Why and how do microbes mimic human proteins, especially the human hormones? What is the role of these microbial mimics in human disease? These are the main questions that we try to address in our lab. We recently discovered that viruses can synthesize proteins mimicking the human hormones. The role of these microbial hormones in human disease including cancer, diabetes and autoimmune disorders is unknown. The main goal of our lab is to better understand the role of microbial mimicry mechanisms in human diseases and characterize these microbial proteins. In addition to the potential effects on metabolism and physiology of the host, these microbial mimickers have the potential to cause autoimmune diseases, including Type 1 diabetes. To this end, we initially focus on two different but related projects: (a) characterization of viral insulins and their role in diabetes and cancer and (b) exploring the role of the microbiome in type 1 diabetes onset. Our work uses a combination of molecular biology, cell biology, microbiology, virology, tissue culture studies, mouse models of diabetes analysis of human samples and bioinformatics to better understand how microbial mimics function in microbe survival, host biology, and diabetes.
Characterization of Viral Insulin/IGF-1-like Peptides (VILPs) and Their Role in Human Disease
The interaction between the host and the pathogen resulted in co-evolution of their genomes. As a result, microbes have developed several mechanisms to manipulate their hosts, including mimicry mechanisms, expressing important host-like proteins. We recently showed that viruses carry sequences with significant homology to several human peptide hormones. Because the strongest homologies were those for four VILPs, each encoded by a different member of the family Iridoviridae viruses, we decided to characterize these insulin like-peptides. We have shown that VILPs can bind to human and murine IGF-1/insulin receptors and stimulate receptor autophosphorylation and downstream signaling. Human microbiome studies reveal the presence of these Iridoviridae DNA in blood and fecal samples. Thus, VILPs are new members of the insulin/IGF superfamily with ability to be active on human and rodent cells, raising the possibility for a potential role of VILPs in human disease (PNAS March 6, 2018 115 (10) 2461-2466). The main goal of this project is using in vivo and in vitro models to elucidate the molecular and cellular mechanisms through which viral insulins affect the host cell machinery and understand their role in diabetes and cancer. Using one of these four VILP carrying viruses, Grouper Iridovirus, as a model system, we also investigate the role of viral insulins for the viral replication and cellular processes during the infection of the host.
The Role of Microbiome and Virome in Type 1 Diabetes Autoimmunity
Type 1 diabetes (T1D) is a chronic disease characterized by autoimmune destruction of pancreatic β-cells. Studies suggest an environmental factor initiating this autoimmune response, but the cause of T1D autoimmunity is still unknown. An early marker of T1D autoimmunity is the development of four types of pancreatic islet autoantibodies. Among them, insulin autoantibodies (IAA) are the only autoantibodies specific to β-cells, the only cell type that is able to produce insulin in mammals. Molecular mimicry is one mechanism of autoimmune disease in which a foreign antigen that shares a structural similarity with a host protein can modify disease pathogenesis. Given that insulin (especially B chain, 9-23 peptide) is the main autoantigen targeted by the T-cells in T1DM, we hypothesized that VILPs and/or other microbial peptides with sequences similar to insulin B:9-23 will stimulate an autoimmune response against host insulin, through a molecular mimicry mechanism. Based on this hypothesis, we identified several B:9-23 epitope-like sequences in different microbial proteins and showed that, only one microbial B:9-23 like sequence identified in Parabacteroides distasonis stimulated the insulin- specific reactive T cells obtained from T1D patients and NOD mice (Altindis et al, Diabetes, 2018). Because P. distasonis is a commensal member of the human gut microbiome, it has potential to manipulate the immune response in the gut. Analysis of the published T1D metagenomic gut microbiome data showed that the abundance of this bacterial peptide and thus the bacteria significantly differed between controls and children at risk for T1D. Building upon this study, our lab continues to explore the potential role of the microbiome and virome in Type 1 diabetes autoimmunity using in vitro and in vivo models.
Girdhar, K., Soto, M., Huang, Q., Orliaguet, L., Cederquist, C., Sundaresh, B., Hu, J., Figura, M., Raisingani, A., Canfora, E.E., Altindis, E. (2022c). Gut Microbiota Regulate Pancreatic Growth, Exocrine Function, and Gut Hormones. Diabetes.
Girdhar, K., Huang, Q., Chow, I.-T., Brady, C., Raisingani, A., Autissier, P., Atkinson, M.A., Kwok, W.W., Ronald Kahn, C., and Altindis, E. (2022). A Gut Microbial Peptide and Molecular Mimicry in the Pathogenesis of Type 1 Diabetes. bioRxiv, 2020.2010.2022.350801.
Girdhar, K., Huang, Q., Dogru, Y.D., Yang, Y., Tolstikov, V., Chrudinova, M., Raisingani, A., Ludvigsson, J.F., Kiebish, M.A., Palm, N.W., Altindis, E. (2022b). Dynamics of Gut Microbiome, IgA Response and Plasma Metabolome in Development of Pediatric Celiac Disease. bioRxiv, 2020.2002.2029.971242.
