IL-10 Restrains IL-17 to Limit Lung Pathology Characteristics following Pulmonary Infection with Francisella tularensis Live Vaccine Strain
ABSTRACT IL-10 production during intracellular bacterial infections is generally thought to be detrimental because of its role in suppressing protective T-helper cell 1 (Th1) responses. Francisella tularensis is a facultative intracellular bacterium that activates both Th1 and Th17 protective immune responses. Herein, we report that IL-10-deficient mice (Il10(-/-)), despite having increased Th1 and Th17 responses, exhibit increased mortality after pulmonary infection with F. tularensis live vaccine strain. We demonstrate that the increased mortality observed in Il10(-/-)-infected mice is due to exacerbated IL-17 production that causes increased neutrophil recruitment and associated lung pathology. Thus, although IL-17 is required for protective immunity against pulmonary infection with F. tularensis live vaccine strain, its production is tightly regulated by IL-10 to generate efficient induction of protective immunity without mediating pathology. These data suggest a critical role for IL-10 in maintaining the delicate balance between host immunity and pathology during pulmonary infection with F. tularensis live vaccine strain.
- SourceAvailable from: Sunagar Raju[Show abstract] [Hide abstract]
ABSTRACT: Fc gamma receptor IIB (Fcí µí»¾RIIB) is the only Fc gamma receptor (Fcí µí»¾R) which negatively regulates the immune response, when engaged by antigen-(Ag-) antibody (Ab) complexes. Thus, the generation of Ag-specific IgG in response to infection or immunization has the potential to downmodulate immune protection against infection. Therefore, we sought to determine the impact of Fcí µí»¾RIIB on immune protection against Francisella tularensis (Ft), a Category A biothreat agent. We utilized inactivated Ft (iFt) as an immunogen. Na¨ve and iFt-immunized Fcí µí»¾RIIB knockout (KO) or wildtype (WT) mice were challenged with Ft-live vaccine strain (LVS). While no significant difference in survival between na¨ve Fcí µí»¾RIIB KO versus WT mice was observed, iFt-immunized Fcí µí»¾RIIB KO mice were significantly better protected than iFt-immunized WT mice. Ft-specific IgA in serum and bronchial alveolar lavage, as well as IFN-í µí»¾, IL-10, and TNF-í µí»¼ production by splenocytes harvested from iFt-immunized Fcí µí»¾RIIB KO, were also significantly elevated. In addition, iFt-immunized Fcí µí»¾RIIB KO mice exhibited a reduction in proinflammatory cytokine levels in vivo at 5 days after challenge, which correlates with increased survival following Ft-LVS challenge in published studies. Thus, these studies demonstrate for the first time the ability of Fcí µí»¾RIIB to regulate vaccine-induced IgA production and downmodulate immunity and protection. The immune mechanisms behind the above observations and their potential impact on vaccine development are discussed.Journal of Immunology Research; 01/2015
- [Show abstract] [Hide abstract]
ABSTRACT: Each year, up to one fifth of the United States population is infected with influenza virus. Although mortality rates are low, hundreds of thousands are hospitalized each year in the United States. Specific high risk groups, such as those with suppressed or dysregulated immune systems, are at greater danger for influenza complications. Respiratory infections are a common cause of hospitalizations and early mortality in patients with systemic lupus erythematosus (SLE); however, whether this increased infection risk is a consequence of the underlying dysregulated immune background and/or immunosuppressing drugs is unknown. To evaluate the influenza immune response in the context of lupus, as well as assess the effect of infection on autoimmune disease in a controlled setting, we infected lupus-prone MRL/MpJ-Faslpr mice with influenza virus A PR/8/34 H1N1. Interestingly, we found that Faslpr mice generated more influenza A virus specific T cells with less neutrophil accumulation in the lung during acute infection. Moreover, Faslpr mice produced fewer flu-specific IgG and IgM antibodies, but effectively cleared the virus. Further, increased extrinsic apoptosis during influenza infection led to a delay in autoimmune disease pathology with decreased severity of splenomegaly and kidney disease. Following primary influenza A infection, Faslpr mice had severe complications during the contraction and resolution phase with widespread severe pulmonary inflammation. Our findings suggest that influenza infection may not exacerbate autoimmune pathology in mice during acute infection as a direct result of virus induced apoptosis. Additionally, autoimmunity drives an enhanced antigen-specific T cell response to clear the virus, but persisting pulmonary inflammation following viral clearance may cause complications in this lupus animal model.Journal of Autoimmunity 01/2015; 57. DOI:10.1016/j.jaut.2014.12.003 · 7.02 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Francisella tularensis, a facultative intracellular Gram-negative bacterium, causes the illness tularemia. The infection of mice with live vaccine strain is considered to be a model of human tularemia. F. tularensis infects predominantly such phagocytic cells as macrophages or neutrophils, but it also infects non-phagocytic hepatocytes, epithelial cells, and murine and human B cell lines. Based on work with the murine tularemia model, we report here that F. tularensis LVS infects peritoneal CD19+ cells – exclusively B-1a cells – early after intraperitoneal infection in vivo. The peritoneal and consequently spleen CD19+ cells are activated by the F. tularensis LVS infection to express the activation markers from MHC class II, CD25, CD54, CD69, and the co-stimulatory molecules CD80 and CD86. As early as 12 h post-infection, the peritoneal CD19+ cells produce IFN-γ, IL-1β, IL-4, IL-6, IL-12, IL-17, IL-23, and TNF-α. The spleen CD19+ cells respond to infection with some delay. Moreover, the F. tularensis infected A20 B cell line activates CD3+ spleen cells isolated from naïve mice. Thus, the data presented here suggest that B cells have all the attributes to actively participate in the induction and regulation of the adaptive immune response during early stages of F. tularensis infection.Microbial Pathogenesis 10/2014; 75. DOI:10.1016/j.micpath.2014.08.009 · 2.00 Impact Factor