| 1. |
- Haggar, Axana
(författare)
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Interaction between extracellular adherence protein (Eap) from Staphylococcus aureus and the human host
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Staphylococcus aureus is one of the most common agents causing bacterial infections in humans and animals. The emergence of extended antibiotic resistance among S. aureus strains as a worldwide epidemic has driven the development of alternative strategies to combat this microorganism. This thesis is based on the interaction between Extracellular Adherence Protein (Eap) from S. aureus and the human host. Eap is an extracellular protein capable of binding to several plasma proteins including fibronectin, fibrinogen and prothrombin. Adherence and internalization into host cells are key steps during the infectious process; adherence for successful colonization and internalization to shield the bacteria from host defense and antibiotic treatment. Using a mutant strain, Newman AH12 lacking the eap gene we were able to demonstrate a clear role for Eap in adherence and internalization. Strain Newman (wild type strain) could adhere to and become internalized better by eukaryotic cells than the isogenic mutant and externally added Eap enhanced adherence and internalization of strain Newman, Newman AH12, and clinical strains. Antibodies against Eap were able to block the adherence and internalization process in strain Newman. In the second part of this thesis we confirm the role of Eap as an immunomodulating protein. We could demonstrate that Eap inhibits the binding of neutrophils to the endothelium under static and dynamic flow conditions and also inhibits transendothelial migration of neutrophils in an in vitro model. We could also show that Eap blocked to the same extent as human ICAM-1 antibodies. This data together with previous reports suggest that Eap also in this setting elicits its effect mainly by binding to ICAM-1. On the other hand, we could also demonstrate a direct effect of Eap on peripheral blood mononuclear cells (PBMCs), which was concentration dependent. At low concentrations, Eap elicited a stimulatory effect on PBMC and at high concentrations it had an inhibitory effect through induction of apoptosis in T and B cells. Protective cellular immunity is the main mechanisms of defense used by the host to eliminate S. aureus infection. The presence of Eap during a S. aureus infection will have a major impact on this system by virtue of (i) Eap mediated adherence and internalization into host cells, (ii) inhibition of neutrophils migration to the site of infection (iii) inhibition of T and B cell proliferation. Hence, these studies imply that intervention directed against Eap could be a novel approach to prevent or improve therapy of Staphylococcal infections.
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| 2. |
- Johansson, Linda, et al.
(författare)
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Neutrophil-Derived Hyperresistinemia in Severe Acute Streptococcal Infections
- 2009
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 183:6, s. 4047-4054
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Tidskriftsartikel (refereegranskat)abstract
- The concept of neutrophil activation and degranulation as important contributors to disease pathology in invasive group A streptococcal infections has recently been emphasized. This study focuses on two of the most severe streptococcal manifestations, toxic shock syndrome and necrotizing fasciitis, and the newly described proinflammatory molecule resistin, known to derive from adipocytes and monocytes. We demonstrate for the first time that these conditions are characterized by hyperresistinemia in circulation as well as at the local site of infection. Importantly, analyses of patient tissue biopsies and whole blood revealed that neutrophils represent a novel and dominant source of resistin in bacterial septic shock. This was confirmed by the identification of resistin within neutrophil azurophilic granules. In vitro assays using primary neutrophils showed that resistin release was readily triggered by streptococcal cell wall components and by the streptococcal M1 protein, but not by the potent streptococcal superantigens. This is the first report demonstrating that resistin is released from neutrophils in response to microbial stimuli, which adds resistin to the neutrophil granule proteins that are likely to contribute to the pathologic inflammatory responses associated with severe streptococcal infections. The Journal of Immunology, 2009, 183: 4047-4054.
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| 3. |
- Vikerfors, Anna, et al.
(författare)
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Severe group A streptococcal infections in Uppsala County, Sweden : clinical and molecular characterization of a case cluster from 2006 to 2007
- 2009
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Ingår i: Scandinavian Journal of Infectious Diseases. - : Informa UK Limited. - 0036-5548 .- 1651-1980. ; 41:11-12, s. 823-830
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Tidskriftsartikel (refereegranskat)abstract
- This study describes a recent cluster of 30 patients (median age 52 years) with serious group A streptococcal (GAS) infections in Uppsala County, Sweden, from December 2006 to May 2007. Patients hospitalized with a severe GAS infection, i.e. cases with either invasive GAS (iGAS) disease or patients with a positive non-sterile site culture/rapid antigen test for GAS and clinically considered as having a critical disease, were included in the study. Common clinical presentations were skin and soft tissue infections (53%) and pneumonia (17%). Eight patients (27%) were diagnosed with streptococcal toxic shock syndrome. In 40% of the cases no relevant underlying disease was reported. Among the 16 patients with soft tissue infections, the upper chest, neck or upper arm area was frequently affected and the infection was associated with severe pain. Among the 20 collected isolates, the T1/emm1 type dominated (80%). The majority (86%) of 7 analysed acute sera lacked neutralizing activity against superantigens produced by the patients' own infecting isolate. The study underscores the association between T1/emm1 and outbreaks of serious GAS infections. This highlights the importance of surveillance for prompt identification of more aggressive isolates in the community, thereby increasing awareness among healthcare professionals of these life-threatening infections.
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