Over the course of the last year the Inflammation and Innate Immunity Unit in the Laboratory of Clinical Infectious Diseases has moved into its permanent BL2 laboratory space on October 1st 2016 in Bldg. 33. The Inflammation and Innate Immunity Unit has been focusing on purchasing equipment and research supplies, recruiting post-doctoral fellows and advancing research projects in various areas related to host resistance against Mycobacterium tuberculosis infection as detailed below. The laboratory own BL3 laboratory is in the process fully equipped and currently being set-up and certified. The development of effective vaccines and host directed therapies (HDT) against M. tuberculosis (Mtb) infection requires a detailed understanding of the cellular basis of protective immunity. Considerable progress has been made in our understanding of protective adaptive immunity, yet relatively little is known about the contribution of innate effector cells. Particularly, the biological relevance of granulocytes like neutrophils and eosinophils is poorly understood. The innate inflammatory response is a prime target for HDT and manipulation of granulocytes could have major inflammatory and immunoregulatory implications for host resistance. Similar to neutrophils, eosinophils are phagocytic cells of the myeloid lineage that are thought to play an important effector role in the innate immune response. Their lineage-specific secondary granules contain cytotoxic cationic granular proteins that have been shown to exhibit anti-microbial activity and cause tissue damage. Preformed cytokines contained in these same granules include inflammatory cytokines like TNF-alpha, IL-1, IL-6 and IL-8 and pro-fibrogenic cytokines that can stimulate fibroblast proliferation, fibrotic and wound healing responses. In addition, lipid bodies, which form in response to eosinophil activation, contain a wide variety of leukotrienes, prostaglandins and reactive oxygen species that can contribute to these processes. More recently, eosinophils have been shown to play an important role in immunoregulation and homeostatic functions, including maintenance of long-lived plasma cells in the bone marrow and alternatively activated macrophages in adipose tissue. Eosinophils and their biological functions of have been studied primarily in the context of type 2 immunity, including parasitic helminth and pulmonary fungal infection, allergies and asthma. The role of eosinophils during bacterial infection remains largely unexplored. Indeed, eosinophils have been shown to exhibit bactericidal activities in response to E. coli and after P. Aeruginosa infection in vivo (Persson et al. 2001, Linch et al. 2009). There have also been reports of eosinophilic infiltration in BALF after Mtb infection in Guinea pigs (Lasco et al. 2009) and patients (Flores et al. 1983, Vijayan et al. 1992). However, a comprehensive study on the role of eosinophils during Mtb infection is lacking, both in animal models as well human clinical studies. Another barrier to our understanding of eosinophils in host resistance to TB is a paucity of data from the mouse model of Mtb infection. There are likely two major contributing factors to be considered for this: 1) Mtb infection primarily causes a type I immune response, and eosinophils are rare in numbers compared to neutrophils in the lungs of Mtb infected mice (KDMB unpublished data) and 2) the pathology of Mtb infected mouse lungs and human lungs is vastly different. Eosinophils were found to be enriched in areas of tissue remodeling and fibrosis in TB resected lungs from patients (KDMB unpublished data). While fibrotic responses are often seen in TB patients they are not considered a feature in the mouse model of Mtb infection. Therefore, we are currently re-evaluating the role of eosinophils in the mouse model of aerosol infection, in non-human primates infected with Mtb (in collaboration with Dan Barber) and in humans (in collaboration with Amy Klion, Ka-Wing Wong and Robert Wilkinson). In collaboration with the Sher laboratory, we have previously characterized two major innate pathways, IL-1 and type I interferons, respectively, that play pivotal roles in governing host resistance versus disease in the murine model of Mtb infection by intersecting the eicosanoid lipid network (Mayer-Barber et al. 2011, 2014). In particular, we uncovered that IL-1 can in turn counter-regulate type I IFN driven detrimental responses during Mtb infection. In murine and human macrophages IL-1 and IL-1 potently inhibit type I IFN induction at both the mRNA and