Inverse correlation between Leishmania-induced TLR1/2 and TGF-β differentially regulates parasite persistence in bone marrow during the chronic phase of infection

Abstract

Host-tissue preference is a critical aspect of parasitic infections and is directly correlated with species diversity. Even the same species, Leishmania donovani, infects the host's bone marrow, spleen, and liver differentially. The tissue-specific persistence of Leishmania results from host-pathogen immune conflicts and arguments. The protective pro-host or destructive pro-parasitic role of TLRs during L. donovani infection has been well established, but what entirely missing is the influence of TLRs on tissue-specific parasite persistence. We observed that the parasites induced differential expression of TLR1/2 in the bone marrow but not in the spleen. Interestingly, the rate of Leishmania infection was found to be positively correlated with TLR1/2-mediated upregulation of myelopoietic cytokines, M-CSF, GM-CSF, IL-6, and IL-3, leading to the expansion of Ly6C^hiCCR2⁺ monocytes, however, negatively correlated with the expression of the disease hallmark cytokines, TNF-α, TGF-β, and IL-10, along the course of infection in the bone marrow. Leishmania induced the activation of bone marrow-specific TLR1/2 to promote Ly6C^hiCCR2⁺ monocytes for its safe shelter vis-à-vis infection establishment. Consequently, the established infection initiated the release of TNF-α, TGF-β, and IL-10 in the bone marrow. Post-infection time-kinetic study affirmed that TGF-β had a significant negative influence on the expression of TLR1/2 heterodimer in the bone marrow niche. To the best of our knowledge, this is the first report to show that the inverse correlation of TLR1/2 - TGF-β can be instrumental in tissue-specific parasite persistence during Leishmania infection.

Keywords: Bone marrow; Inverse correlation; Leishmania donovani; TGF-β; TLR1/2.