Clement+Utti

 COURSE : MEDICAL MICROBIOLOGY ASSIGNMENT: PATHOGENESIS OF ACUTE PHARYNGITIS ID No :000567768

CONTENTS:
 * Introduction**
 * Survival of GAS in blood**
 * Epithelial cell adherence**
 * Intracellular invasion**
 * //Immune system avoidance//**
 * //References//**

**Introduction ** Group A Streptococcus (GAS) is a pathogen that causes acute bacterial pharyngitis in human and it can be spread through aerosols among individuals, or by eating contaminated food (Bisno et al., 2003). The site of infection of GAS is in the pharyngeal mucosa, where it causes pharyngitis (Carapetis et al., 2005). The pathogen enters the body through the ciliated epithelium in the nose, which results in edema and hyperemia of the nasal mucous membranes. This condition induces high secretory activity of the mucous glands thus causing disruptive symptoms (Red Book, 2006). GAS pharyngitis pathogenesis is divided into three stages as follows: adherence to the pharyngeal epithelium, collection of nutrients needed for proliferation and avoidance of the host immune response (Bisno et al., 2003).

GAS is open to the elements of human plasma at the points of inflammation where it causes superficial infections as a result of vascular seepage, which is facilitated by the action of M protein interacting with fibrinogen and the b2-integrin adhesion molecule on the neutrophils surface. This consequently leads to an inflammatory cascade which involves the discharge of heparin-binding protein and induces vascular seepage (Herwald et al., 2004). Shock is underlined by the pathophysiological mechanism of vascular permeability, cross linking of the M protein and fibrinogen with b2-integrin might be instrumental in what causes or leads to the development of streptococcal toxic shock syndrome. Plasma is a rich medium that aids bacterial growth. It also contains immune system components that GAS must elude to survive, including opsonizing antibodies and complement. The normal function of hosts defences is disrupted by the several interactions between plasma proteins and GAS proteins (Walker et al., 2005). Also, GAS expresses surface proteins that have a high affinity for several human plasma proteins such as albumin, fibrinogen, a2-macroglobulin, IgG and plasminogen (McArthur et al., 2006) which suggests that the pathogen has evolved mechanisms to capture and to use host proteins for enhanced survival in vivo. Recent discovery reveals that GAS pili-like cell surface structures are key factors in pharyngeal epithelial cell adherence and biofilm formation. Pili are programmed by genes found in the fibronectin, collagen-binding, T-antigen, FCT, gene region and are composed of the main pilus subunit (spy0128 in the serotype M1 strain SF370) and two ancillary proteins ( [|Mora, et al., 2005] ). The pri ncipal pilus subunit tallies with the T antigen of the Lancefield T serotypes, which is one of the major GAS classification scheme. Assembly of GAS pili depends on a sortase encoded by genes in the FCT region and in M3 strains, on a signal peptidase encoded upstream of the T antigen ( [|Zahner, et al., 2007] ). Other GA S proteins are also involved in epithelial cell adherence. For example, the serotype M3 GAS emergence has been connected to the accumulation of a bacteriophage-encoded phospholipase A2 (SlaA) whose mechanism of action appears to involve penetrating host cells hence allowing adherence and binding to host epithelium. The The ability of A ΔslaA strain to cause pharyngitis in the cynomolgus macaque is impaired thus providing a significant support for the key role of SlaA in GAS pharyngeal pathogenesis ( [|Sitkiewicz et al., 2006] ).
 * Survival of GAS in blood **
 * Epithelial cell adherence **

