Why do microbes mimic human proteins? 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 that mimic human hormones, which in humans are produced by a specific cell type, and are transported by body fluids, to exert their action on different cells. 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. Moreover, these microbial mimickers have the potential to cause autoimmune diseases, including Type 1 diabetes. To this end, we 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.
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, we decided to characterize these insulin like-peptides. We have shown that chemically-synthesized VILPs can bind to human and murine IGF-1/insulin receptors and stimulate receptor autophosphorylation and downstream signaling. VILPs can also increase glucose uptake in adipocytes and stimulate proliferation of fibroblasts, whereas injection of VILPs into mice significantly lowers blood glucose. 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. (Altindis et. al, 2018, PNAS). The main goal of this project is to further characterize the viral insulins using in vivo and in vitro models and to understand their role in diabetes and cancer. Moreover, using one of these four VILP carrying viruses, grouper iridovirus, as a model system, we 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. Given that insulin (especially the B-chain, B: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 bacterial B:9-23 like sequence identified in Parabacteroides distasonis genome stimulated the insulin- specific reactive T cells obtained from T1D patients and NOD mice. 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 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 will continue to explore the potential role of both VILPs and cross reactive microbial insulin epitopes mimics from gut microbiome in Type 1 diabetes autoimmunity. . Using bioinformatics tools as well as NOD mice and germ free mice models, we attempt to better understand the role of single bacterial species in Type 1 Diabetes.