Protection conferred by intraperitoneal Group A Streptococcus immunization relies on macrophages and IFN-γ but not on concurrent adaptive immune responses.
Group A Streptococcus (GAS; Streptococcus pyogenes) is an important bacterial pathogen estimated to cause over 700 million superficial infections and around 500.000 deaths due to invasive disease or severe post-infection sequelae in the world yearly. In spite of this major impact on society, there is currently no vaccine available against this bacterium. GAS strains can be separated into >200 distinct emm (M)-types, and protective immunity against GAS is believed to in part be dependent on type-specific antibodies. Here, we analyze the nature of protective immunity generated against GAS in a model of intraperitoneal immunization in mice. We demonstrate that multiple immunizations are required for the ability to survive a subsequent lethal challenge, and although significant levels of GAS-specific antibodies are produced, these are redundant for protection. Instead, our data show that the immunization-dependent protection in this model is induced in the absence of B and T cells, is accompanied by an altered cytokine profile upon subsequent infection and requires macrophages and the macrophage-activating cytokine IFN-{gamma}. To our knowledge these findings are the first to suggest that GAS has the ability to induce forms of trained innate immunity. Taken together, the current study reveals a novel mechanism of the innate immune system in response to GAS infections that potentially could be leveraged for future development of effective vaccines. Author summaryThe bacterium Group A Streptococcus (GAS) causes many hundred million infections and around 500.000 deaths in the world every year. GAS can give rise to a wide spectrum of diseases ranging from mild strep throat to life-threatening necrotizing fasciitis (often referred to as "flesh-eating disease"). There is currently no vaccine available for this pathogen, much due to our incomplete knowledge of how the immune system reacts to different GAS infections, what immune responses are in fact required for long-term protection and how these are generated. Here we show that protective immunity arising after immunization through the intraperitoneal (ip) cavity requires multiple injections using heat killed GAS. Surprisingly, although typical adaptive immune responses are activated and generate production of GAS-specific antibodies these are redundant for protection, which instead hinges on macrophages and the cytokine IFN-{gamma}. Our findings suggest that ip GAS immunizations trigger what is known as trained immunity, where innate immune cells become imprinted to respond with increased efficiency towards subsequent infection. Overall, these observations highlight a previously unknown ability of GAS to induce non-canonical forms of protective immunity, discoveries that may significantly contribute to our thinking about how the immune system reacts to such infections and broaden the scope for future vaccine strategies.