Wnt5A-Mediated Actin Organization Regulates Host Response to Bacterial Pathogens and Non-Pathogens

Jati, Suborno; Sengupta, Soham; Sen, Malini

doi:10.3389/fimmu.2020.628191

Cited by 13 publications

(12 citation statements)

References 54 publications

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“…A Wnt5A-Actin axis supports the survival of commensal bacteria. In light of the demonstrated association of actin dynamics with Wnt5A signaling (9,17,32), we investigated if Wnt5A assisted survival of the commensal bacteria is linked with actin assembly. Indeed, Wnt5A depletion induced reduction in E. faecalis and L. rhamnosus survival in macrophages was clearly associated with diminution in actin assembly as demonstrated by confocal microscopy and subsequent ImageJ (intensity) analysis of phalloidin stained cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Cells: RAW264.7 cell line was obtained from ATCC (ATCC©TIB71 TM ). Peritoneal macrophages and cells of Peyer's patches were harvested and cultured following previously published protocols (17,19,(57)(58)(59). Cells were grown at 37°C with 5% CO 2 in DMEM High Glucose containing 10% FBS, 2 mM L-glutamine, 100 U/ml penicillin and 100 mg/ml streptomycin.…”

Section: Cells and Reagentsmentioning

confidence: 99%

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Wnt5A Signaling Regulates Gut Bacterial Survival and T cell Homeostasis

Sengupta

Jati

Maity

et al. 2022

Preprint

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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 colony forming units 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 the wild type counterparts. Alterations in gut commensal bacterial population resulting from either the lack of a copy of the Wnt5A gene or inhibitor mediated attenuation of Wnt5A signaling correlate with significantly different ratios of regulatory vs. activated CD4 T cells associated with the Peyer’s patches. Taken together, our study reveals the importance of 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.Significance StatementGut commensal bacterial diversity and T cell homeostasis are crucial entities of the host innate immune network. Yet 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 importance 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.

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Section: Resultsmentioning

confidence: 99%

Section: Cells and Reagentsmentioning

confidence: 99%

Wnt5A Signaling Regulates Gut Bacterial Survival and T cell Homeostasis

Sengupta

Jati

Maity

et al. 2022

Preprint

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“…Wnt5A is associated with an altered profile of macrophages, T cells and secreted cytokines. In view of the documented role of Wnt5A signaling in macrophage and T cell activation (6)(7)(8)(9)(10)19,29,30) we wanted to examine if the Wnt5A mediated inhibition of disease progression in mice by L. donovani infection is linked with changes in the status of macrophages, T cells and cytokines. In essence, we evaluated the immune potential of rWnt5A in relation to rWnt3A and the vehicle control (vc), toward restriction of disease progression.…”

Section: Inhibition Of Progression Of Experimental Visceral Leishmaniasis Bymentioning

confidence: 99%

Wnt5A Signaling Blocks Progression of Experimental Visceral Leishmaniasis

Maity

Chakraborty

Mahata

et al. 2021

Preprint

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Visceral Leishmaniasis, caused by L. donovani infection is fatal if left untreated. The intrinsic complexity of visceral leishmaniasis complicated further by the increasing emergence of drug resistant L. donovani strains warrants fresh investigations into host defense schemes that counter infections. Accordingly, using a mouse model of experimental visceral leishmaniasis we explored the utility of host Wnt5A in restraining L. donovani infection, using both antimony sensitive and antimony resistant L. donovani strains. We found that Wnt5A heterozygous (Wnt5A +/-) mice are more susceptible to L. donovani infection than their wild type (Wnt5A +/+) counterparts as depicted by the respective Leishman Donovan Units (LDU) enumerated from the liver and spleen harvested from infected mice. Higher LDU in Wnt5A +/-mice correlated with increased level of plasma gammaglobulin, liver granuloma and disorganization of splenic germinal centers. Progression of infection in mice by both antimony sensitive and antimony resistant strains of L. donovani could be prevented by activation of Wnt5A signaling as evident from the lowered LDU and gammaglobulin level, and intactness of splenic germinal centers through intravenous administration of rWnt5A prior to L. donovani infection. Wnt5A mediated blockade of L. donovani infection correlated with the preservation of splenic macrophages and activated T cells, and a TH1 like cytokine thrust. Taken together our results indicate that depletion of Wnt5A promotes susceptibility to visceral leishmaniasis and revamping Wnt5A signaling in the host is able to curb L. donovani infection irrespective of antimony sensitivity or resistance and mitigate the progression of visceral leishmaniasis.

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“…In this scenario it is important to understand the intricacies of the hostparasite interactions and how host immunity can be boosted to counter the parasite infection. Keeping in mind the documented role of Wnt5A signaling in the regulation of bacterial infections and immune homeostasis (6)(7)(8)(9)(10), we became interested in evaluating the influence of Wnt5A on L. donovani infection and progression of VL.…”

Section: Introductionmentioning

confidence: 99%

Wnt5A Signaling Blocks Progression of Experimental Visceral Leishmaniasis

et al. 2022

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Visceral leishmaniasis, caused by L. donovani infection is fatal if left untreated. The intrinsic complexity of visceral leishmaniasis complicated further by the increasing emergence of drug resistant L. donovani strains warrants fresh investigations into host defense schemes that counter infections. Accordingly, in a mouse model of experimental visceral leishmaniasis we explored the utility of host Wnt5A in restraining L. donovani infection, using both antimony sensitive and antimony resistant L. donovani strains. We found that Wnt5A heterozygous (Wnt5A +/-) mice are more susceptible to L. donovani infection than their wild type (Wnt5A +/+) counterparts as depicted by the respective Leishman Donovan Units (LDU) enumerated from the liver and spleen harvested from infected mice. Higher LDU in Wnt5A +/- mice correlated with increased plasma gammaglobulin level, incidence of liver granuloma, and disorganization of splenic white pulp. Progression of infection in mice by both antimony sensitive and antimony resistant strains of L. donovani could be prevented by activation of Wnt5A signaling through intravenous administration of rWnt5A prior to L. donovani infection. Wnt5A mediated blockade of L. donovani infection correlated with the preservation of splenic macrophages and activated T cells, and a proinflammatory cytokine bias. Taken together our results indicate that while depletion of Wnt5A promotes susceptibility to visceral leishmaniasis, revamping Wnt5A signaling in the host is able to curb L. donovani infection irrespective of antimony sensitivity or resistance and mitigate the progression of disease.

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Wnt5A-Mediated Actin Organization Regulates Host Response to Bacterial Pathogens and Non-Pathogens

Cited by 13 publications

References 54 publications

Wnt5A Signaling Regulates Gut Bacterial Survival and T cell Homeostasis

Wnt5A Signaling Regulates Gut Bacterial Survival and T cell Homeostasis

Wnt5A Signaling Blocks Progression of Experimental Visceral Leishmaniasis

Wnt5A Signaling Blocks Progression of Experimental Visceral Leishmaniasis

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