Group A streptococcus GAS) or Streptococcus pyogenes has been recognized as an important human pathogen since early days of modern microbiology, and it remains among the top ten causes of mortality from an infectious disease. Clinical manifestations attributable to this organism are perhaps the most diverse of any single human pathogen. These encompass invasive GAS infections, with high mortality rates despite effective antimicrobials, toxin-mediated diseases including scarlet fever and streptococcal toxic shock syndrome, the autoimmune sequelae of rheumatic fever and glomerulonephritis with potential for long-term disability, and nuisance manifestations of superficial skin and pharyngeal infection, which continue to consume a sizable proportion of healthcare resources.
Although an historical perspective indicates major overall reductions in GAS infection rates in the modern era, chiefly as a result of widespread improvements in socioeconomic circumstances, this pathogen remains as a leading infectious cause of global morbidity and mortality. More than 18 million people globally are estimated to suffer from serious GAS disease. This burden disproportionally affects least affluent populations, and is a major cause of illness and death among children and young adults, including pregnant women, in low-resource settings.
Our studies are focused on two subjects. The first one focuses on GAS CXC protease, ScpC. This protease cleaves CXC chemokines include interleukin 8 (IL-8) and thereby inactivates host neutrophil’s protective function such as chemotaxis, phagocytic killing and neutrophil extracellular traps (NETs) formation. Recently we discovered that ScpC also specifically cleaves the human antimicrobial cathelcidin peptide LL-37. We have identified the cleavage site and demonstrated that LL-37 cleavage into two fragments modulates both pro-and anti- inflammatory activities of LL-37. On one hand it abrogates LL-37 ability to recruit neutrophils and produce IL-8 by keratinocytes. On the other hand it diminishes neutrophil-life span in soft tissues. Our current working hypothesis is that by cleaving of LL-37 the bacteria allows the bacterium to maintain controlled influx of neutrophils but also controls they life span thus enabling the bacteria to achieve appropriate level of local inflammation that is required for GAS survivable in the host.
The second subject that we study is how bacteria alters its response with different host environment. Previously we deciphered a mechanism that we termed Host Sensing. Upon attachment to its host GAS delivers the streptolysin toxins SLO and SLS. These toxins cause endoplasmic reticulum (ER) stress and unfolded protein response (UPR). This upregulates host asparagine (ASN) production and release. ASN is sensed by the bacteria to regulate its profile of gene expression as well as rate of proliferation. This mechanism was deciphered using GAS quorum-sensing (QS) sil as a transcriptional reporter. Most recently we identified a group A Streptococcus (GAS) strain possessing the QS system sil, which produces functional bacteriocins, through a sequential signaling pathway integrating host and bacterial signals. ASN sensing upregulates the expression of the sil autoinducer peptide-SilCR. This consequently switches on the autoinduction cycle of SilCR production. The autoinduction process propagates throughout the GAS population, resulting in synchronous production of bacteriocins. The sequential host-bacterial signal transduction process occurs also in vivo. In accordance, subcutaneous co-injection of mice with the bacteriocin-producing strain and the globally disseminated M1T1 GAS clone results in disappearance of M1T1 from the fascia. The described mechanism explains how a fraction of a bacterial population, in close proximity to host cells, imposes its output signaling on the entire bacterial community.
Project: Neutrophils II
Baruch M, Hertzog BB, Ravins M, Anand A, Cheng CY, Biswas D, Tirosh B, Hanski E. Induction of endoplasmic reticulum stress and unfolded protein response constitutes a pathogenic strategy of group A streptococcus. (2014). Front Cell Infect Microbiol. 2014 Aug 4;4:105. doi: 10.3389/fcimb..
Baruch M., Belotserkovsky I., Hertzog BB., Ravins M., Dov E, McIver KS, Le Breton YS2, Zhou Y, Cheng CY, Hanski E. (2014). An extracellular bacterial pathogen modulates host metabolism to regulate its own sensing and proliferation. Cell. 2014 Jan 16;156(1-2):97-108
Belotserkovsky, I., Baruch, M., Peer, A., Dov, E., Ravins, M., Mishalian, I., Persky, M., Smith, Y., and Hanski, E. (2009). Functional analysis of the quorum-sensing streptococcal invasion locus (sil). PLoS Pathog. 5(11):e1000651.
Hidalgo-Grass, C., Mishalian, I., Dan-Goor, M., Belotserkovsky, I., Eran, Y., Nizet, V., Peled, A., and Hanski, E. (2006). A streptococcal protease that degrades CXC chemokines and impairs bacterial clearance from infected tissues. EMBO J. 25, 4628-4637.
Hidalgo-Grass, C. Dan-Goor, M., Maly, M. Eran, Y. Kwinn, L.A., Nizet, V. Ravins, M. Jaffe, J. Peyser, A. Moses, A. E., and Hanski, E. (2004). Degradation of host chemokines in group A streptococcal necrotizing soft tissue Infections: a novel bacterial virulence mechanism that is reversed by a bacterial pheromone peptide. Lancet, 363, 696-703.