1. Innate Lymphoid Cell (ILC) biology
The Mortha lab has a strong interest in understanding the biology of innate lymphocytes. ILCs are a new family of human and murine lymphocytes composing of at least 3 individual lineages (ILC1, ILC2 and ILC3). These cells are rare in our circulating blood, rare to moderately represented in lymphoid tissues but highly abundant at mucosal tissue sites (i.e. intestine, liver, lung, adipose tissue or skin). ILCs are tissue-resident cells, characterized by the lack of an antigen receptor, the expression of lineage-defining transcription factors (ILC1: Tbet, ILC2: Gata3 and ILC3: Rorc), the fast release of cytokines and their instructive communication with non-hematopoietic tissue cells (intestinal epithelial cells, hepatocytes, adipocytes and fibroblasts). ILCs play an important role in defining and tuning the activation state of the tissue in the steady state and during disease. They promote antimicrobial activity, tissue regeneration, metabolic activity and organogenesis and are thus key player in our body’s physiology. Our laboratory has several aims addressing key questions and problems in ILC biology:
- We aim to identify tissue-specific determinants of ILC lineage commitment, function and plasticity.
- We aim to generate ILC-specific transgenic tools using CRISPR/Cas9 technology.
- We aim to design translational approaches targeting ILC-specific functions for therapy.
- We aim to understand how ILCs control adaptive immunity in the steady state and during disease.
2. Host-microbiome interactions
A second research topic of the laboratory is the crosstalk of the host immune system and commensal microbiota. The commensal microbiota is an essential community of microbes composed of viruses, bacteria, fungi and protists settling on our body’s mucosal surfaces. The sum of all genes (metagenome) provided by our commensal flora allows us to access new metabolites, vitamins and proteins that are essential to healthy life. Preventing our immune system from attacking our commensal communities is thus a key target to maintain equilibrium. Mononuclear phagocytes (MNP) are sentinel cells of our body and directly and indirectly interacting with our microflora. While MNP are found at every mucosal surface of our body, the microbes they are interacting with are vastly different between those sites. The interactions and the location of the MNP within the tissue will determine the underlying immune response. We aim to understand the nature of these signals and the immunologic consequences underlying the encounter of microbial signals by MNP.
3. Macrophage heterogeneity
Macrophages are key sentinels of tissue homeostasis. The associate with hematopoietic and non-hematopoietic cells in selective tissue niche across the intestinal tract. Within the lab, we are employing single cell RNA Sequencing and spatial transcriptional profiling of macrophages and their niche cells to understand the fundamental biological interactions between tissue sentinels and non-immune cells in the gut. We believe that a better understanding of their interaction will help to understand the regulation of epithelial cells, endothelial cells, stromal cells and neuronal networks at the body’s largest mucosal surface.
4. Mucosal antibody responses
An emerging topic in the lab centers around the understanding of mucosal antibody responses. Using genetic tool, we are currently exploring environmental factors that control B cell differentiation and antibody secretion. We have a strong focus on IgA antibodies and are eager to understand how these molecules regulate mucosal immunity, interactions with the microbiota and barrier integrity in the gut. Expanding our understanding of these interactions will inspire the development of new vaccines and adjuvants formulations.
Beyond Immunity: Underappreciated Functions of Intestinal Macrophages.
Chiaranunt P, Tai SL, Ngai L, Mortha A.
Front Immunol. 2021 Sep 28;12:749708.
Anti–GM-CSF autoantibodies promote a “pre-diseased” state in Crohn’s Disease.
Arthur Mortha, Romain Remark, Diane Marie Del Valle, Ling-Shiang Chuang, Zhi Chai, Inês Alves, Catarina Azevedo, Joana Gaifem, Jerome Martin, Kevin Tuballes, Vanessa Barcessat, Siu Ling Tai, Hsin-Hui Huang, Ilaria Laface, Yeray Arteaga Jerez, Gilles Boschetti, Nicole Villaverde, Mona D. Wang, Ujunwa M. Korie, Joseph Murray, Rok-Seon Choung, Takahiro Sato, Renee M. Laird, Scott Plevy, Adeeb Rahman, Joana Torres, Chad Porter, Mark S. Riddle, Ephraim Kenigsberg, Salomé S. Pinho, Judy H. Cho, Miriam Merad, Jean-Frederic Colombel, Sacha Gnjatic
Nlrp1b and Nlrp3 control the host response following colonization with the commensal protist Tritrichomonas musculis.
Pailin Chiaranunt, Kyle Burrows, Louis Ngai, Eric Y. Cao, Helen Liang, Catherine J. Streutker, Stephen E. Girardin, Arthur Mortha
Vasoactive intestinal peptide promotes host defense against enteric pathogens by modulating the recruitment of group 3 innate lymphoid cells.
Yu HB, Yang H, Allaire JM, Ma C, Graef FA, Mortha A, Liang Q, Bosman ES, Reid GS, Waschek JA, Osborne LC, Sokol H, Vallance BA, Jacobson K.
