**Acknowledgements**

*Vector-Borne Diseases - Recent Developments in Epidemiology and Control*

using live cell dyes [42]. Electron microscopic (EM) images showed Wnt5A induced increased membranous vesicle fusions with PV in the infected cells. The EM images also revealed a low abundance of the PV upon Wnt5A treatment. The apparent membranous wrappings in degraded PV, as suggested by EM may be due to the formation of autophagosomes through fusion of PV with membranous aggregates during cytoskeletal movements [42]. One of the strategies that a host may adopt through Wnt5A signaling is laminate the parasitophorous vacuole so that the solutes cannot easily reach the parasite thereby slowly starving the parasite to death. While laminating the parasitophorous vacuole it may also ensure that the NADPH oxidase is well assembled so as to generate adequate amounts of ROS, which could lead to killing of parasites. The membrane lamination on the parasitophorous vacuoles through enhanced cytoskeletal dynamics could also lead to increased PV-lysosomal fusion thereby promoting rapid degradation of the parasite. Our study demonstrates that Wnt5A signaling mediated killing of *L. donovani* in macrophages is abrogated when inhibitors of cytoskeletal proteins like Rac1 GTPase and Rho kinase are used, thus implying that the effects of Wnt5A signaling on infection are at least partly mediated through the small molecular weight actin associated GTPases. The possible mechanism of Wnt5A signaling mediated parasite clearance is depicted in **Figure 2**. It will be important to validate the effect of Wnt5A signaling on *L. donovani* infection *in vivo* and also check the load of *L. donovani* infection in Wnt5A heterozygous mice (Wnt5A null are lethal). Analysis of the cytokine milieu *in vivo* upon activation of Wnt5A signaling at the onset of infection will also provide useful information about the mechanism of Wnt5A induced containment of infection.

Wnt5A signaling maintains immune homeostasis [40]. If Wnt5A signaling is not sufficient a disturbed immune homeostasis could lead to adverse effects during *L. donovani* infection. Recently, it has been suggested that *L. donovani* infection associated with a skewed hematopoiesis program promotes the visceral disease [60]. Since Wnt5A signaling is involved in hematopoiesis [61], it is important to have a clear understanding of the role of Wnt5A directed hematopoiesis during *L. donovani*

*L. donovani* through its evolution has undergone various changes to accommodate itself efficiently in its ever-changing environment. Often drugs have been rendered useless by the emergence of drug resistant strains. Therefore, it would be an efficient strategy to identify host cell factors, which act against these infections and revamp them. Our results indicate that host Wnt5A signaling restricts infection by both antimony drug sensitive and resistant *L. donovani* strains at least partly by prohibiting parasite niche formation within host macrophages. Interestingly, in a follow up study we found a similar kind of result with *Pseudomonas aeruginosa* or *Streptococcus pneumoniae*. These pathogenic bacteria degrade Wnt5A from the system and when Wnt5A is added exogenously the macrophages efficiently lower the bacterial load. The clearance of bacteria was found to happen through cytoskeletal reorganization and efficient formation of LC3B containing phagosome [43]. Recently high serum levels of the Wnt antagonist Dkk1 has been correlated with a predominantly Th2 phenotype during the onset of experimental cutaneous leishmaniasis [62]. Since Wnt5A supports a pro-inflammatory cytokine signature its potential for protection against parasite infection may also involve prevention of the predominantly Th2 signature that sustains infection. Thus Wnt5A signaling plays an important role in maintaining an innate immune readiness within macrophages

**110**

for pathogenic onslaught.

**5. Conclusion**

infection.

This work was supported by ICMR, Govt. of India (2016-0222/CMB/ADHOC-BMS dated 04/12/2018), Institutional funding (BSC0114, BSC0116). SM was supported by Research Scholar Fellowship from UGC, Govt. of India.
