Specificity for Human Hemoglobin Enhances Staphylococcus aureus Infection

Pishchany, Gleb; McCoy, Amanda L.; Torres, Victor J.; Krause, Jens C.; Crowe, James E.; Fabry, Mary E.; Skaar, Eric P.

doi:10.1016/j.chom.2010.11.002

Cited by 128 publications

(150 citation statements)

References 31 publications

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“…Recognition of host hemoglobin during infection is the crucial initiating step of this process and occurs via the staphylococcal hemoglobin receptor IsdB (9). Moreover, the IsdB-hemoglobin interaction is critical to staphylococcal pathogenesis in a murine model of infection (10,42,49). Consistent with this, IsdB is highly immunogenic and has garnered attention as a potential staphylococcal vaccine target (53,54).…”

Section: Discussionmentioning

confidence: 67%

“…Hemoglobin binding by S. aureus strains was assessed as described previously (10). Briefly, hemoglobin was purified from human blood obtained from anonymous donors.…”

Section: Methodsmentioning

confidence: 99%

“…Host hemoglobin is primarily targeted through specific recognition by the staphylococcal hemoglobin receptor IsdB (9). IsdB has evolved to preferentially recognize human hemoglobin over hemoglobin from other animal species, indicating that interaction with this molecule may contribute to the species specificity of this pathogen (10). Upon hemoglobin binding, IsdB extracts heme and transfers it to IsdA or IsdC, which shuttle the molecule through the thick peptidoglycan layer to the membrane transport system, IsdDEF (11).…”

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confidence: 99%

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Regulation of Host Hemoglobin Binding by the Staphylococcus aureus Clp Proteolytic System

et al. 2013

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Protein turnover is a key process for bacterial survival mediated by intracellular proteases. Proteolytic degradation reduces the levels of unfolded and misfolded peptides that accumulate in the cell during stress conditions. Three intracellular proteases, ClpP, HslV, and FtsH, have been identified in the Gram-positive bacterium Staphylococcus aureus, a pathogen responsible for significant morbidity and mortality worldwide. Consistent with their crucial role in protein turnover, ClpP, HslV, and FtsH affect a number of cellular processes, including metabolism, stress responses, and virulence. The ClpP protease is believed to be the principal degradation machinery in S. aureus. This study sought to identify the effect of the Clp protease on the iron-regulated surface determinant (Isd) system, which extracts heme-iron from host hemoglobin during infection and is critical to S. aureus pathogenesis. Inactivation of components of the Clp protease alters abundance of several Isd proteins, including the hemoglobin receptor IsdB. Furthermore, the observed changes in IsdB abundance are the result of transcriptional regulation, since transcription of isdB is decreased by clpP or clpX inactivation. In contrast, inactivation of clpC enhances isdB transcription and protein abundance. Loss of clpP or clpX impairs host hemoglobin binding and utilization and results in severe virulence defects in a systemic mouse model of infection. These findings suggest that the Clp proteolytic system is important for regulating nutrient iron acquisition in S. aureus. The Clp protease and Isd complex are widely conserved in bacteria; therefore, these data reveal a novel Clp-dependent regulation pathway that may be present in other bacterial pathogens.

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Section: Discussionmentioning

confidence: 67%

“…Hemoglobin binding by S. aureus strains was assessed as described previously (10). Briefly, hemoglobin was purified from human blood obtained from anonymous donors.…”

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Regulation of Host Hemoglobin Binding by the Staphylococcus aureus Clp Proteolytic System

et al. 2013

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“…Importantly, IsdB represents an example of S. aureus' evolution as a human-specific pathogen. IsdB preferentially binds human hemoglobin (13); therefore, the Isd system is a logical target for intervention against S. aureus. While active IsdB immunization of patients prior to thoracic surgery was not efficacious in a phase III clinical trial (14), other approaches to manipulate the heme biosynthesis pathway may hold promise.…”

Section: Metabolic and Nutritional Pathwaysmentioning

confidence: 99%

Targeting fundamental pathways to disrupt Staphylococcus aureus survival: clinical implications of recent discoveries

Thomsen¹,

Liu²

2018

JCI Insight

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“…Certain organisms (Haemophilus influenzae, Salmonella typhi, Vibrio cholera, and numerous others) are strictly pathogenic in humans, while others, such as Listeria monocytogenes, show a more intermediate level of host specificity 1 . Host specificity has been documented in many aspects of pathogenesis, including colonization 2 , dissemination 3 , immune evasion 4 , and nutrient acquisition 5 . Thus, it is of utmost importance to select optimal host model systems.…”

Section: Introductionmentioning

confidence: 99%

Human Placental and Decidual Organ Cultures to Study Infections at the Maternal-fetal Interface

Rizzuto

Kapidzic

Gormley

et al. 2016

JoVE

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Citation: Rizzuto, G.A., Kapidzic, M., Gormley, M., Bakardjiev, A.I. Human Placental and Decidual Organ Cultures to Study Infections at the Maternal-fetal Interface. J. Vis. Exp. (113), e54237, doi:10.3791/54237 (2016). AbstractThe placenta shows a large degree of interspecies anatomic variability. To best understand biology and pathophysiology of the human placenta, it is imperative to design experiments using human cells and tissues. An advantage of organ culture is maintenance of three-dimensional (3D) structural organization and extracellular matrix. The goal of the method described here is successful establishment of ex vivo human gestational tissue organ cultures and their healthy culture maintenance for 72-96 hr. The protocol details the immediate processing of researchconsented, placental and decidual specimens fresh from the operating suite. These are abundant specimens that would otherwise be discarded. Detailed instructions on the sterile collection of these samples, including morphologic details on how to select appropriate tissues to establish 3D organ cultures, is provided. Placental villous and decidual tissues are microdissected into 2-3 mm 3 pieces and placed separately on matrixlined transwell filters and cultured for several days. Villous and decidual organ cultures are well suited for the study of human host-pathogen interaction. As compared to other model organisms, these human cultures are particularly advantageous to examine mechanism of infection for pathogens that demonstrate variable patterns of host specificity. As an example, we demonstrate infection of placental and decidual organ cultures with the clinically relevant, facultative intracellular bacterial pathogen Listeria monocytogenes.

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Specificity for Human Hemoglobin Enhances Staphylococcus aureus Infection

Cited by 128 publications

References 31 publications

Regulation of Host Hemoglobin Binding by the Staphylococcus aureus Clp Proteolytic System

Regulation of Host Hemoglobin Binding by the Staphylococcus aureus Clp Proteolytic System

Targeting fundamental pathways to disrupt Staphylococcus aureus survival: clinical implications of recent discoveries

Human Placental and Decidual Organ Cultures to Study Infections at the Maternal-fetal Interface

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