Interleukin-4 activated macrophages mediate immunity to filarial helminth infection by sustaining CCR3-dependent eosinophilia

Abstract

Eosinophils are effectors in immunity to tissue helminths but also induce allergic immunopathology. Mechanisms of eosinophilia in non-mucosal tissues during infection remain unresolved. Here we identify a pivotal function of tissue macrophages (Mϕ) in eosinophil anti-helminth immunity using a BALB/c mouse intra-peritoneal Brugia malayi filarial infection model. Eosinophilia, via C-C motif chemokine receptor (CCR)3, was necessary for immunity as CCR3 and eosinophil impairments rendered mice susceptible to chronic filarial infection. Post-infection, peritoneal Mϕ populations proliferated and became alternatively-activated (AAMϕ). Filarial AAMϕ development required adaptive immunity and interleukin-4 receptor-alpha. Depletion of Mϕ prior to infection suppressed eosinophilia and facilitated worm survival. Add back of filarial AAMϕ in Mϕ-depleted mice recapitulated a vigorous eosinophilia. Transfer of filarial AAMϕ into Severe-Combined Immune Deficient mice mediated immunological resistance in an eosinophil-dependent manner. Exogenous IL-4 delivery recapitulated tissue AAMϕ expansions, sustained eosinophilia and mediated immunological resistance in Mϕ-intact SCID mice. Co-culturing Brugia with filarial AAMϕ and/or filarial-recruited eosinophils confirmed eosinophils as the larvicidal cell type. Our data demonstrates that IL-4/IL-4Rα activated AAMϕ orchestrate eosinophil immunity to filarial tissue helminth infection.

Eosinophil-Mediated Immune Control of Adult Filarial Nematode Infection Can Proceed in the Absence of IL-4 Receptor Signaling

“…The mechanisms coordinating eosinophil recruitment to the site of infection remain to be resolved. In a previous investigation, we reported that macrophages polarized to an alternatively activated phenotype through IL-4R activation mediated immunity to the human lymphatic filarial pathogen, Brugia malayi, by sustaining a vigorous CCR3-dependent eosinophilia at the site of infection (18). We demonstrated that this mechanism substantially influenced numbers of infectious-stage larvae surviving to the immature adult developmental stage.…”

Preclinical development of an oral anti- Wolbachia macrolide drug for the treatment of lymphatic filariasis and onchocerciasis

“…We tested the efficacy of tylosin A in two mouse models of lymphatic filariasis (9,10). In the first model, interleukin-4 receptor alphadeficient (IL-4R −/− ) BALB/c immunodeficient mice were infected with third-stage larvae (L3) of B. malayi, a human lymphatic filarial pathogen (9). In the second model, BALB/c mice were infected with L3 larvae of Litomosoides sigmodontis, which naturally infects cotton rats (10).…”

“…The efficacy of A-1535469 and A-1574083 against B. malayi developing larvae (L3 to L4 stage) in susceptible IL-4R −/− BALB/c immunodeficient mice was compared to that of tylosin A and a human equivalent dose of doxycycline ( fig. S2) (9,11). Fourteen-day oral dosing with A-1535469 at ≥25 mg/kg delivered superior efficacy versus doxycycline (50 mg/kg) [Kruskal-Wallis one-way analysis of variance (ANOVA) statistic = 90.7, P < 0.0001; Fig.…”

Comparison of immune responses to Loa loa stage-specific antigen extracts in Loa loa-exposed BALB/c mice upon clearance of infection

“…Thus, to begin deciphering host immunity against L. loa, we analysed immune responses in immune-competent BALB/c mice upon exposure to different L. loa developmental stages. Previously, it was shown that L. loa cannot be maintained in wildtype BALB/c mice probably due to type-2 associated immunity [23,36] that clears L. loa larvae after 1 week [24]. Indeed, we did not isolate any L. loa developmental stages 42 days pi which was reflected in the relatively comparable levels of systemic cytokine, chemokine and immunoglobulins between the infected groups.…”