条
[1]  
Asad M. D., 2014, Proceedings of the Indian National Science Academy, V80, P247
[2]   MicroRNAs: new regulators of immune cell development and function [J].
Baltimore, David ;
Boldin, Mark P. ;
O'Connell, Ryan M. ;
Rao, Dinesh S. ;
Taganov, Konstantin D. .
NATURE IMMUNOLOGY, 2008, 9 (08) :839-845
[3]  
BRAHMACHARI UN, 1989, INDIAN J MED RES-A, V89, P492
[4]   Leishmania donovani restricts mitochondrial dynamics to enhance miRNP stability and target RNA repression in host macrophages [J].
Chakrabarty, Yogaditya ;
Bhattacharyya, Suvendra N. .
MOLECULAR BIOLOGY OF THE CELL, 2017, 28 (15) :2091-2105
[5]   The lignan niranthin poisons Leishmania donovani topoisomerase IB and favours a Th1 immune response in mice [J].
Chowdhury, Sayan ;
Mukherjee, Tulika ;
Mukhopadhyay, Rupkatha ;
Mukherjee, Budhaditya ;
Sengupta, Souvik ;
Chattopadhyay, Sharmila ;
Jaisankar, Parasuraman ;
Roy, Syamal ;
Majumder, Hemanta K. .
EMBO MOLECULAR MEDICINE, 2012, 4 (10) :1126-1143
[6]   Leishmania-Induced Inactivation of the Macrophage Transcription Factor AP-1 Is Mediated by the Parasite Metalloprotease GP63 [J].
Contreras, Irazu ;
Gomez, Maria Adelaida ;
Nguyen, Oliver ;
Shio, Marina T. ;
McMaster, Robert W. ;
Olivier, Martin .
PLOS PATHOGENS, 2010, 6 (10)
[7]  
Courret N, 2002, J CELL SCI, V115, P2303
[8]   Drug resistance in leishmaniasis [J].
Croft, SL ;
Sundar, S ;
Fairlamb, AH .
CLINICAL MICROBIOLOGY REVIEWS, 2006, 19 (01) :111-+
[9]   Whole genome sequencing of multiple Leishmania donovani clinical isolates provides insights into population structure and mechanisms of drug resistance [J].
Downing, Tim ;
Imamura, Hideo ;
Decuypere, Saskia ;
Clark, Taane G. ;
Coombs, Graham H. ;
Cotton, James A. ;
Hilley, James D. ;
de Doncker, Simonne ;
Maes, Ilse ;
Mottram, Jeremy C. ;
Quail, Mike A. ;
Rijal, Suman ;
Sanders, Mandy ;
Schoenian, Gabriele ;
Stark, Olivia ;
Sundar, Shyam ;
Vanaerschot, Manu ;
Hertz-Fowler, Christiane ;
Dujardin, Jean-Claude ;
Berriman, Matthew .
GENOME RESEARCH, 2011, 21 (12) :2143-2156
[10]   Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? [J].
Filipowicz, Witold ;
Bhattacharyya, Suvendra N. ;
Sonenberg, Nahum .
NATURE REVIEWS GENETICS, 2008, 9 (02) :102-114