Insights into the Staphylococcus aureus-Host Interface: Global Changes in Host and Pathogen Gene Expression in a Rabbit Skin Infection Model

Małachowa, Natalia; Kobayashi, Scott D.; Sturdevant, Daniel E.; Scott, Dana; DeLeo, Frank R.

doi:10.1371/journal.pone.0117713

Cited by 22 publications

(21 citation statements)

References 38 publications

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“…This is exemplified by the transition from bacteremia to thromboembolic lesions during systemic infection, wherein S. aureus produces more adhesins, metal acquisition proteins, immune evasion factors, and toxins during the transition (82). Indeed, transcriptome studies suggest that Sal1 and Sal2 are differentially up-regulated in a range of deep tissues, but not superficial sites of infection, such as the skin (83)(84)(85)(86). Thus, we suspect S. aureus may alter its Geh expression pattern in a manner that depends on the infection site.…”

Section: Discussionmentioning

confidence: 99%

Bacterial lipolysis of immune-activating ligands promotes evasion of innate defenses

Chen

Alonzo

2019

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

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Commensal and pathogenic bacteria hydrolyze host lipid substrates with secreted lipases and phospholipases for nutrient acquisition, colonization, and infection. Bacterial lipase activity on mammalian lipids and phospholipids can promote release of free fatty acids from lipid stores, detoxify antimicrobial lipids, and facilitate membrane dissolution. The gram-positive bacterium Staphylococcus aureus secretes at least two lipases, Sal1 and glycerol ester hydrolase (Geh), with specificities for short- and long-chain fatty acids, respectively, each with roles in the hydrolysis of environmental lipids. In a recent study from our group, we made the unexpected observation that Geh released by S. aureus inhibits activation of innate immune cells. Herein, we investigated the possibility that S. aureus lipases interface with the host immune system to blunt innate immune recognition of the microbe. We found that the Geh lipase, but not other S. aureus lipases, prevents activation of innate cells in culture. Mutation of geh leads to enhancement of proinflammatory cytokine production during infection, increased innate immune activity, and improved clearance of the bacterium in infected tissue. These in vitro and in vivo effects on innate immunity were not due to direct functions of the lipase on mammalian cells, but rather a result of inactivation of S. aureus lipoproteins, a major pathogen-associated molecular pattern (PAMP) of extracellular gram-positive bacteria, via ester hydrolysis. Altogether, these studies provide insight into an adaptive trait that masks microbial recognition by innate immune cells through targeted inactivation of a broadly conserved PAMP.

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Section: Discussionmentioning

confidence: 99%

Bacterial lipolysis of immune-activating ligands promotes evasion of innate defenses

Chen

Alonzo

2019

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

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“…Tissue sections were immediately flash frozen in liquid nitrogen and stored at -80°C until used. To isolate total RNA, frozen samples were pulverized using a hammer, as described previously (42). Pulverized samples were added to lysis buffer containing 2-mercaptoethanol and homogenized in a FastPrep-24 sample preparation system (MP Biomedicals, Santa Ana, CA).…”

Section: Methodsmentioning

confidence: 99%

Vaccine Protection against Multidrug-Resistant Klebsiella pneumoniae in a Nonhuman Primate Model of Severe Lower Respiratory Tract Infection

