Chronic filarial infection provides protection against bacterial sepsis by functionally reprogramming macrophages

PLoS Pathog. 2015 Jan 22;11(1):e1004616. doi: 10.1371/journal.ppat.1004616. eCollection 2015 Jan.

Abstract

Helminths immunomodulate their hosts and induce a regulatory, anti-inflammatory milieu that prevents allergies and autoimmune diseases. Helminth immunomodulation may benefit sepsis outcome by preventing exacerbated inflammation and severe pathology, but the influence on bacterial clearance remains unclear. To address this, mice were chronically infected with the filarial nematode Litomosoides sigmodontis (L.s.) and the outcome of acute systemic inflammation caused by i.p. Escherichia coli injection was determined. L.s. infection significantly improved E. coli-induced hypothermia, bacterial clearance and sepsis survival and correlated with reduced concentrations of associated pro-inflammatory cytokines/chemokines and a less pronounced pro-inflammatory macrophage gene expression profile. Improved sepsis outcome in L.s.-infected animals was mediated by macrophages, but independent of the alternatively activated macrophage subset. Endosymbiotic Wolbachia bacteria that are present in most human pathogenic filariae, as well as L.s., signal via TLR2 and modulate macrophage function. Here, gene expression profiles of peritoneal macrophages from L.s.-infected mice revealed a downregulation of genes involved in TLR signaling, and pulsing of macrophages in vitro with L.s. extract reduced LPS-triggered activation. Subsequent transfer improved sepsis outcome in naïve mice in a Wolbachia- and TLR2-dependent manner. In vivo, phagocytosis was increased in macrophages from L.s.-infected wild type, but not TLR2-deficient animals. In association, L.s. infection neither improved bacterial clearance in TLR2-deficient animals nor ameliorated E. coli-induced hypothermia and sepsis survival. These results indicate that chronic L.s. infection has a dual beneficial effect on bacterial sepsis, reducing pro-inflammatory immune responses and improving bacterial control. Thus, helminths and their antigens may not only improve the outcome of autoimmune and allergic diseases, but may also present new therapeutic approaches for acute inflammatory diseases that do not impair bacterial control.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chronic Disease
  • Coinfection
  • Escherichia coli / immunology*
  • Escherichia coli Infections / immunology*
  • Escherichia coli Infections / prevention & control
  • Female
  • Filariasis / immunology*
  • Filarioidea / immunology*
  • Filarioidea / microbiology
  • Gene Expression Regulation / immunology
  • Macrophages, Peritoneal / immunology*
  • Macrophages, Peritoneal / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Sepsis / immunology
  • Sepsis / prevention & control*
  • Wolbachia / immunology

Grant support

This work was funded by the German Research Foundation (HU 2144/1–1); intramural funding by the University Hospital of Bonn (BONFOR, 2010–1–16 and 2011–1–10); and the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme FP7/2007–2013 under Research Executive Agency Grant GA 276704. AB was supported by the German Academic Exchange Service (DAAD) and BCB was supported by the Jürgen Manchot Stiftung, Düsseldorf. AH is a member of the German Centre for Infection Research (DZIF), and of the Excellence Cluster Immunosensation (DFG, EXC 1023).