protein level and similarly IFN mRNA and protein levels are upregulated in the lungs of Mtb infected Il1r1-/- deficient mice. This inhibition is of functional importance because mice doubly deficient in Il1r1,Ifnar1-/- are partially protected while Il1r1-/- singly deficient animals succumb rapidly to Mtb aerosol challenge. Moreover, when IL-1 is present in type I IFN treated cultures, it even suppresses the pro-bacterial effects downstream of IFN that lead to increased bacterial replication. Interestingly, IL-1 induced PGE2 is also able to potently inhibit type I IFNs in a dose dependent manner. Targeting PGE2 during Mtb infection, either via direct administration or its enhancement by 5 lipoxygenase (5-LO) blockade with Zileuton, reversed type I IFN driven mortality. These data highlighted and provided proof-of-concept that the cross-talk of IL-1 and type I IFN provides a valuable target for host-directed therapies of Mtb and plays a major role during infection in mice. However, the mechanisms how IL-1 and type I IFNs modulates bacterial replication and spread are unknown and we are currently investigating how diverse cell death modalities contribute to IL-1 mediated protection against Mtb. In addition, we are investigating the requirement for IL-1R1 expression on a variety of cell types, including macrophages, neutrophils and dendritic cells for bacterial control and protective function in pulmonary Mtb disease. References: Persson T, Andersson P, Bodelsson M, Laurell M, Malm, Egesten A. Bactericidal activity of human eosinophilic granulocytes against Escherichia coli. Infect Immun. 2001 Jun;69(6):3591-6. PMID:11349018 LinchSN1,Kelly AM,Danielson ET,Pero R,Lee JJ,GoldJA. Mouseeosinophilspossess potent antibacterial properties in vivo. Infect Immun.2009 Nov;77(11):4976-82. PMID: 19703974 LascoTM,Turner OC,Cassone L,Sugawara I,Yamada H,McMurray DN,OrmeIM. Rapid accumulation of eosinophils in lung lesions in guinea pigs infected with Mycobacterium tuberculosis. Infect Immun. 2004 Feb;72(2):1147-9. PMID:14742563 Flores, M., J. Merino-Angulo, J. G. Tanago, and C. Aguirre. 1983. Late generalized tuberculosis and eosinophilia. Arch Intern Med.1983 Jan;143(1):182. PMID:6849600 Vijayan, V.-K., A.-M. Reetha, M. S. Jawahar, K. Sankaran, and R. Prabhakar. 1992. Pulmonary eosinophilia in pulmonary tuberculosis. Chest.1992 Jun;101(6):1708-9. PMID:1600796 Mayer-BarberKD,Andrade BB,Barber DL,Hieny S,Feng CG,Caspar P,Oland S,Gordon S,Sher A. Innate and adaptive interferons suppress IL-1 and IL-1 production by distinct pulmonary myeloid subsets during Mycobacterium tuberculosis infection. Immunity.2011 Dec 23;35(6):1023-34. PMID:22195750 Mayer-Barber KD, Andrade BB, Oland SD, Amaral EP, Barber DL, Gonzales J, et al. Host-directed therapy of tuberculosis based on interleukin-1 and type I interferon crosstalk. Nature 2014, 511(7507): 99-103.

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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
Amaral, Eduardo P; Riteau, Nicolas; Moayeri, Mahtab et al. (2018) Lysosomal Cathepsin Release Is Required for NLRP3-Inflammasome Activation by Mycobacterium tuberculosis in Infected Macrophages. Front Immunol 9:1427
Charmoy, Melanie; Hurrell, Benjamin P; Romano, Audrey et al. (2016) The Nlrp3 inflammasome, IL-1?, and neutrophil recruitment are required for susceptibility to a nonhealing strain of Leishmania major in C57BL/6 mice. Eur J Immunol 46:897-911
Mayer-Barber, Katrin D; Yan, Bo (2016) Clash of the Cytokine Titans: counter-regulation of interleukin-1 and type I interferon-mediated inflammatory responses. Cell Mol Immunol :
Arbore, Giuseppina; West, Erin E; Spolski, Rosanne et al. (2016) T helper 1 immunity requires complement-driven NLRP3 inflammasome activity in CD4? T cells. Science 352:aad1210
McNab, Finlay; Mayer-Barber, Katrin; Sher, Alan et al. (2015) Type I interferons in infectious disease. Nat Rev Immunol 15:87-103
Sionov, Edward; Mayer-Barber, Katrin D; Chang, Yun C et al. (2015) Type I IFN Induction via Poly-ICLC Protects Mice against Cryptococcosis. PLoS Pathog 11:e1005040
Mayer-Barber, Katrin D; Sher, Alan (2015) Cytokine and lipid mediator networks in tuberculosis. Immunol Rev 264:264-75
Mayer-Barber, Katrin D; Barber, Daniel L (2015) Innate and Adaptive Cellular Immune Responses to Mycobacterium tuberculosis Infection. Cold Spring Harb Perspect Med :
Andrade, Bruno B; Pavan Kumar, Nathella; Amaral, Eduardo P et al. (2015) Heme Oxygenase-1 Regulation of Matrix Metalloproteinase-1 Expression Underlies Distinct Disease Profiles in Tuberculosis. J Immunol 195:2763-73