Wnt Signaling Regulates Macrophage Mediated Immune Response to Pathogens

Infection with pathogenic microbes is a global threat. Macrophages play a fundamental role in promoting host resistance to deadly infections from pathogenic microbes by virtue of a well-orchestrated immune defense system. Phagocytosis and obliteration of invading pathogens by macrophages are an innate immune function that not only sustains immune homeostasis but also bolsters adaptive immune response through antigen processing and presentation. Wnt signaling, where Wnt, a secreted glycoprotein which interacts with Frizzled and ROR cell surface receptors to initiate cellular interactions, could be vital for the immune response executed and propagated by macrophages in both innate and adaptive immune responses. The goal of this chapter is to describe how Wnt signaling influences phagocytosis, autophagy, and transcriptional activation to enable the macrophage to exercise its immune response program to resist infection

Wnt5A Signaling Antagonizes <em>Leishmania donovani</em> Infection

Infection by the parasite Leishmania donovani causes Visceral Leishmaniasis, a deadly disease if not properly treated. L. donovani captures the immune defense potential of host macrophages. It disrupts immune homeostasis at least partly by inducing expression of anti-inflammatory cytokines and altering the cellular cytoskeletal framework, thereby creating a niche for its own survival. While inhibition of macrophage Wnt5A signaling promotes infection by the parasite, activation of Wnt5A signaling significantly dampens infection. Experimental evidence suggests that the antagonistic effect of Wnt5A signaling on parasite infection in macrophages may be on account of its influence on the actin cytoskeleton. Importantly, the inhibitory effect of Wnt5A on infection is sustained independent of drug sensitivity and resistance. Keeping in mind that drugs used to treat Visceral Leishmaniasis are quite toxic and the parasite develops drug resistance, revamping host Wnt5A signaling may be useful for eliminating infection independent of drug sensitivity or resistance

COMPARATIVE STUDY OF AQUEOUS AND ETHANOLIC EXTRACT OF AMORPHOPHALLUS PAEONIIFOLIUS TUBER ON CENTRAL NERVOUS SYSTEM ACTIVITY IN MICE

Objective: The objective of the present study was to perform phytochemical screening &amp; to carry out a comparative study on aqueous and ethanolic extract of Amorphophallus paeoniifolius tuber on CNS activity in swiss albino mice. Methods: A. paeoniifolius tuber was collected, shed dried and powdered. Extracts of the powder were prepared separately using ethanol &amp; water. Phytochemical screening was also done from the extract. The animals were divided in six groups. Group 1 received DMSO solution (Control). Group 2 animals received Diazepam (1.5mg/kg, Standard). Group 3 and 4 received A. paeoniifolius aqueous extract (200mg/kg , 400mg/kg respectively). Group 5 and 6 received A. paeoniifolius ethanolic extract (200mg/kg , 400mg/kg respectively). In vivo CNS activities of the extracts were checked by actophotometer, rotarod, forced swim test. Results: The extracts show presence of Alkaloids, flavonoids, steroids, terpenoids, reducing sugar, carbohydrate, tannin. The aqueous &amp; ethanolic extract of A. paeoniifolius tuber showed significant decrease in locomotor activity when compared to control. Among the extracts the 400mg/kg ethanolic extract shows maximum CNS depression. All the extracts showed significant muscle relaxant similar to the standard drug. The extracts also exhibited significant increase in immobility time in a dose dependent manner in forced swim test. Conclusion: The aqueous &amp; ethanolic extract of A. paeoniifolius tuber (200mg/kg, 400mg/kg) shows significant CNS depressant and muscles relaxant and anxiolytic properties

Prahlad and Shanta : the city's madness

This article explores the irreverent and supposedly irrational actions of two protagonists, Prahlad and Shanta, characters that the authors encountered during the course of their extended fieldwork in Kolkata. Prahlad is an Oriya migrant plumber who passionately seeks god at the cost of making money, and resists adhering to rational economic behaviour in the city. Shanta is a grieving mother who relentlessly seeks justice for her son’s disappearance during a revolutionary movement that consumed the majority of urban youth in the 1970s. Family, friends, neighbours and employers describe and at time dismiss rgen as pagla or insane. This article foregrounds these expressions of paglami or madness in Kolkata. We ask: how does close ethnographic attention to quotidian madness–its articulations, exploitations and resistances–enable us to rethink urban lives? We argue that dissension, alienation and ‘unreasonable fixations’ are affective thresholds of a changing city. They corroborate the ways in which the city’s transforming political landscape impinges on its ordinary lives

