Viral Hormones: Expanding Dimensions in Endocrinology

Abstract

Viruses have developed different mechanisms to manipulate their hosts, including the process of viral mimicry in which viruses express important host proteins. Until recently, examples of viral mimicry were limited to mimics of growth factors and immunomodulatory proteins. Using a comprehensive bioinformatics approach, we have shown that viruses possess the DNA/RNA with potential to encode 16 different peptides with high sequence similarity to human peptide hormones and metabolically important regulatory proteins. We have characterized one of these families, the viral insulin/IGF-1-like peptides (VILPs), which we identified in four members of the Iridoviridae family. VILPs can bind to human insulin and IGF-1 receptors and stimulate classic postreceptor signaling pathways. Moreover, VILPs can stimulate glucose uptake in vitro and in vivo and stimulate DNA synthesis. DNA sequences of some VILP-carrying viruses have been identified in the human enteric virome. In addition to VILPs, sequences with homology to 15 other peptide hormones or cytokines can be identified in viral DNA/RNA sequences, some with a very high identity to hormones. Recent data by others has identified a peptide that resembles and mimics α-melanocyte-stimulating hormone's anti-inflammatory effects in in vitro and in vivo models. Taken together, these studies reveal novel mechanisms of viral and bacterial pathogenesis in which the microbe can directly target or mimic the host endocrine system. These findings also introduce the concept of a system of microbial hormones that provides new insights into the evolution of peptide hormones, as well as potential new roles of microbial hormones in health and disease.

Figure 1.

Predicted tertiary structure of VILPs and comparison with insulin and IGF-1. The structure is very well conserved among different VILPs. The A-chain is red; the B-chain is blue; the C-peptide is gray. The C-peptide of human IGF-1 is not cleaved, shown in gray. PyMOL (v1.8.6.2; Schrodinger, Inc., New York, NY) was used to make the illustrations. Predicted VILP structures were obtained using I-TASSER (Zhang Lab, University of Michigan, Ann Arbor, MI). For human insulin, see Protein Data Bank ID 2KQP; for human IGF-1, see Protein Data Bank ID 3LRI. T2D, type 2 diabetes.

Figure 2.

VILPs and their potential role in diabetes and cancer. VILPs bind to IR (red), IGF1R (orange), and hybrid receptors (red and orange) of targeted cells via autocrine, paracrine, endocrine, and other signaling to affect the pathogenesis of diabetes and cancer.