Abstract
Streptococcus pyogenes (group A Streptococcus [GAS]) is an important human pathogen causing a broad spectrum of diseases and associated with significant global morbidity and mortality. Almost all GAS isolates express a surface hyaluronic acid capsule, a virulence determinant that facilitates host colonization and impedes phagocyte killing. However, recent epidemiologic surveillance has reported a sustained increase in both mucosal and invasive infections caused by nonencapsulated GAS, which questions the indispensable role of hyaluronic acid capsule in GAS pathogenesis. In this study, we found that pilus of M4 GAS not only significantly promotes biofilm formation, adherence, and cytotoxicity to human upper respiratory tract epithelial cells and keratinocytes, but also promotes survival in human whole blood and increased virulence in murine models of invasive infection. T4 antigen, the pilus backbone protein of M4 GAS, binds haptoglobin, an abundant human acute-phase protein upregulated upon infection and inflammation, on the bacterial surface. Haptoglobin sequestration reduces the susceptibility of nonencapsulated M4 GAS to antimicrobial peptides released from activated neutrophils and platelets. Our results reveal a previously unappreciated virulence-promoting role of M4 GAS pili, in part mediated by co-opting the biology of haptoglobin to mitigate host antimicrobial defenses.IMPORTANCE Group A Streptococcus (GAS) is a strict human pathogen causing more than 700 million infections globally each year. The majority of the disease-causing GAS are encapsulated, which greatly guarantees survival and dissemination in the host. Emergence of the capsule-negative GAS, such as M4 GAS, in recent epidemiologic surveillance alarms the necessity to elucidate the virulence determinants of these pathogens. Here, we found that M4 pili play an important role in promoting M4 GAS adherence and cytotoxicity to human pharyngeal epithelial cells and keratinocytes. The same molecule also significantly enhanced M4 GAS survival and replication in human whole blood and experimental murine infection. T4 antigen, which composes the backbone of M4 pili, was able to sequester the very abundant serum protein haptoglobin to further confer M4 GAS resistance to antibacterial substances released by neutrophils and platelets.
Highlights
Streptococcus pyogenes is an important human pathogen causing a broad spectrum of diseases and associated with significant global morbidity and mortality
As prior studies of Group A Streptococcus (GAS) pili centered on a few pilus types, and because biological functions attributed to the T4 antigen and FCT-5-type pilus of M4 GAS have not previously been explored, we performed precise allelic exchange mutagenesis to delete the pilus backbone gene (Fig. 1A) in the background of M4 GAS strain 4063-05 to gain insight into its biological function
Together our results indicate that T4 antigen of M4 GAS plays an important role in detoxifying the bactericidal activity of antimicrobial substances released from activated neutrophils and platelets, in part via sequestration of host Hp on the bacterial surface
Summary
Streptococcus pyogenes (group A Streptococcus [GAS]) is an important human pathogen causing a broad spectrum of diseases and associated with significant global morbidity and mortality. The hyaluronic acid (HA) capsule, a major virulence factor expressed by the vast majority of GAS strains for full pathogenesis, has antiphagocytic, adhesive, and signaling properties that cooperatively promote colonization, subvert host antibacterial responses, and contribute to invasive disease potential [5,6,7,8]. Recent epidemiologic surveillance has reported a sustained increase in both mucosal and invasive infections caused by nonencapsulated GAS, including all tested isolates of the M4 and M22 serotypes [9,10,11] and some recent emerging isolates of M28, M87, and M89 serotypes [12,13,14] These observations indicate that HA capsule expression is somehow dispensable for GAS disease pathogenesis, provided the strains are equipped with alternative virulence-related mechanisms to interact with the host and thwart the host immune responses to survive and spread in vivo. Expression of fibronectinbinding protein (Fba) and the host complement regulator C4b binding protein (C4BP) on the bacterial surface was suggested to endow M4 GAS with host cell adherence and phagocyte resistance properties, respectively [18, 20]; the detailed molecular mechanisms that confer full virulence potential to nonencapsulated M4 GAS strains remain largely unexplored
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