Interleukin-6 mediates delirium-like phenotypes in a murine model of urinary tract infection

Abstract Background Urinary tract infection (UTI) is frequently implicated as a precipitant of delirium, which refers to an acute confusional state that is associated with high mortality, increased length of stay, and long-term cognitive decline. The pathogenesis of delirium is thought to involve cytokine-mediated neuronal dysfunction of the frontal cortex and hippocampus. We hypothesized that systemic IL-6 inhibition would mitigate delirium-like phenotypes in a mouse model of UTI. Methods C57/BL6 mice were randomized to either: (1) non-UTI control, (2) UTI, and (3) UTI + anti-IL-6 antibody. UTI was induced by transurethral inoculation of 1 × 108Escherichia coli. Frontal cortex and hippocampus-mediated behaviors were evaluated using functional testing and corresponding structural changes were evaluated via quantification of neuronal cleaved caspase-3 (CC3) by immunohistochemistry and western blot. IL-6 in the brain and plasma were evaluated using immunohistochemistry, ELISA, and RT-PCR. Results Compared to non-UTI control mice, mice with UTI demonstrated significantly greater impairments in frontal and hippocampus-mediated behaviors, specifically increased thigmotaxis in Open Field (p < 0.05) and reduced spontaneous alternations in Y-maze (p < 0.01), while treatment of UTI mice with systemic anti-IL-6 fully reversed these functional impairments. These behavioral impairments correlated with frontal and hippocampal neuronal CC3 changes, with significantly increased frontal and hippocampal CC3 in UTI mice compared to non-UTI controls (p < 0.0001), and full reversal of UTI-induced CC3 neuronal changes following treatment with systemic anti-IL-6 antibody (p < 0.0001). Plasma IL-6 was significantly elevated in UTI mice compared to non-UTI controls (p < 0.01) and there were positive and significant correlations between plasma IL-6 and frontal CC3 (r2 = 0.5087/p = 0.0028) and frontal IL-6 and CC3 (r2 = 0.2653, p < 0.0001). Conclusions These data provide evidence for a role for IL-6 in mediating delirium-like phenotypes in a mouse model of UTI. These findings provide pre-clinical justification for clinical investigations of IL-6 inhibitors to treat UTI-induced delirium.

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Proteus mirabilis fimbriae: construction of an isogenic pmfA mutant and analysis of virulence in a CBA mouse model of ascending urinary tract infection.

Infection and Immunity ◽

10.1128/iai.62.2.536-542.1994 ◽

1994 ◽

Vol 62 (2) ◽

pp. 536-542 ◽

Cited By ~ 45

Author(s):

G Massad ◽

C V Lockatell ◽

D E Johnson ◽

H L Mobley

Keyword(s):

Urinary Tract Infection ◽

Urinary Tract ◽

Tract Infection ◽

Mouse Model ◽

Proteus Mirabilis

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The PavA-like Fibronectin-Binding Protein of Enterococcus faecalis, EfbA, Is Important for Virulence in a Mouse Model of Ascending Urinary Tract Infection

The Journal of Infectious Diseases ◽

10.1093/infdis/jis440 ◽

2012 ◽

Vol 206 (6) ◽

pp. 952-960 ◽

Cited By ~ 27

Author(s):

R. Torelli ◽

P. Serror ◽

F. Bugli ◽

Francesco Paroni Sterbini ◽

A. R. Florio ◽

...

Keyword(s):

Urinary Tract Infection ◽

Urinary Tract ◽

Tract Infection ◽

Mouse Model ◽

Enterococcus Faecalis ◽

Binding Protein ◽

Fibronectin Binding Protein ◽

Fibronectin Binding

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Role of Ethanolamine Utilization Genes in Host Colonization during Urinary Tract Infection

Infection and Immunity ◽

10.1128/iai.00542-17 ◽

2017 ◽

Vol 86 (3) ◽

Cited By ~ 5

Author(s):

Anna Sintsova ◽

Sara Smith ◽

Sargurunathan Subashchandrabose ◽

Harry L. Mobley

Keyword(s):

