Activation of neutrophils excels the therapeutic potential of Mycobacterium indicus pranii and heat-induced promastigotes against antimony-resistant Leishmania donovani infection.

Repurposing drugs and adjuvants is an attractive choice of present therapy that reduces the substantial costs, chances of failure, and systemic toxicity. Mycobacterium indicus pranii was originally developed as a leprosy vaccine but later has been found effective against Leishmania donovani infection. To extend our earlier study, here we reported the immunotherapeutic modulation of the splenic and circulatory neutrophils in favour of hosts as neutrophils actually serve as the pro-parasitic portable shelter to extend the Leishmania infection specifically during the early entry into the hosts' circulation. We targeted to disrupt this early pro-parasitic incidence by the therapeutic combination of M. indicus pranii and heat-induced promastigotes against antimony-resistant L. donovani infection. The combination therapy induced the functional expansion of CD11b+Ly6CintLy6Ghi neutrophils both in the post-infected spleen, and also in the circulation of post-treated animals followed by the immediate Leishmania infection. More importantly, the enhanced expression of MHC-II, phagocytic uptake of the parasites by the circulatory neutrophils as well as the oxidative burst were induced that limited the chances of the very early establishment of the infection. The enhanced expression of pro-inflammatory cytokines, like IL-1α and TNF-α indicated resistance to the parasite-mediated takeover of the neutrophils, as these cytokines are critical for the activation of T cell-mediated immunity and host-protective responses. Additionally, the induction of essential transcription factors and cytokines for early granulocytic lineage commitment suggests that the strategy not only contributed to the peripheral activation of the neutrophils but also promoted granulopoiesis in the bone marrow.

Insect vectors' saliva and gut microbiota as a blessing in disguise: probability versus possibility.

Drawing of host blood is a natural phenomenon during the bite of blood-probing insect vectors. Along with the blood meal, the vectors introduce salivary components and a trail of microbiota. In the case of infected vectors, the related pathogen accompanies the aforementioned biological components. In addition to Anopheles gambiae or Anopheles stephensi, the bites of other nonmalarial vectors cannot be ignored in malaria-endemic regions. Similarly, the bite incidence of Phlebotomus papatasi cannot be ignored in visceral leishmaniasis-endemic regions. Even the chances of getting bitten by uninfected vectors are higher than the infected vectors. We have discussed the probability or possibility of uninfected, infected, and/or nonvector's saliva and gut microbiota as a therapeutic option leading to the initial deterrent to pathogen establishment.