Mikael Rhen Group

Salmonella enterica as a model for intracellular parasitism

Salmonella enterica causes annually some 350 000 deaths associated with an ever increasing antibiotic resistance. This research project details the infection pathogenesis in order to enable prevention and treatment regimens for salmonellosis.

The bacterial species Salmonella enterica includes more than 2000 so-called serovars, many of which infect man and animals, possibly even plants. In man, S. enterica mainly causes two types of diseases; a rather common variant in the form of an inflammatory gastroenteritis, and a severe form termed typhoid or paratyphoid fever affecting annually no less than 20 million individuals. On top of this burden, S. enterica is increasingly becoming resistant to antibiotics.

S. enterica is a bacterium closely related to Escherichia coli and easily accessible in terms of biochemical and genetic probing. A very hallmark of salmonellosis is the tight interplay between the pathogen and host cells. Thus, S. enterica has served as a classical model organism not only for dissecting basic cellular biochemical and genetic principles, but also for dissecting aspects of bacterial intracellular parasitism. This prospect of combining basic biochemistry and bacterial genetics with microbial pathogenesis provides the basis of our very research interests.

We have previously demonstrated that S. enterica experience dramatic differential in environment as it transits form an external milieu into the intravacuolar compartment of mammalian cells. In part, this environmental shift is primed by innate host defence measures, such as the production of reactive oxygen (ROS) and nitrogen species. This had leaded us to probe for the involvement of various oxidoprotective mechanisms in the virulence of the bacteria. Our results indicate that S. enterica possesses several overlapping measures for protection in the form of enzymes degrading ROS and repairing ROS-mediated protein damage. In addition, some of the enzymes involved, such as the thioredoxin 1 and the ScsABCD oxidoreductases, are also engaged in regulating virulence.

Apart from damaging protein and lipids, ROS-species also affect nucleic acids. In E. coli and man RNA damaged by oxidation is degraded by an exoribonuclease termed polybucleotide phosphorylase (PNPase). In S. enterica the gene for PNPase (pnp) is tightly linked to a gene coding for a lipoprotein NlpI and an RNA helicase DeaD. Mutational inactivation of either PNPase or NlpI results in redox-associated phenotypes regarding bacterial virulence. Thus, a further ambition is to probe to what extent RNA degradation in S. enterica is affected by oxidative stress, and to what extent PNPase, NlpI and DeaD contribute to the regulation of virulence gene expression, notably under oxidative stress.

In all, we wish to detail the interplay between bacterial 'house-keeping' functions, such redox management, and the very ability of bacteria to cause disease and colonization. Furthermore, as the antibacterial activities of selected antibiotics are connected to induction of endogenous redox stress, our findings may also aid the development of future regimens for antibacterial treatment.

Publications

BcsZ inhibits biofilm phenotypes and promotes virulence by blocking cellulose production in Salmonella enterica serovar Typhimurium.
Ahmad I, Rouf S, Sun L, Cimdins A, Shafeeq S, Le Guyon S, et al
Microb. Cell Fact. 2016 Oct;15(1):177

The Typhoid Toxin Promotes Host Survival and the Establishment of a Persistent Asymptomatic Infection.
Del Bel Belluz L, Guidi R, Pateras I, Levi L, Mihaljevic B, Rouf S, et al
PLoS Pathog. 2016 Apr;12(4):e1005528

CD244 is expressed on dendritic cells and regulates their functions.
Georgoudaki A, Khodabandeh S, Puiac S, Persson C, Larsson M, Lind M, et al
Immunol. Cell Biol. 2015 Jul;93(6):581-90

Fitness of Salmonella mutants resistant to antimicrobial peptides.
Lofton H, Anwar N, Rhen M, Andersson D
J. Antimicrob. Chemother. 2015 Feb;70(2):432-40

Modulation of biofilm-formation in Salmonella enterica serovar Typhimurium by the periplasmic DsbA/DsbB oxidoreductase system requires the GGDEF-EAL domain protein STM3615.
Anwar N, Rouf S, Römling U, Rhen M
PLoS ONE 2014 ;9(8):e106095

Dissecting the cyclic di-guanylate monophosphate signalling network regulating motility in Salmonella enterica serovar Typhimurium.
Le Guyon S, Simm R, Rehn M, Römling U
Environ. Microbiol. 2015 Apr;17(4):1310-20

Independent bottlenecks characterize colonization of systemic compartments and gut lymphoid tissue by salmonella.
Lim C, Voedisch S, Wahl B, Rouf S, Geffers R, Rhen M, et al
PLoS Pathog. 2014 Jul;10(7):e1004270

