Sci. Signal., 2 February 2010
Host-Pathogen Interactions Keeping the Host Live
Nancy R. Gough
Science Signaling, AAAS, Washington, DC 20005, USA
Helminths are parasitic worms (flukes) that cause chronic infections in their hosts, an effect that involves the suppression of the proinflammatory T helper cell 1 (Th1) response and induction of the anti-inflammatory Th2 cell response. Helminths secrete cysteine proteases of the papain family, which perform many functions in the parasitic lifestyle, including evasion of the immune response. Donnelly et al. report that the FheCL1 protease secreted by the human liver fluke Fasciola hepatica and the SmB1 protease secreted by the blood fluke Schistosoma mansoni inhibit signaling through macrophage Toll-like receptor 3 (TLR3) to decrease production of inflammatory mediators. Injection of FheCL1 promoted mouse survival to a normally lethal dose of lipopolysaccharide (LPS), a TLR4 agonist, and reduced the serum and peritoneal cavity concentrations of proinflammatory mediators. This appeared to be due to decreased responsiveness of macrophages, because either naïve macrophages exposed to FheCL1 in vitro or macrophages isolated from the peritoneal cavity of mice exposed to either FheCL1 or SmB1 exhibited decreased production of inflammatory mediators in response to LPS. Coapplication of a protease inhibitor or application of a protease-inactive mutant of FheCL1 prevented this reduction in macrophage responsiveness. TLR4 can signal through a MyD88-dependent or a TRIF-dependent pathway, and the TRIF-dependent pathway appeared to be selectively inhibited by FheCL1. To further investigate the effects on TRIF-dependent signaling, the authors investigated the response of macrophages exposed to FheCL1 to the TLR3 agonist poly(I:C), because TLR3 couples only to the TRIF-dependent pathway. TLR3 signaling was reduced in macrophages exposed to FheCL1. Macrophages from mice exposed to FheCL1 did not exhibit any decrease in the abundance of surface receptors involved in LPS signaling—TLR4, MD2, and CD14—nor was there a decrease in the abundance of TRIF. Instead, the abundance of TLR3 was reduced in the macrophages from the mice exposed to FheCL1. In the macrophages from mice injected with FheCL1, FheCL1 was localized to early endosomes, which is also the site of TLR3 (although colocalization experiments were not performed). Thus, FheCL1 appears be internalized and cleaves endosomally localized TLR3. How this compromises the TRIF-mediated signaling downstream of TLR4 remains to be determined but points to an interaction between TRIF-dependent TLR3 and TLR4 signaling that may be exploited by pathogens.
S. Donnelly, S. M. ONeill, C. M. Stack, M. W. Robinson, L. Turnbull, C. Whitchurch, J. P. Dalton, Helminth cysteine proteases inhibit TRIF-dependent activation of macrophages via degradation of TLR3. J. Biol. Chem. 285, 3383–3392 (2010). [Abstract] [Full Text]
Citation: N. R. Gough, Keeping the Host Live. Sci. Signal. 3, ec41 (2010).
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