Fig. 3. Molecular determinants of asymptomatic bacteriuria.

Asymptomatic bacteriuria (ABU) is explained by both bacterial factors and host determinants that facilitate symbiosis. A | Bacterial factors: ABU strains coexist with their hosts without triggering symptoms. Several mechanisms contribute to this effect. Aa | ABU strains do not provoke a potent innate immune response in the host owing to a lack functional virulence genes. Ab | ABU strains modify the host environment by actively inhibiting host gene expression. They secrete inhibitors of host RNA polymerase II (Pol II) such as NlpD, which targets the Pol II phosphorylation complex and inhibits gene expression, including pro-inflammatory genes. B | Host determinants: Toll-like receptor 4 (TLR4) signalling controls many aspects of the innate response to urinary tract infection. TLR4 signalling is attenuated in patients with ABU. At least two mechanisms contribute to this effect. Ba | Attenuating TLR4 promoter polymorphisms are prevalent in patients with ABU. These polymorphisms reduce TLR4 expression and the inflammatory response to bacteriuria. Bb | Optimal TLR4 activation by lipopolysaccharide (LPS) requires co-receptors, such as CD14 and lymphocyte antigen 96 (MD2). As the bladder epithelium does not express surface CD14, the cells remain refractory to bacterial LPS alone and ABU strains do not efficiently activate TLR4 signalling. Virulence factors such as P fimbriae enable pathogens to overcome the lack of CD14 and trigger a TLR4-mediated inflammatory cascade. MyD88, myeloid differentiation primary response protein 88; PMN, polymorphonuclear neutrophil; TRAM, TRIF-related adaptor molecule; TRIF, Toll/interleukin 1 receptor (TIR)-domain containing adapter-inducing interferon-β.