Article

A Salmonella enterica serovar Typhi plasmid induces rapid and massive apoptosis in infected macrophages

Medical College of Soochow University, Suzhou, China.
Cellular & molecular immunology (Impact Factor: 4.19). 07/2010; 7(4):271-8. DOI: 10.1038/cmi.2010.17
Source: PubMed

ABSTRACT pR(ST98) is a chimeric plasmid isolated from Salmonella enterica serovar Typhi (S. typhi) that mediates the functions of drug resistance and virulence. Previously, we reported that Salmonella plasmid virulence (spv) genes were present in S. typhi. In our current study, we investigated whether plasmid pR(ST98) exhibits significant cytotoxicity in macrophages. pR(ST98) was transferred into the avirulent Salmonella enterica serovar Typhimurium (S. typhimurium) strain RIA to create the transconjugant pR(ST98)/RIA. The standard S. typhimurium virulent strain SR-11, which carries a 100-kb virulence plasmid, was used as a positive control. The bacterial strains were incubated with a murine macrophage-like cell line (J774A.1) in vitro. Apoptosis of J774A.1 cells was examined by electron microscopy and flow cytometry after annexin-V/propidium iodide labeling, and the survival of Salmonella strains in J774A.1 cells was determined. Results showed that macrophages infected with strain pR(ST98)/RIA displayed greater levels of apoptosis than those infected with RIA and that pR(ST98 )may increase bacterial survival in macrophages. Further studies showed that the pR(ST98)-induced death of macrophages was associated with the loss of mitochondrial membrane potential and that pR(ST98 )may activate caspase-9 and then caspase-3. The research data indicate that the virulence of bacteria that contain the pR(ST98) plasmid is enhanced; the presence of this plasmid increases the survival of the bacterial pathogen and acts through the mitochondrial pathway to mediate macrophage apoptosis.

