Immune evasion in Staphylococcus aureus infection

Staphylococcus aureus (S. aureus) is a commensal bacterium, which has the potential to cause a broad range of conditions from minor skin infections to invasive and potentially fatal systemic infections [1, 2]. Infection with resistant Staphylococcus aureus is a growing challenge worldwide and the need for novel therapeutics is evident.

Upon infection of the host, S. aureus initiate classical innate immune responses, which have been well established [3, 4]. A scientific gap, on the other hand, exists in the knowledge of T- and NK cell-mediated responses to S. aureus.

A critical role for NK cells in host defense against pulmonary S. aureus infection has been suggested [5], and T-cell memory has been detected in mice challenged repeatedly with S. aureus [6]. However, little remains known regarding the underlying molecular mechanisms.

Treatment of S. aureus is now relying on “last-line” of therapeutics due to development of therapy-resistance, methicillin- and daptomycin-resistant S. aureus strains are becoming more frequent [3, 7]. The emergence of these new resistant S. aureus strains and their interaction with the human immune system is poorly understood. However, the consequences they have for human health underlines the need for development of novel therapeutics for treatment.

The aim of this project is to investigate the activity of human T- and NK cells upon co-cultivation with different methicillin- and daptomycin-resistant/sensitive S. aureus strains.

We expect that this project will contribute to the fundamental understanding of the human T- and NK cell-mediated immune response to S. aureus. Since pathogenicity of bacteria is highly dependent on immune evasion we anticipate that this expanding knowledge will set the stage for development of future novel therapeutics for treatment of S. aureus infection.

Contact: PhD Student Maiken Mellergaard or PhD Student Rikke Illum Høgh.

References:

1. Foster, T.J., et al., Adhesion, invasion and evasion: the many functions of the surface proteins of Staphylococcus aureus. Nat Rev Microbiol, 2013. 12(1): p. 49-62.

2. Frees, D., U. Gerth, and H. Ingmer, Clp chaperones and proteases are central in stress survival, virulence and antibiotic resistance of Staphylococcus aureus. Int J Med Microbiol, 2014. 304(2): p. 142-9.

3. Abtin, A., et al., Perivascular macrophages mediate neutrophil recruitment during bacterial skin infection. Nat Immunol, 2014. 15(1): p. 45-53.

4. Miller, L.S. and J.S. Cho, Immunity against Staphylococcus aureus cutaneous infections. Nat Rev Immunol, 2011. 11(8): p. 505-18.

5. Small, C., McCormick, S., Gill, N., Kugathasan, K., Santosuosso, M.,Donaldson, N.,Heinrichs, D.E., Ashkar, A., and Xing, Z.,, NK Cells Play a Critical Protective Role in Host Defense against Acute Extracellular Staphylococcus aureus Bacterial Infection in the Lung. The Journal of Immunology, 2008. 180: p. 5558-5568.

6. Murphy, A.G., et al., Staphylococcus aureus infection of mice expands a population of memory gammadelta T cells that are protective against subsequent infection. J Immunol, 2014. 192(8): p. 3697-708.

7. Larsen, A.R., et al., Emergence and characterization of community-associated methicillin-resistant Staphyloccocus aureus infections in Denmark, 1999 to 2006. J Clin Microbiol, 2009. 47(1): p. 73-8.