GAS is mainly an extracellular pathogen, the past decade data have shown that the organism may invade and persist within epithelial cells ( [|Wang et al., 2006] ). The ex act role of this event in GAS pathogenesis is yet unclear. Many of the proteins that are involved in GAS epithelial cell invasion also take part in adherence, this includes FnBPs, M protein and streptocococcal collagen-like protein. This protein is located on the cell wall and it is required for invasive infection. T cells when exposed to the M protein cross-react with similar epitopes on human cardiac myosin and laminin, leading to the pathogenesis of rheumatic heart disease, (Guilherme, etal, 2006). The signalling pathways mediating GAS invasion begin with bacterial binding to eukaryotic cell surface integrins, which results in actin cytoskeletal rearrangement and GAS internalization ( [|Purushothaman et al., 2003] ). The binding of GAS with integrin-bound Fn leads to upregulation of growth factor β1, which in turn triggers cell surface expression of 5 integrin and Fn, this consequently makes the cells better targets for streptococcal binding ( [|Wang et al., 2006] ). For GAS to cau se pharyngitis and start the colonization of the oropharynx, the host innate immune response must be overcome for a periods of time (Ashbaugh et al., 2000; Virtaneva et al., 2005). GAS has modified several mechanisms for escaping the host innate immune response as observed in M protein and hyaluronic acid capsule (Cunningham, 2000). There are other immune proteins which add to GAS pharyngitis such as streptococcal inhibitor of complement (Sic), and secreted DNases. ScpA is a cell surface serine protease that specifically cleaves C5a, thereby decreasing C5apolymorphonuclear (PMN) leucocyte binding and subsequent PMN recruitment (Brown et al., 2005). Sic is a protein secreted to produce protean effects on host immunity at the back of pharynx. In the course of pharyngitis, the gene that encodes Sic is quickly upregulated (Virtaneva et al., 2005). In addition to preventing the complement membrane attack complex, Sic gets involved with pharyngeal immune defence function such as lysozyme, b-defensins, and the cathelicidin LL-37. Due to the interaction of Sic with proteins of the immune system, the bactericidal activity against GAS is strongly reduced.
 * Intracellular invasion **
 * Immune system avoidance **

**REFERENCES ** <span style="line-height: 150%; margin-bottom: .0001pt; margin-bottom: 0cm; mso-outline-level: 4; text-align: justify;"><span style="color: black; font-family: 'Times New Roman',serif; font-size: 14pt; line-height: 150%;">Ashbaugh, C. D., Moser, T. J., Shearer, M. H., White, M. H., Kennedy, R. C. and Wessel, M. R. (2000) 'Bacterial determinants of persistent throat colonization and the associated immune response in a primate model of human group A streptococcal pharyngeal infection.' //Cellular Microbiology,// 2(4), 283-292. <span style="line-height: 150%; margin-bottom: .0001pt; margin-bottom: 0cm; mso-outline-level: 4; text-align: justify;"><span style="color: black; font-family: 'Times New Roman',serif; font-size: 14pt; line-height: 150%;"> <span style="line-height: 150%; margin-bottom: .0001pt; margin-bottom: 0cm; mso-outline-level: 4; text-align: justify;"><span style="color: black; font-family: 'Times New Roman',serif; font-size: 14pt; line-height: 150%;"> <span style="font-family: 'Times New Roman',serif; font-size: 19px; line-height: 28px;">Edwards, A.M., Manetti, A.G., Falugi, F., Zingaretti, C., Capo, S., Buccato, S., Bensi, G., Telford, J. L., Mar (2008) 'Scavenger receptor gp340 aggregates group A streptococci by binding pili.' //Molecular Microbiology,// 68(6), 1378-1394. <span style="line-height: 150%; margin-bottom: .0001pt; margin-bottom: 0cm; mso-outline-level: 4; text-align: justify;"><span style="color: black; font-family: 'Times New Roman',serif; font-size: 14pt; line-height: 150%;"> <span style="line-height: 150%; margin-bottom: .0001pt; margin-bottom: 0cm; mso-outline-level: 4; text-align: justify;"><span style="color: black; font-family: 'Times New Roman',serif; font-size: 14pt; line-height: 150%;"> <span style="font-family: 'Times New Roman',serif; font-size: 19px; line-height: 28px;">Guilherme, L., Kalil, J. and Cunningham, M. (2006) 'Molecular mimicry in the autoimmune pathogenesis of rheumatic heart disease.' //Autoimmunity,// 39(1), 31-9. <span style="color: black; font-family: 'Times New Roman',serif; font-size: 14pt; line-height: 150%;"> <span style="color: black; font-family: 'Times New Roman',serif; font-size: 14pt; line-height: 150%;"> <span style="color: black; font-family: 'Times New Roman',serif; font-size: 14pt; line-height: 150%;">Herwald, H., Cramer, H., Morgein, M., Russell, W., Sollenberg, U., Norrby-Teglund, A., Flodgaard, H., Lindbom, L. and Bjorck, L. (2004) 'M protein, a classical bacterial virulence determinant, forms complexes with fibrinogen that induce vascular leakage.' //Cell,// 116, 367–379. <span style="color: black; font-family: 'Times New Roman',serif; font-size: 14pt; line-height: 150%;"> <span style="color: black; font-family: 'Times New Roman',serif; font-size: 14pt; line-height: 150%;"> <span style="font-family: 'Times New Roman',serif; font-size: 19px; line-height: 28px;">Shelburne, S.A., Sumby, P., Sitkiewicz, I., Granville, C.N., DeLeo, F.R. and Musser, J.M. (2005a) 'Central role of a two-component gene regulatory system of previously unknown function in pathogen persistence in human saliva.' //Proc Natl Acad Sci USA,// 102: 16037-16042. <span style="color: black; font-family: 'Times New Roman',serif; font-size: 14pt; line-height: 150%;"> <span style="line-height: 150%; margin-bottom: .0001pt; margin-bottom: 0cm; mso-outline-level: 4; text-align: justify;"><span style="color: black; font-family: 'Times New Roman',serif; font-size: 14pt; line-height: 150%;"> <span style="line-height: 150%; margin-bottom: .0001pt; margin-bottom: 0cm; mso-outline-level: 4; text-align: justify;"><span style="color: black; font-family: 'Times New Roman',serif; font-size: 14pt; line-height: 150%;">Sumby, P., Tart, A. H. and Musser, J. M. (2008) 'A non-human primate model of acute group a Streptococcus pharyngitis.' //Methods Mol Biol,// 431: 255-267.