Chrudinova, M., Moreau, F., Noh, H.L., Panikova, T., Zakova, L., Friedline, R.H., Valenzuela, F.A., Kim, J.K., Jiracek, J., Kahn, C.R., Altindis, E. (2021). Characterization of viral insulins reveals white adipose tissue-specific effects in mice. Mol Metab 44, 101121.
Girdhar, K., Powis, A., Raisingani, A., Chrudinova, M., Huang, R., Tran, T., Sevgi, K., Dogus Dogru, Y., and Altindis, E. (2021). Viruses and Metabolism: The Effects of Viral Infections and Viral Insulins on Host Metabolism. Annu Rev Virol 8, 373-391.
Zhang, F., Altindis, E., Kahn, C.R., DiMarchi, R.D., and Gelfanov, V. (2021). A viral insulin-like peptide is a natural competitive antagonist of the human IGF-1 receptor. Mol Metab 53, 101316.
Garcia-Martin, R., Brandao, B.B., Thomou, T., Altindis, E., and Kahn, C.R. (2022). Tissue differences in the exosomal/small extracellular vesicle proteome and their potential as indicators of altered tissue metabolism. Cell Rep 38, 110277.
Dedrick, S., Sundaresh, B., Huang, Q., Brady, C., Yoo, T., Cronin, C., Rudnicki, C., Flood, M., Momeni, B., Ludvigsson, J., and Altindis, E. (2020). The Role of Gut Microbiota and Environmental Factors in Type 1 Diabetes Pathogenesis. Front Endocrinol (Lausanne) 11, 78.
Huang, Q., Kahn, C.R., and Altindis, E. (2019). Viral Hormones: Expanding Dimensions in Endocrinology. Endocrinology 160, 2165-2179.
Altindis, E., Cai, W., Sakaguchi, M., Zhang, F., GuoXiao, W., Liu, F., De Meyts, P., Gelfanov, V., Pan, H., DiMarchi, R., et al. (2018). Viral insulin-like peptides activate human insulin and IGF-1 receptor signaling: A paradigm shift for host-microbe interactions. Proc Natl Acad Sci U S A 115, 2461-2466.
Altindis E, Cai W, Sakaguchi M, Zhang F, Guoxiao W, Liu F, Gelfanov V, De Meyts P, DiMarchi R and Kahn CR. Viral Hormones and Insulin-like Peptides: A New Paradigm for Host-Microbe Interaction (PNAS, February 2018)
Fujisaka S, Pacheco JA., Soto M, Kostic Aleksandar, Dreyfuss JM, Pan H., Ussar S., Altindis E, Li N., Bry L., , Clish CB., and Kahn CR. Diet, genetics and gut microbiome drive dynamic changes in plasma metabolites. (Cell Metabolism, March 2018)
Fujisaka S, Ussar S, Clish C., Devkota S., Dreyfuss J, Sakaguchi M, Konishi M, Softic S, Altindis E, Bry L and Kahn CR. Antibiotic Modification of Gut Microbiota Improves Insulin Signaling Via Effects on Bile Acids Depending on Host Genetics. J Clin Invest. 2016 Dec 1;126(12):4430-4443.
Altindis E*, Dong T*, Catalano J, Mekalanos JJ. Secretome analysis of Vibrio cholerae Type VI Secretion System reveals a new effector-immunity pair. mBio. 2015 Mar 10;6(2):e00075
Altindis E, Cozzi R, Di Palo B., Neccho F., Mishra P. R., Fontana M. R., Soriani M., Bagnoli F., Maione D., Grandi G., Liberatori S. Protectome analysis: a new selective bioinformatics tool for bacterial vaccine candidate discovery. Mol Cell Proteomics. 2015 Feb;14(2):418-29
Altindis E, Fu Y., Mekalanos JJ. Proteomic analysis of the Vibrio cholerae outer membrane vesicles. PNAS, 2014 Apr 15;111(15):E1548-56.
Mishra R, Mariotti P, Fiaschi L., Nosari S,, Maccari S., Liberatori S, Fontana M R, Pezzicoli A, Falugi F, Altindis E, Serruto D, Grandi G and Bagnoli F. Staphylococcus aureus FhuD2 is involved in the early phase of staphylococcal dissemination and generates protective immunity in mice. The Journal of Bacteriology, 2012 Oct 1;206(7):1041-9
Doro F, Liberatori S, Rodríguez-Ortega MJ, Rinaudo CD, Rosini R, Mora M, Scarselli M, Altindis E, D'Aurizio R, Stella M, Margarit I, Maione D, Telford JL, Norais N, Grandi G. Surfome analysis as a fast track to vaccine discovery: identification of a novel protective antigen for Group B Streptococcus hypervirulent strain COH1. Mol Cell Proteomics, 2009 Jul; 8(7):1728-37.
Altindis E, Tefon BE, Yildirim V, Ozcengiz E, Becher D, Hecker M, Ozcengiz G. Immunoproteomic analysis of Bordetella pertussis and identification of new immunogenic proteins. Vaccine, 2009 Jan 22; 27(4):542-8.