Two-component gene regulatory systems in bacteria play important roles in regulating expression of genes encoding bacterial toxins, along with other virulence factors that interact with the host and promote survival of bacteria in vivo. In Group A Streptococcus pyogenes (GAS), ∼13 such regulators are known. The most well studied of these is the control of virulence (cov) intracellular responder (covR)/extracellular sensor (covS) system (CovRS), in which environmental changes are "sensed" by the gene product (CovS) of covS and transmitted to its cognate protein product of covR (CovR) via phosphorylation-dephosphorylation. CovRS regulates a large number of GAS virulence genes involved in invasiveness and antiphagocytosis, e.g., cysteine protease (speB), fibronectin binding protein (sfb1), hyaluronic acid capsule (hasABC), and streptokinase (sk). Deletion of CovRS derepressed the expression of these virulence factors and enhanced the survival of GAS in murine infection models. However, specific mechanisms by which the CovRS system regulates the phagocytosis of GAS in humans are incomplete. The goal of this study is centered on examining the role of the CovRS system in regulating complement-mediated opsonophagocytosis of GAS using both in vitro and in vivo systems.Evasion of complement-mediated opsonophagocytosis enables GAS to establish infection. In general, GAS inhibits the amplification of the complement cascade on its cell surface by facilitating the degradation of C3b, an opsonin, to an inactive product, inactivated C3b (iC3b), in a step catalyzed by factor I (FI) and its cofactor, factor H (FH), with or without the participation of human host plasmin (hPm). Using GAS strain AP53, which strongly binds host human plasminogen/plasmin (hPg/hPm), this study identified a key role for CovRS in the regulation of opsonophagocytosis of GAS by the host complement system. AP53 cells displayed potent binding of the host complement inhibitor, Factor H (FH), which concomitantly led to minimal C3b deposition on AP53 cells. This resulted in weak killing of the bacteria by human neutrophils and a corresponding high death rate of mice after injection of these cells. AP53 recruits FH to its cell surface via a FH receptor, which is transcriptionally controlled by CovRS. Further, the data show that both FI-FH and hPm sequentially cleave C3b. Whereas FI-FH proteolytically cleaves C3b into iC3b, hPm catalyzes cleavage of iC3b into multiple smaller peptides.  In addition, the role of CovRS system was also examined in the regulation of HtpA in the AP53 strain. HtpA is a novel Histidine Triad Proteins (HTP) that is thought to be regulated by CovRS in other strain (M23ND), participate in Zinc binding, and considered as an effective vaccine candidate against GAS infections. Interestingly, our data demonstrate that while HtpA has a role in avoiding the host innate immunity, it is not regulated by CovRS in the AP53 strain. Taken together, these results indicate that CovRS is a critical transcriptional regulator of genes directing GAS killing by neutrophils and thus protection of bacterial cells from the host complement response.