0 Followers
 · 
119 Views
  • Source
    • "This is the case of cytolysis of infected host cells due to pyroptosis (reviewed in Fink and Cookson 2005; Bergsbaken et al. 2009) or apoptotic secondary necrosis (reviewed in Silva 2010a). Pathogen-induced cytolysis of infected host cells has been reported in infections by Y. pestis (Zauberman et al. 2006; Bergsbaken and Cookson 2007; Bi et al. 2009), F. tularensis (Bar-Haim et al. 2008; Lai and Sjostedt 2003; Mariathasan et al. 2005; Henry et al. 2007; Santic et al. 2010), S. Thyphimurium (Brennan and Cookson 2000; Fink et al. 2008; Wu et al. 2010), B. cenocepacia (Kotrange et al. 2011), and B. pseudomallei (Sun et al. 2005). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Classically labeled facultative intracellular pathogens are characterized by the ability to have an intracellular phase in the host, which is required for pathogenicity, while capable of extracellular growth in vitro. The ability of these bacteria to replicate in cell-free conditions is usually assessed by culture in artificial bacteriological media. However, the extracellular growth ability of these pathogens may also be expressed by a phase of extracellular infection in the natural setting of the host with pathologic consequences, an ability that adds to the pathogenic potential of the infectious agent. This infective capability to grow in the extracellular sites of the host represents an additional virulence attribute of those pathogens which may lead to severe outcomes. Here we discuss examples of infectious diseases where the in vivo infective extracellular life is well documented, including infections by Francisella tularensis, Yersinia pestis, Burkholderia pseudomallei, Burkholderia cenocepacia, Salmonella enterica serovar Typhimurium and Edwardsiella tarda. The occurrence of a phase of systemic dissemination with extracellular multiplication during progressive infections by facultative intracellular bacterial pathogens has been underappreciated, with most studies exclusively centered on the intracellular phase of the infections. The investigation of the occurrence of a dual lifestyle in the host among bacterial pathogens in general should be extended and likely will reveal more cases of infectious diseases with a dual infective intracellular/extracellular pattern.
    Immunobiology 06/2012; 218(3). DOI:10.1016/j.imbio.2012.05.011 · 3.18 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Salmonella enterica serovar Typhi (S. typhi) evades from innate immunity by expression of a variety of pathogenic factors. The "pR(ST98)" plasmid of S. typhi is involved in multidrug-resistant and virulence of S. typhi. However, its exact effect on host cell function remains elusive. Dendritic cells (DCs) play an important role in shaping immune response against Salmonella. For the purpose of investigation whether pR(ST98) might target DCs involved in adaptive immune response, murine DCs were infected with S. typhi wild type and mutant strains. S. typhi stimulation resulted in up-regulation of costimulatory molecules on DCs. S. typhi wild type resulted in decreased up-regulation of CD40, CD80, and CD86 expression. Experiments with S. typhi pR(ST98) mutant (S. typhi-Δ-pR(ST98)) and S. typhi-Δ-pR(ST98) with a complemented plasmid encoding pR(ST98) (S. typhi-c-pR(ST98)) revealed that pR(ST98) accounts for inhibition of surface molecule expression and functional maturity. S. typhi-Δ-pR(ST98) gave maximal levels of IL-12 and IFN-γ release compared with wild type S. typhi or the complemented strains. In contrast to IL-12 and IFN-γ, IL-10 secretion by S. typhi-Δ-pR(ST98)-infected DCs was significantly lower than induction by S. typhi wild type. This indicates that immunity in response to pR(ST98) is skewed away from a protective Th1 response. Moreover, infection with S. typhi-Δ-pR(ST98) induced autophagy in DCs. We herein demonstrate S. typhi pR(ST98) plays essential roles in modulating DCs maturation, activation, inflammatory responses, and autophagy. Together, these data prove that pR(ST98) targets functions of DCs that are required for T-cell activation. This might contribute to evasion of adaptive immune responses by S. typhi.
    Current Microbiology 05/2012; 65(2):133-40. DOI:10.1007/s00284-012-0136-1 · 1.36 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Salmonella enterica infections result in diverse clinical manifestations. Typhoid fever, caused by S. enterica serovar Typhi (S. Typhi) and S. Paratyphi A, is a bacteremic illness but whose clinical features differ from other Gram-negative bacteremias. Non-typhoidal Salmonella (NTS) serovars cause self-limiting diarrhea with occasional secondary bacteremia. Primary NTS bacteremia can occur in the immunocompromised host and infants in sub-Saharan Africa. Recent studies on host-pathogen interactions in Salmonellosis using genome sequencing, murine models, and patient studies have provided new insights. The full genome sequences of numerous S. enterica serovars have been determined. The S. Typhi genome, compared to that of S. Typhimurium, harbors many inactivated or disrupted genes. This can partly explain the different immune responses both serovars induce upon entering their host. Similar genome degradation is also observed in the ST313 S. Typhimurium strain implicated in invasive infection in sub-Saharan Africa. Virulence factors, most notably, type III secretion systems, Vi antigen, lipopolysaccharide and other surface polysaccharides, flagella, and various factors essential for the intracellular life cycle of S. enterica have been characterized. Genes for these factors are commonly carried on Salmonella Pathogenicity Islands (SPIs). Plasmids also carry putative virulence-associated genes as well as those responsible for antimicrobial resistance. The interaction of Salmonella pathogen-associated molecular patterns (PAMPs) with Toll-like receptors (TLRs) and NOD-like receptors (NLRs) leads to inflammasome formation, activation, and recruitment of neutrophils and macrophages and the production of pro-inflammatory cytokines, most notably interleukin (IL)-6, IL-1β, tumor necrosis factor (TNF)-α, and interferon-gamma (IFN)-γ. The gut microbiome may be an important modulator of this immune response. S. Typhimurium usually causes a local intestinal immune response, whereas S. Typhi, by preventing neutrophil attraction resulting from activation of TLRs, evades the local response and causes systemic infection. Potential new therapeutic strategies may lead from an increased understanding of infection pathogenesis.
    PLoS Pathogens 10/2012; 8(10):e1002933. DOI:10.1371/journal.ppat.1002933 · 8.06 Impact Factor
Show more

Preview

Download
2 Downloads
Available from