ROLE OF HYALURONIDASE AND THE HYALURONIC ACID CAPSULE IN THE SURVIVAL AND DISSEMINATION OF GROUP A STREPTOCOCCI IN THE HAMSTER CHEEK POUCH1

A quantitative study of the combined antiphagocytic effects of the M protein and the hyaluronic acid capsules of four strains of Group A streptococci revealed the following facts relating to their intraperitoneal virulence in mice and rats: 1. The most virulent strain, S23M (matt), produced both a large hyaluronic acid capsule and a full complement of M protein, the combined effects of which rendered the organism highly resistant to surface phagocytosis. 2. The slightly less virulent strain, T14/46 (matt virulent) was somewhat more susceptible to surface phagocytosis owing to the fact that its smaller capsule was less antiphagocytic than that of the S23M organism. 3. The glossy variant of the S23 strain (S23G), which ranked third in virulence, was still more susceptible to surface phagocytosis because of its lack of detectable M substance. Its large hyaluronic acid capsule, however, was capable of protecting it against phagocytosis on glass. 4. The least virulent strain, T14 (matt avirulent), was the most susceptible of all to phagocytosis. Though it possessed both M substance and capsule, which together prevented its phagocytosis on glass, each of them was shown to be quantitatively and functionally deficient as compared to Strain S23M. The differences in phagocytability, which appear to be directly related to the pathogenicity of the organisms, could be adequately demonstrated in vitro only by phagocytic tests designed to measure surface phagocytosis in the absence of opsonins. This fact is in keeping with the observation, previously reported, that surface phagocytosis plays a critical role in the defense of the host, particularly during the earliest stages of experimental streptococcal infections. Its possible relation to suppuration during the later stages of infection is also discussed.

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Inactivation of the cysteine protease SpeB affects hyaluronic acid capsule expression in group A streptococci

Microbial Pathogenesis ◽

10.1006/mpat.1999.0341 ◽

2000 ◽

Vol 28 (4) ◽

pp. 221-226 ◽

Cited By ~ 14

Author(s):

Markus Woischnik ◽

Bettina A (Leonard) Buttaro ◽

Andreas Podbielski

Keyword(s):

Hyaluronic Acid ◽

Cysteine Protease ◽

Group A Streptococci ◽

Group A ◽

Hyaluronic Acid Capsule

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T4 Pili Promote Colonization and Immune Evasion Phenotypes of Nonencapsulated M4 Streptococcus pyogenes

mBio ◽

10.1128/mbio.01580-20 ◽

2020 ◽

Vol 11 (4) ◽

Author(s):

Yi-Hsuan Chen ◽

Shao-Hui Li ◽

Yao-Cheng Yang ◽

Shu-Hao Hsu ◽

Victor Nizet ◽

...

Keyword(s):

Hyaluronic Acid ◽

Epithelial Cells ◽

Streptococcus Pyogenes ◽

Whole Blood ◽

Human Pathogen ◽

Human Whole Blood ◽

Epidemiologic Surveillance ◽

Group A ◽

Hyaluronic Acid Capsule

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.

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PROTECTIVE EFFECT OF HYALURONIDASE AND TYPE-SPECIFIC ANTI-M SERUM ON EXPERIMENTAL GROUP A STREPTOCOCCUS INFECTIONS IN MICE

Journal of Experimental Medicine ◽

10.1084/jem.88.3.325 ◽

1948 ◽

Vol 88 (3) ◽

pp. 325-342 ◽

Cited By ~ 30

Author(s):

Sidney Rothbard

Keyword(s):

Hyaluronic Acid ◽

Group A Streptococcus ◽

Single Injection ◽

Group A Streptococci ◽

Enzyme Therapy ◽

Fundamental Factor ◽

Combined Use ◽

Group A ◽

Hyaluronic Acid Capsule ◽

Experimental Group

Five strains of encapsulated group A streptococci of different serological types, each with a glossy and a matt variant, were studied to compare the rôles of the M substance and the hyaluronic acid capsule in virulence of these microorganisms. The results indicated that both contribute to the virulence of group A streptococci but that the M antigen is the more fundamental factor. Encapsulated variants, both glossy and matt, were slightly less susceptible to phagocytosis than those from which the capsule had been removed with hyaluronidase. Glossy variants, containing no M substance, were readily phagocyted; matt, M-containing variants were resistant to phagocytosis except in the presence of anti-M serum when they became fully susceptible. Only the M-containing, matt strains were mouse-virulent. Mice were protected against infections with these strains: (a) By removal of the capsule with hyaluronidase, which resulted in slight protection, but only against 10 M.L.D. Early and intensive treatment was required to produce this effect; i.e., simultaneous injection of enzyme and streptococci followed by prolonged enzyme therapy. (b) By a single injection of anti-M serum administered the day before inoculation of the streptococci, which resulted in protection against 100,000 M.L.D. (c) By combined use of enzyme and anti-M serum, an additive effect of the two protective agents occurred, which resulted in protection against 1,000,000 M.L.D.

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STUDIES OF PHAGOCYTOSIS OF GROUP A STREPTOCOCCI BY POLYMORPHONUCLEAR LEUCOCYTES IN VITRO

Journal of Experimental Medicine ◽

10.1084/jem.111.3.309 ◽

1960 ◽

Vol 111 (3) ◽

pp. 309-322 ◽

Cited By ~ 38

Author(s):

James G. Hirsch ◽

Alice B. Church

Keyword(s):

Hyaluronic Acid ◽

M Protein ◽

Rabbit Serum ◽

Polymorphonuclear Leucocytes ◽

Group A Streptococci ◽

Test Conditions ◽

Human Sera ◽

Group A ◽

Hyaluronic Acid Capsule

Studies have been made on phagocytosis and killing of Group A streptococci during mixing with suspensions of leucocytes in vitro. Under appropriate test conditions an anti-phagocytic effect can be demonstrated for the streptococcal hyaluronic acid capsule as well as for its M protein. The results obtained suggest an explanation for the suitability of human, but not rabbit, blood for opsonophagocytic tests designed to measure type-specific streptococcal antibodies. Human sera contain a factor which counteracts the anti-phagocytic effects of streptococcal hyaluronic acid capsules, and hence human blood serves well for detection of antibodies which combine with the only other phagocytosis-resisting component of this microorganism, namely M protein. In contrast, rabbit sera contain none of this factor, and addition of antibody to M protein to phagocytic test systems employing rabbit serum does not necessarily render the streptococci susceptible to engulfment by white cells, since the hyaluronic acid capsule may continue to interfere with phagocytosis. The nature of the human serum factor which opsonizes encapsulated streptococci is unknown. It does not appear to be an antibody or an enzyme capable of depolymerizing hyaluronic acid.

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