Urinary Tract Infection ◽

Urinary Tract ◽

Tract Infection ◽

Mouse Model ◽

Virulence Determinants ◽

Content Type ◽

Immunocompromised Mouse ◽

Common Infection ◽

Increased Susceptibility

ABSTRACTUrinary tract infection (UTI) is the second most common infection in humans, making it a global health priority. Nearly half of all women will experience a symptomatic UTI, with uropathogenicEscherichia coli(UPEC) being the major causative agent of the infection. Although there has been extensive research on UPEC virulence determinants, the importance of host-specific metabolism remains understudied. We report here that UPEC upregulates the expression of ethanolamine utilization genes during uncomplicated UTIs in humans. We further show that UPEC ethanolamine metabolism is required for effective bladder colonization in the mouse model of ascending UTI and is dispensable for bladder colonization in an immunocompromised mouse model of UTI. We demonstrate that although ethanolamine metabolism mutants do not show increased susceptibility to antimicrobial responses of neutrophils, this metabolic pathway is important for surviving the innate immune system during UTI. This study reveals a novel aspect of UPEC metabolism in the host and provides evidence for an underappreciated link between bacterial metabolism and the host immune response.

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Metabolic phenotyping in the mouse model of urinary tract infection shows that 3-hydroxybutyrate in plasma is associated with infection

PLoS ONE ◽

10.1371/journal.pone.0186497 ◽

2017 ◽

Vol 12 (10) ◽

pp. e0186497 ◽

Cited By ~ 3

Author(s):

Pei Han ◽

Yong Huang ◽

Yumin Xie ◽

Wu Yang ◽

Yaoyao Wang ◽

...

Keyword(s):

Urinary Tract Infection ◽

Urinary Tract ◽

Tract Infection ◽

Mouse Model ◽

Metabolic Phenotyping

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Loss of Regulatory Protein RfaH Attenuates Virulence of Uropathogenic Escherichia coli

Infection and Immunity ◽

10.1128/iai.70.8.4406-4413.2002 ◽

2002 ◽

Vol 70 (8) ◽

pp. 4406-4413 ◽

Cited By ~ 67

Author(s):

Gábor Nagy ◽

Ulrich Dobrindt ◽

György Schneider ◽

A. Salam Khan ◽

Jörg Hacker ◽

...

Keyword(s):

Escherichia Coli ◽

Urinary Tract Infection ◽

Urinary Tract ◽

Tract Infection ◽

Mouse Model ◽

Type Strain ◽

Wild Type Strain ◽

Regulatory Protein ◽

Wild Type ◽

Serovar Typhimurium

ABSTRACT RfaH is a regulatory protein in Escherichia coli and Salmonella enterica serovar Typhimurium. Although it enhances expression of different factors that are proposed to play a role in bacterial virulence, a direct effect of RfaH on virulence has not been investigated so far. We report that inactivation of rfaH dramatically decreases the virulence of uropathogenic E. coli strain 536 in an ascending mouse model of urinary tract infection. The mortality rate caused by the wild-type strain in this assay is 100%, whereas that of its isogenic rfaH mutant does not exceed 18%. In the case of coinfection, the wild-type strain 536 shows higher potential to colonize the urinary tract even when it is outnumbered 100-fold by its rfaH mutant in the inoculum. In contrast to the wild-type strain, serum resistance of strain 536rfaH::cat is fully abolished. Furthermore, we give evidence that, besides a major decrease in the amount of hemin receptor ChuA (G. Nagy, U. Dobrindt, M. Kupfer, L. Emody, H. Karch, and J. Hacker, Infect. Immun. 69:1924-1928, 2001), loss of the RfaH protein results in an altered lipopolysaccharide phenotype as well as decreased expression of K15 capsule and alpha-hemolysin, whereas levels of other pathogenicity factors such as siderophores, flagella, Prf, and S fimbriae appear to be unaltered in strain 536rfaH::cat in comparison to the wild-type strain. trans complementation of the mutant strain with the rfaH gene restores wild-type levels of the affected virulence factors and consequently restitutes virulence in the mouse model of ascending urinary tract infection.

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