Gunnar Lindahl, MD, PhD, Dr HC

Mobile: +46735342255

E-mail: [email protected] OR [email protected]

Personal background

After medical studies and thesis work (in phage genetics) at Karolinska Institutet in Stockholm, I did post-doctoral work at the Pasteur Institute in Paris. I subsequently joined the faculty of medicine at Lund University in Sweden and eventually became a professor of medical microbiology and immunology. At Lund University, my work has been focused on interactions between pathogenic bacteria and the human immune system. After retirement, I have continued scientific work, being associated with both the medical faculty and the faculty of engineering at Lund University. For several years, I was also a part-time visiting professor at the University of Copenhagen in Denmark.

Research interests: host-pathogen interactions in bacterial infections

When a pathogenic microorganism enters a human host, the outcome depends on interactions between the pathogen and the human immune system. To initiate an infection, the pathogen must escape attack from innate immunity, and to cause a prolonged infection the pathogen must evade attack from adaptive immunity, i.e. antibodies and/or cellular immunity. Studies of these interactions between a pathogen and the human immune system provide fundamental insights about the mechanisms by which microbes cause disease – knowledge that is essential for the development of novel vaccines. Our studies have focused on the interplay between the human immune system and two species of streptococci, which are important causes of human disease: Streptococcus pyogenes (group A streptococci; GAS) and Streptococcus agalactiae (group B streptococci; GBS).

S. pyogenes is best known as the cause of relatively mild throat infections (‘strep throat’) but also causes serious diseases, which globally result in about 500,000 deaths each year. Most of these deaths result from either of two diseases. First, S. pyogenes causes invasive infections with dramatic clinical course and high mortality (“murder bacteria”). Second, an S. pyogenes infection may be followed by rheumatic fever, the classical example of an autoimmune disease, which in many parts of the world is a major cause of death among young individuals, because it causes heart failure.

S. agalactiae (GBS) causes very different infections, being the most important cause of life-threatening bacterial infections in newborns. However, S. agalactiae and S. pyogenes share some properties, which has made it rewarding to study these two streptococcal pathogens in parallel. In both systems, our studies have provided detailed molecular insights into interactions with the human immune system, and for S. agalactiae (GBS) our studies have resulted in the identification of a promising vaccine candidate, which is being evaluated in human trials. However, most of our work has been focused on S. pyogenes and its interactions with the human immune system, and some key findings of that work are summarized below.

Selected key findings

Streptococcal M protein and its hypervariable region. The major virulence factor of S. pyogenes is M protein, a fibrillar surface protein that confers resistance to phagocytosis and contributes to virulence also by other less well-defined mechanisms. Importantly, M protein varies extensively in sequence among strains, but not within a strain, allowing the classification of clinical isolates into about 200 types. The sequence variability is particularly pronounced in the so-called hypervariable region (HVR), which is a key target for protective antibodies. The mechanism, by which M protein confers resistance to phagocytosis, remained unclear for many years, but our work indicates that a key role is played by the human complement inhibitor C4BP, a plasma protein that binds to the HVR of most M proteins. By ‘hi-jacking’ C4BP, the bacteria block surface deposition of complement and thereby interfere with complement-mediated phagocytosis. Remarkably, HVRs with extremely different amino acid sequences share ability to bind human C4BP, implying that evolution has selected for HVRs, which have different antigenic properties but retain ability to bind C4BP.

Intriguingly, our data indicate that the HVR of an M protein evades antibody attack not only by sequence variation, but also by eliciting a weak antibody response. This finding was paradoxical, since it is commonly assumed that a hypervariable region in a microbial surface protein elicits a strong antibody response. However, our data indicate that it is so important for S. pyogenes to evade antibodies against the HVR, that evolution has favored the development of two major mechanisms by which the HVR escapes antibody attack: sequence variability and weak antibody response. Together, these findings focus interest on the remarkable properties of the HVR in M proteins. Studies of this HVR are of general interest, since hypervariability plays a key role in numerous pathogens, including those causing malaria, AIDS and Covid-19.