<span style="color: black; font-family: 'Times New Roman',serif; font-size: 14pt; line-height: 150%;"> <span style="font-family: 'Times New Roman',serif; font-size: 19px; line-height: 28px;">Virtaneva, K., Porcella, S. F., Graham, M. R., Ireland, R. M., Johnson, C. A. and Ricklefs, S. M.(2005) 'Longitudinal analysis of the group A Streptococcus transcriptome in experimental pharyngitis in cynomolgus macaques.' //Proc Natl Acad Sci USA,// 102: 9014-9019. <span style="color: black; font-family: 'Times New Roman',serif; font-size: 14pt; line-height: 150%;"> <span style="color: black; font-family: 'Times New Roman',serif; font-size: 14pt; line-height: 150%;"> <span style="color: black; font-family: 'Times New Roman',serif; font-size: 14pt; line-height: 150%;">Walker, M. J. (2005) 'Is plasminogen deployed as a Streptococcus pyogenes virulence factor?' //Trends Microbiology,// (37)13, 308-313. <span style="line-height: 150%; margin-bottom: .0001pt; margin-bottom: 0cm; mso-outline-level: 4; text-align: justify;"><span style="color: black; font-family: 'Times New Roman',serif; font-size: 14pt; line-height: 150%;"> <span style="line-height: 150%; margin-bottom: .0001pt; margin-bottom: 0cm; mso-outline-level: 4; text-align: justify;"><span style="color: black; font-family: 'Times New Roman',serif; font-size: 14pt; line-height: 150%;"> <span style="line-height: 150%; margin-bottom: .0001pt; margin-bottom: 0cm; mso-outline-level: 4; text-align: justify;"><span style="color: black; font-family: 'Times New Roman',serif; font-size: 14pt; line-height: 150%;">Zahner, D., and Scott, J. R. (2007) 'SipA is required for pilus formation in Streptococcus pyogenes serotype M3.' //J Bacteriol,// 190: 527-535. <span style="color: black; font-family: 'Times New Roman',serif; font-size: 14pt; line-height: 150%;"> <span style="color: black; font-family: 'Times New Roman',serif; font-size: 14pt; line-height: 150%;">
 * Below is a list journals used in the cause of my work on " **the pathogenesis of acute pharyngitis**" as well as journals sent to and shared with group members:**





By Clement Utti.