A major focus of our current research is the analysis of innate recognition pathways involved in the response to mycobacteria. This topic is of importance not only for identifying host resistance mechanisms to pathogenic species such as Mycobacterium tuberculosis (MTb) but also for understanding the potent adjuvant effects of attenuated and dead mycobacteria in promoting immune responses to proteins, unrelated pathogens and tumors. In work reported last year, we demonstrated that the dependence of host resistance to Mtb on the TLR/IL-1R adaptor MyD88 is largely due to a requirement for IL-1 rather than TLR signaling and identified a major role for IL-1beta in this response. In research completed during the report period we established that in addition to IL-1beta, IL-1alpha is independently required for host resistance. Furthermore, we employed newly developed intracellular cytokine staining techniques to identify two multifunctional inflammatory monocyte and DC populations that co-express both IL-1 species at the single cell level in lungs of Mtb infected mice. Importantly, we demonstrated that interferons play important roles in fine-tuning IL-1 production by these cell populations in vivo with type I IFNs inhibiting IL-1 alpha and beta production by both subsets and CD4 T cell derived IFNgamma suppressing IL-1alpha/beta expression in inflammatory monocytes only. These data provide a cellular basis for the anti-inflammatory and often pro-bacterial effects of IFNs during Mtb infection and reveal differential regulation of IL-1 induction from specialized cellular sources as an additional level of complexity governing IL-1 activity in vivo. Although mycobacteria and their products have long been known to display potent adjuvant activity, the innate recognition pathways through which they act are still poorly understood. As introduced in previous reports, we have been studying the role of innate recognition receptors in the T cell immunostimulatory activity of the mycobacteria in Complete Freunds Adjuvant (CFA). Mice immunized with OVA in CFA develop strong OVA-specific Th1 and Th17 responses and we have previously shown that this cytokine polarization (as opposed to T cell priming) is dependent on IL-1beta/IL-1R rather than TLR signaling. Moreover, we demonstrated a major role for inflammasome dependent processing of pro-IL-1 beta in this response. Our most recent work has focused on identifying the mycobacterial ligands and host signaling receptors that mediate both the induction of pro-IL-1beta message and activation of the inflammasome to generate the bioactive cytokine. Our results have implicated mycobacterial trehalose dimycolate (Cord Factor) and peptidoglycan as the two key bacterial components involved respectively. Interestingly the activity of Cord Factor in inducing pro-IL-1beta was found to be dependent on CARD 9, a signaling molecule used by C-type lectin receptors and one of these receptors, Mincle, was demonstrated to be largely responsible for the observed response. As described in last years report a peptidoglycan fraction purified from the mycobacteria was found to stimulate inflammasome function. Importantly, co-injection of Cord Factor and peptidoglycan in mineral oil recapitulated both the IL-1 inducing and adjuvant activities of Complete Freunds adjuvant itself arguing for the synergistic function of these two components in the IL-1 dependent immunostimulatory properties of mycobacteria

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Moreira-Teixeira, LĂșcia; Mayer-Barber, Katrin; Sher, Alan et al. (2018) Type I interferons in tuberculosis: Foe and occasionally friend. J Exp Med 215:1273-1285
Kawabe, Takeshi; Zhu, Jinfang; Sher, Alan (2018) Foreign antigen-independent memory-phenotype CD4+ T cells: a new player in innate immunity? Nat Rev Immunol 18:1
Radtke, Andrea J; Anderson, Charles F; Riteau, Nicolas et al. (2017) Adjuvant and carrier protein-dependent T-cell priming promotes a robust antibody response against the Plasmodium falciparum Pfs25 vaccine candidate. Sci Rep 7:40312
Wipperman, Matthew F; Fitzgerald, Daniel W; Juste, Marc Antoine Jean et al. (2017) Antibiotic treatment for Tuberculosis induces a profound dysbiosis of the microbiome that persists long after therapy is completed. Sci Rep 7:10767
Namasivayam, Sivaranjani; Maiga, Mamoudou; Yuan, Wuxing et al. (2017) Longitudinal profiling reveals a persistent intestinal dysbiosis triggered by conventional anti-tuberculosis therapy. Microbiome 5:71
Iwamura, Chiaki; Bouladoux, Nicolas; Belkaid, Yasmine et al. (2017) Sensing of the microbiota by NOD1 in mesenchymal stromal cells regulates murine hematopoiesis. Blood 129:171-176
Sher, Alan (2016) A Third signal from Conditioned DCs dictates microbial effector choice. Nat Rev Immunol 16:721
Riteau, Nicolas; Radtke, Andrea J; Shenderov, Kevin et al. (2016) Water-in-Oil-Only Adjuvants Selectively Promote T Follicular Helper Cell Polarization through a Type I IFN and IL-6-Dependent Pathway. J Immunol 197:3884-3893
Poholek, Amanda C; Jankovic, Dragana; Villarino, Alejandro V et al. (2016) IL-10 induces a STAT3-dependent autoregulatory loop in TH2 cells that promotes Blimp-1 restriction of cell expansion via antagonism of STAT5 target genes. Sci Immunol 1:
Riteau, Nicolas; Sher, Alan (2016) Chitosan: An Adjuvant with an Unanticipated STING. Immunity 44:522-4

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