IgA-binding streptococcal M proteins. Since S. pyogenes commonly causes infections on mucosal surfaces in the throat, it is of interest that many strains bind IgA, the antibody class that plays a key role for protection against infection on mucosal surfaces. The binding of IgA is promoted by the M protein of the strain, which binds to the conserved Fc-part of IgA. The site in M protein that binds IgA varies in sequence among proteins of different M type but does not exhibit the extreme variability that characterizes the HVR. These IgA-binding M proteins, which have been extensively studied, represent attractive model systems for studies of the interaction between IgA-Fc and specific receptors. The biological role of IgA-binding during an S. pyogenes infection remains unclear, but the available data indicate that it contributes to bacterial immune escape. Interestingly, data obtained in collaborative studies indicate that IgA-binding M proteins contribute to the pathogenesis of IgA-nephritis, a common human disease characterized by IgA deposits in the kidneys.

Localized secretion of M protein. It has been known for more than 60 years that M protein is mainly secreted at the division septum of S. pyogenes. This observation was puzzling, since classical models indicate that the signal sequence of a secreted protein promotes secretion at any site in the cellular membrane. We have identified a molecular basis for this phenomenon by showing that the signal sequence of an M protein selectively directs secretion at the septum. This finding is of considerable general interest, since it demonstrates that the signal sequence of a protein may determine the site at which the protein is secreted, in addition to the classical role of the signal sequence in promoting secretion across the cellular membrane.  Thus, our studies of M protein have provided novel information about a fundamental cell-biological problem.

Molecular basis of childbed fever. One of the most notorious diseases in medical history is puerperal sepsis (childbed fever), which caused the death of numerous newly delivered women in the early parts of the 19^th century. The importance of this disease prompted the classical studies of Semmelweis, who showed that childbed fever is a nosocomial infection that can be prevented by techniques now known to be antiseptic. It was reported more than 90 years ago that childbed fever is caused by infection with S. pyogenes, but little has been known about the pathogenesis. However, epidemiological studies have shown that outbreaks of puerperal sepsis commonly are caused by strains expressing a surface protein designated R28. We have characterized R28 and in a collaborative study we have demonstrated that R28 binds the human immunomodulatory receptor CEACAM1. Several lines of evidence indicate that this interaction triggers the events that initiate puerperal sepsis. Thus, our studies have provided molecular insights into the pathogenesis of one of the most important infectious diseases in medical history.

Selected publications

Human CEACAM1 is targeted by a Streptococcus pyogenes adhesin implicated in puerperal sepsis pathogenesis. Catton E, Bonsor D, Herrera C, Stålhammar-Carlemalm M, Lyndin M, Turner C, Soden J, van Strijp J, Singer B, van Sorge NM*, Lindahl G*, McCarthy AJ* (2023) Nat Commun

Bacterial protein domains with a novel Ig-like fold target human CEACAM receptors. van Sorge NM, Bonsor DA, Deng L, Lindahl E, Schmitt V, Lyndin M, Schmidt A, Nilsson O R, Brizuela J, Boero E, Sundberg EJ, van Strijp JAG, Doran KS, Singer BB, Lindahl G* & McCarthy AJ* (2021) EMBO J

Subdominance in antibody responses: implications for vaccine development. Lindahl G (2020) Microbiol Mol Biol Rev

Variability without change. Lindahl G, and Persson JJ (2016) Nat Microbiol

Factor H binds to the hypervariable region of many Streptococcus pyogenes M proteins but does not promote phagocytosis resistance or acute virulence. Gustafsson MCU, Lannergård J, Nilsson OR, Kristensen B M, Olsen JE, Harris CL, Ufret-Vincenty RL, Stålhammar-Carlemalm M, and Lindahl G (2013) PLoS Pathog

The hypervariable region of Streptococcus pyogenes M protein escapes antibody attack by antigenic variation and weak immunogenicity. Lannergård J, Gustafsson M, Waldemarsson J, Norrby-Teglund A, Stålhammar-Carlemalm M, and Lindahl G (2011) Cell Host & Microbe