The EAL-like protein STM1697 regulates virulence phenotypes, motility and biofilm formation in Salmonella typhimurium.
Ahmad I, Wigren E, Le Guyon S, Vekkeli S, Blanka A, El Mouali Y, et al
Mol. Microbiol. 2013 Dec;90(6):1216-32

Salmonella enterica delivers its genotoxin through outer membrane vesicles secreted from infected cells.
Guidi R, Levi L, Rouf S, Puiac S, Rhen M, Frisan T
Cell. Microbiol. 2013 Dec;15(12):2034-50

Oxidoreductases that act as conditional virulence suppressors in Salmonella enterica serovar Typhimurium.
Anwar N, Sem X, Rhen M
PLoS ONE 2013 ;8(6):e64948

Biotin sulfoxide reductase contributes to oxidative stress tolerance and virulence in Salmonella enterica serovar Typhimurium.
Denkel L, Rhen M, Bange F
Microbiology (Reading, Engl.) 2013 Jul;159(Pt 7):1447-58

Pathogenicity of Salmonella enterica in Caenorhabditis elegans relies on disseminated oxidative stress in the infected host.
Sem X, Rhen M
PLoS ONE 2012 ;7(9):e45417

Modulation of Caenorhabditis elegans infection sensitivity by the LIN-7 cell junction protein.
Sem X, Kreisberg J, Kawli T, Tan M, Rhen M, Tan P
Cell. Microbiol. 2012 Oct;14(10):1584-99

Tissue microbiology provides a coherent picture of infection.
Richter-Dahlfors A, Rhen M, Udekwu K
Curr. Opin. Microbiol. 2012 Feb;15(1):15-22

Genetic analysis of the pnp-deaD genetic region reveals membrane lipoprotein NlpI as an independent participant in cold acclimatization of Salmonella enterica serovar Typhimurium.
Rouf S, Anwar N, Clements M, Rhen M
FEMS Microbiol. Lett. 2011 Dec;325(1):56-63

Comparative tissue transcriptomics reveal prompt inter-organ communication in response to local bacterial kidney infection.
Boekel J, Källskog O, Rydén-Aulin M, Rhen M, Richter-Dahlfors A
BMC Genomics 2011 Feb;12():123

Helicobacter pylori defines local immune response through interaction with dendritic cells.
Andres S, Schmidt H, Mitchell H, Rhen M, Maeurer M, Engstrand L
FEMS Immunol. Med. Microbiol. 2011 Mar;61(2):168-78

Opposing contributions of polynucleotide phosphorylase and the membrane protein NlpI to biofilm formation by Salmonella enterica serovar Typhimurium.
Rouf S, Ahmad I, Anwar N, Vodnala S, Kader A, Römling U, et al
J. Bacteriol. 2011 Jan;193(2):580-2

Thiol peroxidase protects Salmonella enterica from hydrogen peroxide stress in vitro and facilitates intracellular growth.
Horst S, Jaeger T, Denkel L, Rouf S, Rhen M, Bange F
J. Bacteriol. 2010 Jun;192(11):2929-32

Thioredoxin 1 participates in the activity of the Salmonella enterica serovar Typhimurium pathogenicity island 2 type III secretion system.
Negrea A, Bjur E, Puiac S, Ygberg S, Aslund F, Rhen M
J. Bacteriol. 2009 Nov;191(22):6918-27

Cyclic di-GMP signalling controls virulence properties of Salmonella enterica serovar Typhimurium at the mucosal lining.
Lamprokostopoulou A, Monteiro C, Rhen M, Römling U
Environ. Microbiol. 2010 Jan;12(1):40-53

Omeprazole antagonizes virulence and inflammation in Salmonella enterica-infected RAW264.7 cells.
Puiac S, Negrea A, Richter-Dahlfors A, Plant L, Rhen M
Antimicrob. Agents Chemother. 2009 Jun;53(6):2402-9

Genetic analysis of colistin resistance in Salmonella enterica serovar Typhimurium.
Sun S, Negrea A, Rhen M, Andersson D
Antimicrob. Agents Chemother. 2009 Jun;53(6):2298-305

 

Selected publications 1997-2006

Selected publications 1997-2006 (pdf)

 

Group Members

 

Professor

Mikael Rhen

Telefon: 08-517 712 13
Enhet: Mikael Rhen grupp
E-post: Mikael.Rhen@ki.se

Postdoc

Marie Wrande

Enhet: Mikael Rhen grupp
E-post: marie.wrande@ki.se

FOU-praktikant

Kim Vestö

Enhet: Mikael Rhen grupp
E-post: kim.vesto@ki.se

Mikael RhenProfessor
Kim VestöFOU-praktikant, Forskarstuderande
Marie WrandePostdoc