PATHOGENESIS IN STREPTOCOCCAL INFECTIONS
Gunnar Lindahl, MD, PhD
Senior professor of Medical Microbiology and Immunology
Affiliations: Applied Microbiology, Department of Chemistry, Lund University; and Medical Microbiology, Department of Laboratory Medicine, Lund University.
I did my thesis work (in Microbial Genetics) and studied medicine at Karolinska Institutet in Stockholm and did post-doctoral work at the Pasteur Institute in Paris. Returning to Sweden, I joined the Faculty of Medicine at Lund University and eventually became a Professor of Medical Microbiology and Immunology. After my retirement, I have continued in science, first as a visiting professor at the University of Copenhagen and now as a visiting professor at the Applied Microbiology Section, Department of Chemistry, Lund University.
For more than three decades my collaborators and I have studied interactions between pathogenic microorganisms and the human immune system. Insights into these interactions provide basic information about the mechanisms by which pathogens cause disease and are essential for the development of novel vaccines. Most of our work has been focused on Streptococcus pyogenes (group A streptococcus), a common human pathogen. This Gram-positive bacterium is best known as the cause of ‘strep throat’ but also causes serious diseases, which globally result in about 500,000 deaths each year. Thus, a vaccine is urgently needed.
The major virulence factor of S. pyogenes is the M protein, a fibrillar surface protein that prevents phagocytosis and contributes to virulence also by other mechanisms. This classical virulence factor has a “hypervariable region” (HVR), which varies extensively in sequence among strains but not within a strain, allowing the identification of more than 200 M-types. It is commonly assumed that antibodies elicited by the HVR confer type-specific immunity, implying that the sequence variability favors immune escape, but much remains unknown about the immune response to M protein.
The molecular function of M protein has also remained unclear for many years, prompting extensive studies in our group. One important result of this work was the finding that HVRs with extremely divergent sequences share ability to bind the human plasma protein C4BP, a property that contributes to virulence. Thus, the bacteria enhance their ability to cause disease by ‘hijacking’ human C4BP. Since highly variable regions are common in pathogenic microorganisms, this finding is of general interest. Other studies have shown that the antibody response to the hypervariable M proteins has unique features, a finding that similarly if of general interest and is of relevance to vaccine development.
Selected publications (from the last 20 years):
1) Lindahl, G., Sjöbring, U. & Johnsson, E. (2000). Human complement regulators: a major target for pathogenic microorganisms.
Curr Opin Immunol 12, 44-51
2) Morfeldt, E., Berggård, K., Persson, J., Drakenberg, T., Johnsson, E., Lindahl, E., Linse, S. & Lindahl, G. (2001). Isolated hypervariable regions derived from streptococcal M proteins specifically bind human C4b-binding protein: implications for antigenic variation.
J Immunol 167, 3870-3877
3) Carlsson, F., Berggård, K., Stålhammar-Carlemalm, M. & Lindahl, G. (2003). Evasion of phagocytosis through cooperation between two ligand-binding regions in Streptocooccus pyogenes M protein.
J Exp Med 198, 1057-1068
4) Lindahl, G., Stålhammar-Carlemalm, M. & Areschoug, T. (2005). Surface proteins of Streptococcus agalactiae and related proteins in other bacterial pathogens.
Clin Microbiol Rev 18, 102-127
5) Sandin, C., Carlsson, F., & Lindahl, G. (2006). Binding of human plasma proteins to Streptococcus pyogenes M protein determines the location of opsonic and non-opsonic epitopes.
Mol Microbiol 59, 20-30
6) Carlsson, F., Stålhammar-Carlemalm, M., Flärdh, K., Sandin, C., Carlemalm, E. & Lindahl, G. (2006). Signal sequence directs localized secretion of bacterial surface proteins.
Nature 442, 943-946
7) Persson, J., Beall, B., Linse, S. & Lindahl, G. (2006). Extreme sequence divergence but conserved ligand-binding specificity in Streptococcus pyogenes M protein.
PLoS Pathogens 2, 442-452
8) Stålhammar-Carlemalm, M., Waldemarsson, J., Johnsson, E., Areschoug, T. & Lindahl, G. (2007). Non-immunodominant regions are effective as building blocks in a streptococcal fusion protein vaccine.
Cell Host & Microbe 2, 427-434
9) Lannergård. J., Gustafsson, M., Waldemarsson, J., Norrby-Teglund, A., Stålhammar-Carlemalm, M. & Lindahl, G. (2011). The hypervariable region of Streptococcus pyogenes M protein escapes antibody attack by antigenic variation and weak immunogenicity.
Cell Host & Microbe 10, 147-157
10) Gustafsson, M. C. U., Lannergård, J., Nilsson, O. R., Kristensen, B. M., Olsen, J. E., Harris, C. L., Ufret-Vincenty, R. L., Stålhammar-Carlemalm, M. & Lindahl, G. (2013). Factor H binds to the hypervariable region of many Streptococcus pyogenes M proteins but does not promote phagocytosis resistance or acute virulence
PLoS Pathog 9, e1003323
11) Lindahl, G. & Persson, J.J. (2016). Variability without change.
Nature Microbiol 1, doi: 10.1038/NMICROBIOL.2016.218
12) van Sorge, N.M., Deng, L., Bonsor, D.A., Lindahl, E., Schmitt, V., Lyndin, M., Schmidt, A., Nilsson, O.R., Boero, E., Sundberg, E.J., van Strijp, J.A.G., Doran, K.S., Singer, B.B., Lindahl, G. & McCarthy, A.J. (2020). A streptococcal protein domain with unique Ig-like fold targets human CEACAMs.
Submitted for publication.