Tissue deposits of IgA-binding streptococcal M proteins in IgA nephropathy and Henoch-Schönlein purpura. Schmitt R, Carlsson F, Mörgelin M, Tati R, Lindahl G*, and Karpman D* (2010) Am J Pathol

Non-immunodominant regions are effective as building blocks in a streptococcal fusion protein vaccine. Stålhammar-Carlemalm M, Waldemarsson J, Johnsson E, Areschoug T, and Lindahl G (2007) Cell Host & Microbe

Signal sequence directs localized secretion of bacterial surface proteins. Carlsson F, Stålhammar-Carlemalm M, Flärdh K, Sandin C, Carlemalm E, and Lindahl G (2006) Nature

Extreme sequence divergence but conserved ligand-binding specificity in Streptococcus pyogenes M protein. Persson J, Beall B, Linse S, and Lindahl G (2006) PLoS Pathogens

Binding of human plasma proteins to Streptococcus pyogenes M protein determines the location of opsonic and non-opsonic epitopes. Sandin C, Carlsson F, and Lindahl G (2006) Mol Microbiol

Human fibrinogen bound to Streptococcus pyogenes M protein inhibits complement deposition via the classical pathway. Carlsson F, Sandin C and Lindahl G (2005) Mol Microbiol

Surface proteins of Streptococcus agalactiae and related proteins in other bacterial pathogens. Lindahl G, Stålhammar-Carlemalm M, and Areschoug T (2005) Clin Microbiol Reviews

Evasion of phagocytosis through cooperation between two ligand-binding regions in Streptococcus pyogenes M protein. Carlsson F, Berggård K, Stålhammar-Carlemalm M, and Lindahl G (2003) J Exp Med

Streptococcal IgA-binding proteins bind in the Ca2-Ca3 interdomain region and inhibit binding of IgA to human CD89. Pleass R J, Areschoug T, Lindahl G, and Woof J M (2001) J Biol Chem                 

Isolated hypervariable regions derived from streptococcal M proteins specifically bind human C4b-binding protein: implications for antigenic variation. Morfeldt E, Berggård K, Persson J, Drakenberg T, Johnsson E, Lindahl E, Linse S, and Lindahl G (2001) J Immunol

An IgA-binding peptide derived from a streptococcal surface protein. Johnsson E, Areschoug T, Mestecky J and Lindahl G (1999) J Biol Chem

The R28 protein of Streptococcus pyogenes is related to several group B streptococcal surface proteins, confers protective immunity and promotes binding to human epithelial cells. Stålhammar-Carlemalm M, Areschoug T, Larsson C, and Lindahl G (1999) Mol Microbiol

Identification of a family of streptococcal surface proteins with extremely repetitive structure. Wästfelt M, Stålhammar-Carlemalm M, Delisse A-M, Cabezon T, and Lindahl G (1996) J Biol Chem

A highly variable region in members of the streptococcal M protein family binds the human complement regulator C4BP. Johnsson E, Thern A, Dahlbäck B, Hedén L-O, Wikström M, and Lindahl G (1996) J Immunol

Ig-binding surface proteins of Streptococcus pyogenes also bind human C4b-binding protein (C4BP), a regulatory component of the complement system. Thern A, Stenberg L, Dahlbäck B, and Lindahl G (1995) J Immunol

Identification of the IgA-binding region in streptococcal protein Arp. Johnsson E, Andersson G, Lindahl G, and Hedén L-O (1994) J Immunol

Protein Rib: a novel group B streptococcal cell surface protein that confers protective immunity and is expressed by most strains causing invasive infections. Stålhammar-Carlemalm M, Stenberg L, and Lindahl G (1993) J Exp Med

Two major classes in the M-protein family in group A streptococci. O´Toole P W, Stenberg L, Rissler M and Lindahl G (1992) Proc Natl Acad Sci USA

Extensive sequence homology between IgA receptor and M proteins in Streptococcus pyogenes. Frithz E, Hedén L-O, and Lindahl G (1989) Mol Microbiol