Emergent emm4 group A Streptococcus evidences a survival strategy during interaction with immune effector cells

• Published in: Infection and immunity 2024-07, Vol.92 (7), p.e0015224
• Main Authors: Odo, Chioma M, Vega, Luis A, Mukherjee, Piyali, DebRoy, Sruti, Flores, Anthony R, Shelburne, Samuel A
• Format: Article
• Language: English
• Subjects: Animals; Antigens, Bacterial - genetics; Antigens, Bacterial - immunology; Antigens, Bacterial - metabolism; Bacterial Infections; Bacterial Outer Membrane Proteins - genetics; Bacterial Outer Membrane Proteins - metabolism; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Carrier Proteins; Gene Expression Regulation, Bacterial; Host-Pathogen Interactions - immunology; Humans; Macrophages - immunology; Macrophages - microbiology; Mice; Microbial Pathogenesis; Microbial Viability; Mutation; Streptococcal Infections - immunology; Streptococcal Infections - microbiology; Streptococcal Infections - mortality; Streptococcus pyogenes - genetics; Streptococcus pyogenes - immunology; Streptococcus pyogenes - pathogenicity; Streptolysins - genetics; Streptolysins - metabolism; Virulence - genetics; Virulence Factors - genetics
• ISSN: 0019-9567; 1098-5522; 1098-5522
• DOI: 10.1128/iai.00152-24

The major gram-positive pathogen group A (GAS) is a model organism for studying microbial epidemics as it causes waves of infections. Since 1980, several GAS epidemics have been ascribed to the emergence of clones producing increased amounts of key virulence factors such as streptolysin O (SLO). Herein, we sought to identify mechanisms underlying our recently identified temporal clonal emergence among GAS, given that emergent strains did not produce augmented levels of virulence factors relative to historic isolates. By creating and analyzing isoallelic strains, we determined that a conserved mutation in a previously undescribed gene encoding a putative carbonic anhydrase was responsible for the defective growth observed in the emergent strains. We also identified that the emergent strains survived better inside macrophages and killed macrophages at lower rates than the historic strains. the creation of isogenic mutant strains, we linked the emergent strain "survival" phenotype to the downregulation of the SLO encoding gene and upregulation of the operon which encodes proteins involved in defense against extracellular oxidative stress. Our findings are in accord with recent surveillance studies which found a high ratio of mucosal (i.e., pharyngeal) relative to invasive infections among GAS. Since ever-increasing virulence is unlikely to be evolutionarily advantageous for a microbial pathogen, our data further understanding of the well-described oscillating patterns of virulent GAS infections by demonstrating mechanisms by which emergent strains adapt a "survival" strategy to outcompete previously circulating isolates.