Wnt5A Signaling Regulates Gut Bacterial Survival and T Cell Homeostasis

In light of the demonstrated antagonism of Wnt5A signaling toward the growth of several bacterial pathogens, it was important to study the influence of Wnt5A on gut-resident bacteria and its outcome. Here, we demonstrate that in contrast to inhibiting the survival of the established gut pathogen Salmonella enterica, Wnt5A clearly promotes the survival of the common gut commensals Enterococcus faecalis and Lactobacillus rhamnosus within macrophages through a self-perpetuating Wnt5A-actin axis. A Wnt5A-actin axis furthermore regulates the subsistence of the natural bacterial population of the Peyer's patches, as is evident from the diminution in the countable bacterial CFU therein through the application of Wnt5A signaling and actin assembly inhibitors. Wnt5A dependency of the gut-resident bacterial population is also manifested in the notable difference between the bacterial diversities associated with the feces and Peyer's patches of Wnt5A heterozygous mice, which lack a functional copy of the Wnt5A gene, and their wild-type counterparts. Alterations in the gut commensal bacterial population resulting from either the lack of a copy of the Wnt5A gene or inhibitor-mediated attenuation of Wnt5A signaling are linked with significant differences in cell surface major histocompatibility complex (MHC) II levels and regulatory versus activated CD4 T cells associated with the Peyer's patches. Taken together, our findings reveal the significance of steady state Wnt5A signaling in shaping the gut commensal bacterial population and the T cell repertoire linked to it, thus unveiling a crucial control device for the maintenance of gut bacterial diversity and T cell homeostasis. IMPORTANCE Gut commensal bacterial diversity and T cell homeostasis are crucial entities of the host innate immune network, yet the molecular details of host-directed signaling pathways that sustain the steady state of gut bacterial colonization and T cell activation remain unclear. Here, we describe the protective role of a Wnt5A-actin axis in the survival of several gut bacterial commensals and its necessity in shaping gut bacterial colonization and the associated T cell repertoire. This study opens up new avenues of investigation into the role of the Wnt5A-actin axis in protection of the gut from dysbiosis-related inflammatory disorders

Wnt5A Signaling Promotes Defense Against Bacterial Pathogens by Activating a Host Autophagy Circuit

Bacterial pathogens are associated with severe infections (e.g., sepsis) and exacerbation of debilitating conditions such as chronic obstructive pulmonary disease (COPD). The interactions of bacterial pathogens with macrophages, a key component of innate immunity and host defense, are not clearly understood and continue to be intensively studied. Having previously demonstrated a role of Wnt5A signaling in phagocytosis, we proceeded to decipher the connection of Wnt5A signaling with infection by pathogenic bacteria, namely Pseudomonas aeruginosa (PA) and Streptococcus pneumoniae (SP), which are related with the progression of COPD and sepsis. We found that during the initial hours of infection with PA and SP, there is decrease in the steady state levels of the Wnt5A protein in macrophages. Suppression of Wnt5A signaling, moreover, impairs macrophage clearance of the bacterial infection both in vitro and in vivo. Activation of Wnt5A signaling, on the other hand, enhances clearance of the infection. Macrophage-mediated containment of bacterial infection in our study is dependant on Wnt5A-induced Rac1/Disheveled activation and cytochalasin D inhibitable actin assembly, which is associated with ULK1 kinase activity and LC3BII accumulation. Our experimental findings are consistent with Wnt5A signaling-dependent induction of autophagic killing (xenophagy) of PA and SP, as further substantiated by transmission electron microscopy. Overall, our study unveils the prevalence of a Wnt5A—Rac1—Disheveled-mediated actin-associated autophagy circuit as an important component of innate immunity in host macrophages that may turn out crucial for restricting infection by leading bacterial pathogens