Małachowa

Kobayashi

Porter

et al. 2019

mBio

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Klebsiella pneumoniae is a human gut communal organism and notorious opportunistic pathogen. The relative high burden of asymptomatic colonization by K. pneumoniae is often compounded by multidrug resistance—a potential problem for individuals with significant comorbidities or other risk factors for infection. A carbapenem-resistant K. pneumoniae strain classified as multilocus sequence type 258 (ST258) is widespread in the United States and is usually multidrug resistant. Thus, treatment of ST258 infections is often difficult. Inasmuch as new preventive and/or therapeutic measures are needed for treatment of such infections, we developed an ST258 pneumonia model in cynomolgus macaques and tested the ability of an ST258 capsule polysaccharide type 2 (CPS2) vaccine to moderate disease severity. Compared with sham-vaccinated animals, those vaccinated with ST258 CPS2 had significantly less disease as assessed by radiography 24 h after intrabronchial installation of 108 CFU of ST258. All macaques vaccinated with CPS2 ultimately developed ST258-specific antibodies that significantly enhanced serum bactericidal activity and killing of ST258 by macaque neutrophils ex vivo. Consistent with a protective immune response to CPS2, transcripts encoding inflammatory mediators were increased in infected lung tissues obtained from CPS-vaccinated animals compared with control, sham-vaccinated macaques. Taken together, our data provide support for the idea that vaccination with ST258 CPS can be used to prevent or moderate infections caused by ST258. As with studies performed decades earlier, we propose that this prime-boost vaccination approach can be extended to include multiple capsule types. IMPORTANCE Multidrug-resistant bacteria continue to be a major problem worldwide, especially among individuals with significant comorbidities and other risk factors for infection. K. pneumoniae is among the leading causes of health care-associated infections, and the organism is often resistant to multiple classes of antibiotics. A carbapenem-resistant K. pneumoniae strain known as multilocus sequence type 258 (ST258) is the predominant carbapenem-resistant Enterobacteriaceae in the health care setting in the United States. Infections caused by ST258 are often difficult to treat and new prophylactic measures and therapeutic approaches are needed. To that end, we developed a lower respiratory tract infection model in cynomolgus macaques in which to test the ability of ST258 CPS to protect against severe ST258 infection.

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“…IsdA has a function of resistance against the mechanisms of human innate immune defense and its presence on the surface of S. aureus causes that the bacterium to be more hydrophilic and is negatively charged [63,64]. In a rabbit skin infection model, transcription levels of isdB were increased 24 h post infection [65], suggesting that it may have a role during infection of the skin. The Isd proteins bind to the ligands on skin cells, and it is probably Isd that is involved in the skin infection.…”

Section: Involvement Of Cwa Proteins In Skin Infectionsmentioning

confidence: 99%

Surface Proteins of Staphylococcus aureus

Jan‐Roblero¹,

García-Gómez²,

Martínez³

et al. 2017

The Rise of Virulence and Antibiotic Resistance in ≪i>Staphylococcus Aureus

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Staphylococcus aureus is a commensal bacterium that causes infections such as sepsis, endocarditis, and pneumonia. S. aureus can express a variety of virulence factors, including surface proteins. Surface proteins are characterized by presence of a Sec-dependent signal sequence at the amino terminal, and the sorting signal domain. Surface proteins are covalently attached to peptidoglycan and they are commonly known as cell wallanchored (CWA) proteins. CWA proteins have many functions and participate in the pathogenesis of S. aureus. Furthermore, these proteins have been proposed as therapeutic targets for the generation of vaccines. In this chapter, different topics related to CWA proteins of S. aureus are addressed. The molecular structure of CWA proteins and their role as virulence factors of S. aureus are described. Furthermore, the involvement of CWA proteins in the processes of adhesion, invasion of host cells and tissues, evasion of the immune response, and the formation of biofilm is discussed. In addition, the role of CWA proteins in skin infection and the proposal to use them as potential vaccine antigens are described. The information contained in this chapter will help the readers to understand the biology of CWA proteins and to recognize the importance of surface molecules of S. aureus.

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Insights into the Staphylococcus aureus-Host Interface: Global Changes in Host and Pathogen Gene Expression in a Rabbit Skin Infection Model

Cited by 22 publications

References 38 publications

Bacterial lipolysis of immune-activating ligands promotes evasion of innate defenses

Bacterial lipolysis of immune-activating ligands promotes evasion of innate defenses

Vaccine Protection against Multidrug-Resistant Klebsiella pneumoniae in a Nonhuman Primate Model of Severe Lower Respiratory Tract Infection

Surface Proteins of Staphylococcus aureus

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