ABSTRACTFor many years,Streptococcus anginosushas been considered a commensal colonizing the oral cavity, as well as the gastrointestinal and genitourinary tracts. However, recent epidemiological and clinical data designate this bacterium as an emerging opportunistic pathogen. Despite the reported pathogenicity ofS. anginosus, the molecular mechanism underpinning its virulence is poorly described. Therefore, our goal was to develop and optimize efficient and simple infection models that can be applied to examine the virulence ofS. anginosusand to study host-pathogen interactions. Using 23S. anginosusisolates collected from different infections, including severe and superficial infections, as well as an attenuated strain devoid of CppA, we demonstrate for the first time thatDictyostelium discoideumis a suitable model for initial, fast, and large-scale screening of virulence. Furthermore, we found that another nonvertebrate animal model,Galleria mellonella, can be used to study the pathogenesis ofS. anginosusinfection, with an emphasis on the interactions between the pathogen and host innate immunity. Examining the profile of immune defense genes, including antimicrobial peptides, opsonins, regulators of nodulation, and inhibitors of proteases, by quantitative PCR (qPCR) we identified different immune response profiles depending on theS. anginosusstrain. Using these models, we show thatS. anginosusis resistant to the bactericidal activity of phagocytes, a phenomenon confirmed using human neutrophils. Notably, since we found that the data from these models corresponded to the clinical severity of infection, we propose their further application to studies of the virulence ofS. anginosus.