Are bloodstream leukocytes Trojan Horses for the metastasis of Staphylococcus aureus?

Thwaites, Guy; Gant, Vanya

doi:10.1038/nrmicro2508

Cited by 271 publications

(272 citation statements)

References 95 publications

Supporting

Mentioning

269

Contrasting

Unclassified

Order By: Relevance

“…rsp expression is not required for dissemination of S. aureus from the blood or for deep abscess formation, and we have identified and characterized rsp loss-of-function mutants found in human bacteremia. Thus, our data suggest that S. aureus can adopt an attenuated cytotoxic phenotype, with prolonged intracellular residence (51)(52)(53), which permits effective dissemination of the organism with few initial symptoms, followed by deep abscess establishment. The attenuated toxicity phenotype was not noted in isolates from skin and soft tissue infection (17), suggesting that such attenuated toxicity and intracellular survival may be particularly important in bloodstream infection, as opposed to other forms of infection, such as skin and soft tissue infection.…”

Section: Discussionmentioning

confidence: 99%

Natural mutations in a Staphylococcus aureus virulence regulator attenuate cytotoxicity but permit bacteremia and abscess formation

Das

Lindemann

Young

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Staphylococcus aureus is a major bacterial pathogen, which causes severe blood and tissue infections that frequently emerge by autoinfection with asymptomatically carried nose and skin populations. However, recent studies report that bloodstream isolates differ systematically from those found in the nose and skin, exhibiting reduced toxicity toward leukocytes. In two patients, an attenuated toxicity bloodstream infection evolved from an asymptomatically carried high-toxicity nasal strain by loss-of-function mutations in the gene encoding the transcription factor repressor of surface proteins (rsp). Here, we report that rsp knockout mutants lead to global transcriptional and proteomic reprofiling, and they exhibit the greatest signal in a genome-wide screen for genes influencing S. aureus survival in human cells. This effect is likely to be mediated in part via SSR42, a long-noncoding RNA. We show that rsp controls SSR42 expression, is induced by hydrogen peroxide, and is required for normal cytotoxicity and hemolytic activity. Rsp inactivation in laboratory- and bacteremia-derived mutants attenuates toxin production, but up-regulates other immune subversion proteins and reduces lethality during experimental infection. Crucially, inactivation of rsp preserves bacterial dissemination, because it affects neither formation of deep abscesses in mice nor survival in human blood. Thus, we have identified a spontaneously evolving, attenuated-cytotoxicity, nonhemolytic S. aureus phenotype, controlled by a pleiotropic transcriptional regulator/noncoding RNA virulence regulatory system, capable of causing S. aureus bloodstream infections. Such a phenotype could promote deep infection with limited early clinical manifestations, raising concerns that bacterial evolution within the human body may contribute to severe infection.

show abstract

Section: Discussionmentioning

confidence: 99%

Natural mutations in a Staphylococcus aureus virulence regulator attenuate cytotoxicity but permit bacteremia and abscess formation

Das

Lindemann

Young

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Following 72 h of infection with F. alocis, the majority of, but not all, neutrophils were apoptotic. Surviving neutrophils could be involved in transport of F. alocis to remote sites, as has been demonstrated for other pathogenic microorganisms, such as Mycobacterium tuberculosis, Burkholderia pseudomallei, and Leishmania major (39)(40)(41)(42). It has been reported that during inflammation, a portion of the neutrophils that have already left the circulation and transmigrated to the tissues can migrate back to the circulation (43).…”

Section: Discussionmentioning

confidence: 99%

Filifactor alocis Infection and Inflammatory Responses in the Mouse Subcutaneous Chamber Model

Wang

Jotwani

et al. 2014

Infect Immun

View full text Add to dashboard Cite

dRecent microbiome studies have implicated a role for Filifactor alocis in periodontal disease. In this study, we investigated the colonization and survival properties of F. alocis in a mouse subcutaneous chamber model of infection and characterized host innate immune responses. An infection of 10 9 F. alocis successfully colonized all chambers; however, the infection was cleared after 72 h. F. alocis elicited a local inflammatory response with neutrophils recruited into the chambers at 2 h postinfection along with an increase in levels of the proinflammatory cytokines interleukin 1␤ (IL-1␤), IL-6, and tumor necrosis factor (TNF). F. alocis also induced apoptosis in chamber epithelial cells and neutrophils. Consistent with resolution of infection, neutrophil numbers and cytokine levels returned to baseline by 72 h. Fluorescent in situ hybridization (FISH) and quantitative PCR demonstrated that F. alocis exited the chambers and spread to the spleen, liver, lung, and kidney. Massive neutrophil infiltration was observed in the spleen and lungs, and the recruited neutrophils were in close proximity to the infecting bacteria. Significant epithelial injury was observed in the kidneys. Infection of all tissues was resolved after 7 days. This first in vivo study of the pathogenicity of F. alocis shows that in the chamber model the organism can establish a proinflammatory, proapoptotic local infection which is rapidly resolved by the host concordant with neutrophil influx. Moreover, F. alocis can spread to, and transiently infect, remote tissues where neutrophils can also be recruited.

show abstract

“…Intracellular survival within phagocytes may contribute to this disease progression by reducing the effectiveness of phagocyte clearance. In addition, some pathogens actively exploit phagocytes to facilitate traffic between host tissues, and it is possible that a related process may underlie GBS dissemination (37,48).…”

Section: Discussionmentioning

confidence: 99%

The CovS/CovR Acid Response Regulator Is Required for Intracellular Survival of Group B Streptococcus in Macrophages

et al. 2012

View full text Add to dashboard Cite

ABSTRACTGroup BStreptococcus(GBS) is a leading cause of neonatal meningitis and septicemia. The ability of this organism to survive inside phagocytic cells is poorly understood but thought to be an important step for the establishment of disease in the host. Here, we demonstrate that GBS shows prolonged survival within J774 macrophages and that the capacity to survive is not significantly changed across a diverse range of strains representing different serotypes, multilocus sequence types (MLST), and sites of clinical isolation. Using staining for the lysosome-associated membrane protein (LAMP) and by pharmacological inhibition of phagosome acidification, we demonstrate that streptococci reside in a phagosome and that acidification of the phagosome is required for GBS to survive intracellularly. Moreover, we show that the GBS two-component system CovS/CovR, which is the major acid response regulator in this organism, is required for survival inside the phagosome.

show abstract

Are bloodstream leukocytes Trojan Horses for the metastasis of Staphylococcus aureus?

Cited by 271 publications

References 95 publications

Natural mutations in a Staphylococcus aureus virulence regulator attenuate cytotoxicity but permit bacteremia and abscess formation

Natural mutations in a Staphylococcus aureus virulence regulator attenuate cytotoxicity but permit bacteremia and abscess formation

Filifactor alocis Infection and Inflammatory Responses in the Mouse Subcutaneous Chamber Model

The CovS/CovR Acid Response Regulator Is Required for Intracellular Survival of Group B Streptococcus in Macrophages

Contact Info

Product

Resources

About