PMID- 37125906
OWN - NLM
STAT- MEDLINE
DCOM- 20230619
LR  - 20231120
IS  - 2165-0497 (Electronic)
IS  - 2165-0497 (Linking)
VI  - 11
IP  - 3
DP  - 2023 Jun 15
TI  - Leishmania donovani Attenuates Dendritic Cell Trafficking to Lymph Nodes by 
      Inhibiting C-Type Lectin Receptor 2 Expression via Transforming Growth Factor-beta.
PG  - e0412222
LID - 10.1128/spectrum.04122-22 [doi]
LID - e04122-22
AB  - To initiate an antileishmanial adaptive immune response, dendritic cells (DCs) 
      must carry Leishmania antigens from peripheral tissues to local draining lymph 
      nodes. However, the migratory capacity of DCs is largely compromised during 
      Leishmania donovani infection. The molecular mechanism underlying this defective 
      DC migration is not yet fully understood. Here, we demonstrate that L. donovani 
      infection impaired the lymph node homing ability of DCs by decreasing C-type 
      lectin receptor 2 (CLEC-2) expression. L. donovani exerted this inhibitory effect 
      by inducing transforming growth factor-beta (TGF-beta) secretion from DCs. Indeed, 
      TGF-beta produced in this manner inhibited nuclear factor-kappaB (NF-kappaB)-mediated CLEC-2 
      expression on DCs by activating c-Src. Notably, suppression of c-Src expression 
      significantly improved the arrival of DCs in draining lymph nodes by preventing 
      L. donovani-induced CLEC-2 downregulation on DCs. These findings reveal a unique 
      mechanism by which L. donovani inhibits DC migration to lymph nodes and suggest a 
      key role for TGF-beta, c-Src, and CLEC-2 in regulating this process. IMPORTANCE 
      Dendritic cells (DCs) play a key role in initiating T cell-mediated protective 
      immunity against visceral leishmaniasis (VL), the second most lethal parasitic 
      disease in the world. However, the T cell-inducing ability of DCs critically 
      depends on the extent of DC migration to regional lymph nodes. Notably, the 
      migration of DCs is reported to be impaired during VL. The cause of this impaired 
      DC migration, however, remains ill-defined. Here, we provide the first evidence 
      that L. donovani, the causative agent of VL, attenuates the lymph node homing 
      capacity of DCs by decreasing C-type lectin receptor 2 (CLEC-2) expression on 
      DCs. Additionally, we have demonstrated how L. donovani mediates this inhibitory 
      effect. Overall, our work has revealed a unique mechanism underlying L. 
      donovani-induced impairment of DC migration and suggests a potential strategy to 
      improve antileishmanial T cell activity by increasing DC arrival in lymph nodes.
FAU - Yadav, Manisha
AU  - Yadav M
AD  - Division of Cell Biology and Immunology, Council of Scientific and Industrial 
      Research-Institute of Microbial Technology, Chandigarh, India.
FAU - Akhtar, Md Naushad
AU  - Akhtar MN
AD  - Division of Cell Biology and Immunology, Council of Scientific and Industrial 
      Research-Institute of Microbial Technology, Chandigarh, India.
FAU - Mishra, Manish
AU  - Mishra M
AD  - Division of Cell Biology and Immunology, Council of Scientific and Industrial 
      Research-Institute of Microbial Technology, Chandigarh, India.
FAU - Kumar, Sandeep
AU  - Kumar S
AD  - Division of Cell Biology and Immunology, Council of Scientific and Industrial 
      Research-Institute of Microbial Technology, Chandigarh, India.
AD  - Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India.
FAU - Kumar, Raj
AU  - Kumar R
AD  - Division of Cell Biology and Immunology, Council of Scientific and Industrial 
      Research-Institute of Microbial Technology, Chandigarh, India.
FAU - Shubham
AU  - Shubham
AD  - Division of Cell Biology and Immunology, Council of Scientific and Industrial 
      Research-Institute of Microbial Technology, Chandigarh, India.
AD  - Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India.
FAU - Nandal, Anil
AU  - Nandal A
AD  - Division of Cell Biology and Immunology, Council of Scientific and Industrial 
      Research-Institute of Microbial Technology, Chandigarh, India.
FAU - Sen, Pradip
AU  - Sen P
AUID- ORCID: 0000-0003-1712-5312
AD  - Division of Cell Biology and Immunology, Council of Scientific and Industrial 
      Research-Institute of Microbial Technology, Chandigarh, India.
AD  - Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230501
PL  - United States
TA  - Microbiol Spectr
JT  - Microbiology spectrum
JID - 101634614
RN  - 0 (Transforming Growth Factor beta)
RN  - 0 (Lectins, C-Type)
RN  - 0 (Antiprotozoal Agents)
RN  - 76057-06-2 (Transforming Growth Factors)
SB  - IM
MH  - Humans
MH  - *Leishmania donovani/metabolism
MH  - Transforming Growth Factor beta/metabolism
MH  - Lectins, C-Type/genetics/metabolism
MH  - *Leishmaniasis, Visceral/metabolism/parasitology
MH  - *Antiprotozoal Agents
MH  - Lymph Nodes/metabolism
MH  - Dendritic Cells
MH  - Transforming Growth Factors/metabolism
PMC - PMC10269552
OTO - NOTNLM
OT  - CLEC-2
OT  - Leishmania donovani
OT  - NF-kappaB
OT  - TGF-beta
OT  - c-Src
OT  - dendritic cell trafficking
COIS- The authors declare no conflict of interest.
EDAT- 2023/05/01 12:44
MHDA- 2023/06/19 13:08
PMCR- 2023/05/01
CRDT- 2023/05/01 10:06
PHST- 2023/06/19 13:08 [medline]
PHST- 2023/05/01 12:44 [pubmed]
PHST- 2023/05/01 10:06 [entrez]
PHST- 2023/05/01 00:00 [pmc-release]
AID - 04122-22 [pii]
AID - spectrum.04122-22 [pii]
AID - 10.1128/spectrum.04122-22 [doi]
PST - ppublish
SO  - Microbiol Spectr. 2023 Jun 15;11(3):e0412222. doi: 10.1128/spectrum.04122-22. 
      Epub 2023 May 1.