Leishmania survives by exporting miR-146a from infected to resident cells to subjugate inflammation.

Satarupa Ganguly,Shreya Bhattacharjee,Suvendra N Bhattacharyya,Avijit Goswami,Bartika Ghoshal,Kamalika Mukherjee,Ishani Banerji,Sreemoyee Chakraborty

doi:10.26508/lsa.202101229

Abstract

Leishmania donovani, the causative agent of visceral leishmaniasis, infects and resides within tissue macrophage cells. It is not clear how the parasite infected cells crosstalk with the noninfected cells to regulate the infection process. During infection, Leishmania adopts a dual strategy for its survival by regulating the intercellular transport of host miRNAs to restrict inflammation. The parasite, by preventing mitochondrial function of host cells, restricts the entry of liver cell derived miR-122-containing extracellular vesicles in infected macrophages to curtail the inflammatory response associated with miR-122 entry. On contrary, the parasite up-regulates the export of miR-146a from the infected macrophages. The miR-146a, associated with the extracellular vesicles released by infected cells, restricts miR-122 production in hepatocytes while polarizing neighbouring naïve macrophages to the M2 state by affecting the cytokine expression. On entering the recipient macrophages, miR-146a dominates the miRNA antagonist RNA-binding protein HuR to inhibit the expression of proinflammatory cytokine mRNAs having HuR-interacting AU-rich elements whereas up-regulates anti-inflammatory IL-10 by exporting the miR-21 to polarize the recipient cells to M2 stage.

Highlights

Leishmania donovani (Ld) is the causative agent of visceral leishmaniasis that affects a large portion of the human population in the Indian subcontinent and in sub-Saharan Africa (Lenk et al, 2018)
The status of the noninfected macrophages present in the infection niche is not clear, but it is certain that the noninfected macrophages present in the infection niche should not get activated to ensure the overall dominance of an antiinflammatory response that needs to be maintained in the infected tissue
Hepatocytes respond to LPS and altered metabolic function of the hepatocytes exposed to LPS has been documented (Masaki et al, 2004; Momen-Heravi et al, 2015). miR-122 is the key pro-inflammatory miRNA expressed in hepatocytes (MomenHeravi et al, 2015)

Summary

Introduction

Leishmania donovani (Ld) is the causative agent of visceral leishmaniasis that affects a large portion of the human population in the Indian subcontinent and in sub-Saharan Africa (Lenk et al, 2018). The promastigotes enter the mammalian host with the saliva of the sandfly vector introduced during the blood meal and subsequently make entry into the hepatic tissue where they infect the Kupffer cells at the initial stage of infection before the infection load is transferred to the spleen (Walker et al, 2014). How the parasite, which remains within the specialized vacuole structure of the infected host macrophage, crosscommunicates with the resident noninfected macrophages to suppress expression of inflammatory cytokines is an important question to explore. In this context, the extracellular signals derived from resident noninfected macrophages and hepatocytes that can activate the infected macrophage should be counteracted within the infected host cell milieu

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Results

Conclusion