PMID- 37702516
OWN - NLM
STAT- MEDLINE
DCOM- 20231023
LR  - 20240210
IS  - 1098-6596 (Electronic)
IS  - 0066-4804 (Print)
IS  - 0066-4804 (Linking)
VI  - 67
IP  - 10
DP  - 2023 Oct 18
TI  - Plasmodium falciparum GCN5 plays a key role in regulating artemisinin 
      resistance-related stress responses.
PG  - e0057723
LID - 10.1128/aac.00577-23 [doi]
LID - e00577-23
AB  - Plasmodium falciparum causes the most severe malaria and is exposed to various 
      environmental and physiological stresses in the human host. Given that GCN5 plays 
      a critical role in regulating stress responses in model organisms, we aimed to 
      elucidate PfGCN5's function in stress responses in P. falciparum. The protein 
      level of PfGCN5 was substantially induced under three stress conditions [heat 
      shock, low glucose starvation, and dihydroartemisinin, the active metabolite of 
      artemisinin (ART)]. With a TetR-DOZI conditional knockdown (KD) system, we 
      successfully down-regulated PfGCN5 to ~50% and found that KD parasites became 
      more sensitive to all three stress conditions. Transcriptomic analysis via 
      RNA-seq identified ~1,000 up- and down-regulated genes in the wild-type (WT) and 
      KD parasites under these stress conditions. Importantly, DHA induced 
      transcriptional alteration of many genes involved in many aspects of stress 
      responses, which were heavily shared among the altered genes under heat shock and 
      low glucose conditions, including ART-resistance-related genes such as K13 and 
      coronin. Based on the expression pattern between WT and KD parasites under three 
      stress conditions, ~300-400 genes were identified to be involved in 
      PfGCN5-dependent, general, and stress-condition-specific responses with high 
      levels of overlaps among three stress conditions. Notably, using ring-stage 
      survival assay, we found that KD or inhibition of PfGCN5 could sensitize the 
      ART-resistant parasites to the DHA treatment. All these indicate that PfGCN5 is 
      pivotal in regulating general and ART-resistance-related stress responses in 
      malaria parasites, implicating PfGCN5 as a potential target for malaria 
      intervention.
FAU - Lucky, Amuza Byaruhanga
AU  - Lucky AB
AD  - Department of Internal Medicine, Morsani College of Medicine, University of South 
      Florida , Tampa, Florida, USA.
FAU - Wang, Chengqi
AU  - Wang C
AD  - Center for Global Health and Infectious Diseases Research, College of Public 
      Health, University of South Florida , Tampa, Florida, USA.
FAU - Shakri, Ahmad Rushdi
AU  - Shakri AR
AD  - Department of Internal Medicine, Morsani College of Medicine, University of South 
      Florida , Tampa, Florida, USA.
FAU - Kalamuddin, Mohammad
AU  - Kalamuddin M
AD  - Department of Internal Medicine, Morsani College of Medicine, University of South 
      Florida , Tampa, Florida, USA.
FAU - Chim-Ong, Anongruk
AU  - Chim-Ong A
AD  - Department of Internal Medicine, Morsani College of Medicine, University of South 
      Florida , Tampa, Florida, USA.
FAU - Li, Xiaolian
AU  - Li X
AD  - Department of Internal Medicine, Morsani College of Medicine, University of South 
      Florida , Tampa, Florida, USA.
FAU - Miao, Jun
AU  - Miao J
AUID- ORCID: 0000-0001-9374-6749
AD  - Department of Internal Medicine, Morsani College of Medicine, University of South 
      Florida , Tampa, Florida, USA.
AD  - Center for Global Health and Infectious Diseases Research, College of Public 
      Health, University of South Florida , Tampa, Florida, USA.
LA  - eng
GR  - R21 AI149202/AI/NIAID NIH HHS/United States
PT  - Journal Article
DEP - 20230913
PL  - United States
TA  - Antimicrob Agents Chemother
JT  - Antimicrobial agents and chemotherapy
JID - 0315061
RN  - 9RMU91N5K2 (artemisinin)
RN  - 0 (Artemisinins)
RN  - IY9XDZ35W2 (Glucose)
RN  - 0 (Antimalarials)
RN  - 0 (Protozoan Proteins)
SB  - IM
UOF - bioRxiv. 2023 May 09;:. PMID: 36711954
MH  - Humans
MH  - Plasmodium falciparum/metabolism
MH  - *Artemisinins/pharmacology/therapeutic use
MH  - *Malaria, Falciparum/drug therapy
MH  - Glucose/metabolism
MH  - *Antimalarials/pharmacology/therapeutic use
MH  - Protozoan Proteins/genetics/metabolism
MH  - Drug Resistance/genetics
PMC - PMC10583690
OTO - NOTNLM
OT  - GCN5
OT  - Plasmodium falciparum
OT  - artemisinin resistance
OT  - malaria
OT  - stress response
COIS- The authors declare no conflict of interest.
EDAT- 2023/09/13 12:43
MHDA- 2023/10/23 00:44
PMCR- 2023/09/13
CRDT- 2023/09/13 09:04
PHST- 2023/10/23 00:44 [medline]
PHST- 2023/09/13 12:43 [pubmed]
PHST- 2023/09/13 09:04 [entrez]
PHST- 2023/09/13 00:00 [pmc-release]
AID - 00577-23 [pii]
AID - aac.00577-23 [pii]
AID - 10.1128/aac.00577-23 [doi]
PST - ppublish
SO  - Antimicrob Agents Chemother. 2023 Oct 18;67(10):e0057723. doi: 
      10.1128/aac.00577-23. Epub 2023 Sep 13.