Vancomycin-resistant enterococci exploit antibiotic-induced innate immune deficits

Brandl, K. et al., Nature 455 (7214), 804-807 (2008).

Speaker: Kai-yun Lu (呂凱筠)                                       Time: 15:00~16:00, Feb. 25, 2009

Commentator: Dr. Chi-Chang Shieh (謝奇璋醫師)        Place: Room 601

Abstract:

     Infection with highly antibiotic-resistant bacteria, such as vancomycin-resistant Enterococcus (VRE) , is an increasing problem in hospitalized patients.¹ Treatment of such infections with antibiotics kills the commensal flora as well, making patients more susceptible to nasty drug-resistant bacteria. How antibiotic-mediated elimination of commensal bacteria promote the infection of antibiotic-resistant bacteria remains unclear. Previous work by the author had demonstrated that RgeIIIγ (also known as Reg3g), a secreted C-type lectin with potent bactericidal activity against Gram-positive bacteria², is induced by commensal microbes.³ To investigate the defense of commensal microbes against pathogen, the authors exposed broad spectrum antibiotics-treated mice to VRE. The results revealed significantly enhanced VRE intestinal colonization. In mice ileal loop model, treatment of antibiotics reduced RegIIIγ mRNA and protein expression, whereas exogenous RegIIIγ markedly diminished VRE survival, which suggests that RegIIIγ levels correlate with VRE susceptibility. Antibiotic-treated mice showed increasing RegIIIγ expression and luminal killing of VRE after oral administration of lipopolysaccharide (LPS) but not lipoteichoic acid (LTA). Delayed LPS treatment of antibiotic-treated mice also restores RegIIIγ levels and VRE killing. Based on these observations, the authors demonstrated that administration of broad-spectrum antibiotics compromises intestinal innate immune defenses by eliminating commensal microbes. This could diminish the expression of antimicrobial molecules such as RegIIIγ, and lead to increase susceptibility to antibiotic-resistant bacteria. Thus specific induction of antimicrobial molecules could be a potential therapeutic approach.

References:

¹           Brandl, K. et al., Vancomycin-resistant enterococci exploit antibiotic-induced innate immune deficits. Nature 455 (7214), 804-807 (2008).

²           Cash, H.L., Whitham, C.V., Behrendt, C.L., & Hooper, L.V., Symbiotic bacteria direct expression of an intestinal bactericidal lectin. Science 313 (5790), 1126-1130 (2006).

³           Brandl, K., Plitas, G., Schnabl, B., DeMatteo, R.P., & Pamer, E.G., MyD88-mediated signals induce the bactericidal lectin RegIII gamma and protect mice against intestinal Listeria monocytogenes infection. J Exp Med 204 (8), 1891-1900 (2007).