Garima Agrahari, a biochemistry graduate student in the laboratory of Francis J. Castelllino, is a recent recipient of a two year predoctoral fellowship from the Midwest Affiliate of the American Heart Association. The title of her study is “Molecular mechanisms of antiphagocytic activity mediated by Plasminogen binding group A streptococcal M-like protein.”
Agrahari’s study focuses on Streptococcus pyogenes or Group A Streptococcus (GAS) which is a spherical, gram-positive bacterium that is responsible for numerous diseases with diverse clinical manifestations specifically in humans. GAS likely plays a role in global health issues such as impetigo, pharyngitis, scarlet fever and life-threatening diseases such as necrotizing fasciitis, toxic shock, acute post-streptococcal glomerulonephritis, acute rheumatic fever and rheumatic heart disease (RHD). Approximately 18 million prevalent cases are found to be severe with nearly two million worldwide new cases reported per year and till now there is no effective method available for preventing life threatening GAS-associated invasive infections.
The progression of GAS infection is a complex combination of host-pathogen interactions leading to favorable conditions for proliferation and dissemination of the pathogen. GAS is equipped with several surface-expressed extracellular virulence factors that enable it to adhere and colonize on epithelial cells of skin and throat, evade the immune responses, and survive within the host. The pathogenesis of RHD is thought to be mediated by autoimmune mechanisms induced by M or M-Like proteins. M-like proteins, e.g., Plasminogen-binding group A streptococcal M-like protein (PAM), are surface-expressed virulence factors primarily involved in the bacterial cell surface binding of plasminogen (Pg) and plasmin (Pm) that facilitates GAS in adhesion, invasion, dissemination and evasion of innate and adaptive immunity to survive inside the host. Thus, it is hypothesized that direct binding of Pg to PAM leads to assembly of a proteolytic environment on the GAS surface, which is effective in disrupting innate barriers, and leads to the dissemination of the bacterial pathogen into host tissues and organs. The goals of this study are to study the antiphagocytic activity of PAM in human blood and in isolated neutrophils and explore the contribution of PAM in the regulation of the activation of host complement system and the mechanisms of resistance to phagocytosis. Ultimately, the long-term goal of this study is to determine the role of PAM in virulence and elucidate the mechanism of bacterial invasion and survival, which will also lead to identifying suitable drugs and new therapeutic strategies for treating GAS infections.
Originally published by transgene.nd.edu on November 25, 2014.at