Proc Natl Acad Sci U S A. 2021 Oct 12
ILC2 Activation by Protozoan Commensal Microbes.
Burrows K, Ngai L, Wong F, Won D, Mortha A.
Int J Mol Sci. 2019 Sep 30;20(19)
Recirculating Intestinal IgA-Producing Cells Regulate Neuroinflammation via IL-10
Rojas OL, Pröbstel AK, Porfilio AK, Wang AA, (...), Horwitz MS, Winer DA, Mortha A, Mackay F, Prat A, Osborne LC, Robbins C, Baranzini SE, Gommerman JL
Cell. 2019 Jan 24;176(3):610-624
Microbiotas from Humans with Inflammatory Bowel Disease Alter the Balance of Gut Th17 and RORγt+ Regulatory T Cells and Exacerbate Colitis in Mice.
Britton GJ, Contijoch EJ, Mogno I, Vennaro OH, Llewellyn SR, Ng R, Li Z, Mortha A, Merad M, Das A, Gevers D, McGovern DPB, Singh N, Braun J, Jacobs JP, Clemente JC, Grinspan A, Sands BE, Colombel JF, Dubinsky MC, Faith JJ.
Immunity. 2019 Jan 15;50(1):212-224
Cytokine Networks between innate lymphoid cells and myeloid cells
Mortha A, Burrows K
Frontiers in Immunology, 2018 Feb 7;9:191
Host-protozoan interactions protect from mucosal infections through activation of the inflammasome.
Chudnovskiy A*, Mortha A*, Kana V, Kennard A, Ramirez JD, Rahman A, Remark R, Mogno I, Ng R, Gnjatic S, Amir ED, Solovyov A, Greenbaum B, Clemente J, Faith J, Belkaid Y, Grigg ME, Merad M.
Cell. 2016 Oct 6;167(2):444-456.e14
A Frameshift in CSF2RB Predominant Among Ashkenazi Jews Increases Risk for Crohn's Disease and Reduces Monocyte Signaling via GMCSF.
Chuang LS, Villaverde N, Hui KY, Mortha A, Rahman A, (…), Silverberg MS, Muise AM, Brant SR, Daly MJ, Segal AW, Duerr RH, Merad M, McGovern DP, Peter I, Cho JH.
Gastroenterology. 2016 Jul 1;
Neutrophil ageing is regulated by the microbiome.
Zhang D, Chen G, Manwani D, Mortha A, Xu C, Faith JJ, Burk RD, Kunisaki Y, Jang JE, Scheiermann C, Merad M, Frenette PS.
Nature. 2015 Sep 24;525(7570):528-32.
Crosstalk between muscularis macrophages and enteric neurons regulates gastrointestinal motility.
Muller PA, Koscsó B, Rajani GM, Stevanovic K, Berres ML, Hashimoto D, Mortha A, Leboeuf M, Li XM, Mucida D, Stanley ER, Dahan S, Margolis KG, Gershon MD, Merad M, Bogunovic M.
Cell. 2014 Jul 17;158(2):300-13
Microbiota-dependent crosstalk between macrophages and ILC3 promotes intestinal homeostasis.
Mortha A, Chudnovskiy A, Hashimoto D, Bogunovic M, Spencer SP, Belkaid Y and Merad M,
Science. 2014 Mar 28;343(6178):1249288
Innate lymphoid cells integrate stromal and immune signals to enhance antibody production by splenic marginal zone B cells.
Magri G, Miyajima M, Bascones S, Mortha A, Puga I, Cassis L, Barra CM, Comerma L, Chudnovskiy A, Gentile M, Llige D, Cols M, Serrano S, Aróstegui JI, Juan M, Yagüe J, Merad M, Fagarasan S and Cerutti A,
Nat Immunol., 2014 Apr;15(4):354-64.
Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes.
Hashimoto D, Chow A, Noizat C, Teo P, Beasley MB, Leboeuf M, Becker CD, See P, Price J, Lucas D, Greter M, Mortha A, Boyer SW, Forsberg EC, Tanaka M, van Rooijen N, García-Sastre A, Stanley ER, Ginhoux F, Frenette PS, Merad M.
Immunity. 2013 Apr 18;38(4):792-804.
Regulated expression of nuclear receptor RORgt confers distinct functional fates to NK cell receptor-expressing RORgt(+) innate lymphocytes.
Vonarbourg C*, Mortha A*, Bui VL, Hernandez PP, Kiss EA, Hoyler T, Flach M, Bengsch B, Thimme R, Hölscher C, Hönig M, Pannicke U, Schwarz K, Ware CF, Finke D, Diefenbach A.
Immunity. 2010 Nov 24;33(5):736-51 *equal contribution
RORgammat and commensal microflora are required for the differentiation of mucosal interleukin 22-producing NKp46+ cells.
Sanos SL, Bui VL*, Mortha A*, Oberle K, Heners C, Johner C, Diefenbach A.
Nat Immunol. 2009 Jan;10(1):83-91 *equal contribution