IFN-I signaling and inflammasome activation are two innate pathways important for combatting a variety of pathogens. Swanson et al. show that cGAMP activates the inflammasome in addition to IFN-I, and that the activation of both is needed to control infection by a DNA virus.

dPneumocystis pneumonia was first diagnosed in malnourished children and has more recently been found in children with upper respiratory symptoms. We previously reported that there is a significant delay in the immune response in newborn mice infected with Pneumocystis compared to adults (Garvy BA, Harmsen AG, Infect. Immun. 64:3987-3992, 1996, and Garvy BA, Qureshi M, J. Immunol. 165:6480 -6486, 2000). This delay is characterized by the failure of neonatal lungs to upregulate proinflammatory cytokines and attract T cells into the alveoli. Here, we report that regardless of the age at which we infected the mice, they failed to mount an inflammatory response in the alveolar spaces until they were 21 days of age or older. Anti-inflammatory cytokines had some role in dampening inflammation, since interleukin-10 (IL-10)-deficient pups cleared Pneumocystis faster than wildtype pups and the neutralization of transforming growth factor beta (TGF-␤) with specific antibody enhanced T cell migration into the lungs at later time points. However, the clearance kinetics were similar to those of control pups, suggesting that there is an intrinsic deficiency in the ability of innate immunity to control Pneumocystis. We found, using an adoptive transfer strategy, that the lung environment contributes to association of Pneumocystis organisms with alveolar macrophages, implying no intrinsic deficiency in the binding of Pneumocystis by neonatal macrophages. Using both in vivo and in vitro assays, we found that Pneumocystis organisms were less able to stimulate translocation of NF-B to the nucleus of alveolar macrophages from neonatal mice. These data indicate that there is an early unresponsiveness of neonatal alveolar macrophages to Pneumocystis infection that is both intrinsic and related to the immunosuppressive environment found in neonatal lungs.

Background Inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are characterized by chronic intestinal inflammation due to immunological, microbial and environmental factors in genetically predisposed individuals. Advances in the diagnosis, prognosis and treatment of IBD require the identification of robust biomarkers that can be used for molecular classification of diverse disease presentations. We previously identified five genes, RELA, TNFAIP3 (A20), PIGR, TNF and IL8, whose mRNA levels in colonic mucosal biopsies could be used in a multivariate analysis to classify patients with Crohn’s disease (CD) based on disease behavior and responses to therapy. Aim We compared expression of these 5 biomarkers in IBD patients classified as having CD or ulcerative colitis (UC), and in healthy controls. Results Patients with CD were characterized as having decreased median expression of TNFAIP3, PIGR and TNF in non-inflamed colonic mucosa as compared to healthy controls. By contrast, UC patients exhibited decreased expression of PIGR and elevated expression of IL8 in colonic mucosa compared to healthy controls. A multivariate analysis combining mRNA levels for all 5 genes resulted in segregation of individuals based on disease presentation (CD vs. UC) as well as severity, i.e., patients in remission vs. those with acute colitis at the time of biopsy. Conclusion We propose that this approach could be used as a model for molecular classification of IBD patients, which could further be enhanced by the inclusion of additional genes that are identified by functional studies, global gene expression analyses, and genome-wide association studies.

Risks of radiation exposure from nuclear incidents and cancer radiotherapy are undeniable realities. These dangers urgently compel the development of agents for ameliorating radiation–induced injuries. Biologic pathways mediated by myeloid differentiation primary response gene 88 (MyD88), the common adaptor for toll–like receptor (TLR) and Interleukin–1 receptor signaling, are critical for radioprotection. Treating with agonists prior to radiation enhances survival by activating TLR signaling, whereas radiomitigating TLR–activating therapeutics given after exposure are less defined. We examine the radiomitigation capability of TLR agonists and identify one that is superior for its efficacy and reduced toxic consequences compared to other tested agonists. We demonstrate that the synthetic TLR2/6 ligand Fibroblast–stimulating lipopeptide (FSL–1) substantially prolongs survival in both male and female mice when administered 24 hours after radiation and shows MyD88–dependent function. FSL–1 treatment results in accelerated hematopoiesis in bone marrow, spleen and periphery, and augments systemic levels of hematopoiesis–stimulating factors. The ability of FSL–1 to stimulate hematopoiesis is critical, as hematopoietic dysfunction results from a range of ionizing radiation doses. The efficacy of a single FSL–1 dose for alleviating radiation injury while protecting against adverse effects reveals a viable radiation countermeasures agent.