From Normal Flora to Brain Abscesses: A Review of Streptococcus intermedius

Abstract

Streptococcus intermedius is a β-hemolytic Gram-positive member of the Streptococcus anginosus group (SAG). Despite being a part of the normal microbiota, it is one of the most common pathogens associated with brain and liver abscesses and thoracic empyema, increasing as a result the morbidity and mortality rates in affected patients. Though there are numerous published case reports on S. intermedius infections, it is still understudied compared to other SAG members. Our knowledge of the genomic factors contributing to its dissemination to the brain and abscess development is also limited to few characterized genes. In this review, we summarize our current knowledge on S. intermedius identification methods, virulence factors, and insight provided by the whole-genome and correlate patients' metadata, symptoms, and disease outcome with S. intermedius infections in 101 recent case reports obtained from PubMed. This combined information highlights the gaps in our understanding of S. intermedius pathogenesis, suggesting future research directions to unveil the factors contributing to abscess development.

Keywords: Streptococcus anginosus group (SAG); Streptococcus intermedius; brain abscess; fibronectin (FN); laminin; virulence.

FIGURE 1

Representative members of streptococci and SAG members and the distribution of the genome assemblies. (A) Word cloud showing the medically relevant streptococci and SAG members based on a PubMed Central data (last accessed: July 3rd, 2019). (B) Distribution of the genome assemblies on NCBI for SAG members and other medically relevant streptococci (last accessed on 08/05/2019); SAG members are depicted in red.

FIGURE 2

Worldwide reported S. intermedius cases. Dots were colored according to the abscess localizations.

FIGURE 3

Distribution of case reports based on patients’ age categories, sex, and abscess localization. M, male; F, Female.

FIGURE 4

Major S. intermedius virulence factors and regulation of gene expression involved in brain abscess formation. Following S. intermedius infection, tissue damage is caused by the hydrolytic activity of hyaluronidase (hyl) and proinflammatory cytokine build-up from the binding of surface proteins to ECM components and macrophage stimulation by histone-like DNA binding proteins (HLPs). Hyl also degrades the hyaluronate constituent of connective tissues, which serves as a bacterial nutrient. Antigens I/II surface proteins (fbp54 and lmb) bind to fibronectin and laminin of the ECM, which stimulates interleukin 8 release from monocytes followed by neutrophil chemotaxis. Adhesion is also mediated by surface proteins (psaA), enolase (eno), and pullulanase (pulA). S. intermedius escapes host immunological defenses through the expression of lymphocyte-apoptotic superantigens and biofilm formation monitored by the product of the luxS gene, antoinducer-2, and hyaluronidase activity. Invasion is ensured by a complete Streptococcus Invasion locus (sil) system and a homolog of internalin A. Replication and abscess formation are allowed through the polysaccharidic capsular inhibition of phagocytic polymorphonuclear neutrophils. Intermedilysin (ILY) and sialidase A (NanA) are S. intermedius-specific virulence factors. ILY binds to the human complement regulator CD59 (hCD59) and creates pores in membranes of red blood cells allowing for necrosis. NanA releases sialic acid moieties from sugar chains present in the environment and the surface of bacteria to direct inter-bacterial and host-bacterial interactions. Regulation of gene expression depends on carbohydrate supply. Under glucose-poor conditions (light blue), multi-substrate glycosidase A (MsgA) and NanA degrade glycans in the human serum to release N-acetylneuraminic acid and galactose. Galactose inhibits the lactose phosphotransferase system repressor (LacR), an ILY silencer, resulting in a constitutive ILY expression and a positive feedback loop for MsgA and NanA expression. Under glucose-rich conditions (red), the catabolite control protein (CcpA) represses ILY expression via either binding to the ily promoter on the catabolite repressible element (cre) or controlling the concentration of ily transcriptional regulators. ILY, MsgA, and NanA activities are also reduced by immunoglobulins in the human plasma. The luxS pathway (violet) constitutively increase ILY and hyl expression and the ILY hemolytic activity but not that of hyaluronidase (figure created with BioRender).