Biology subjects

Altindis, E.

Publications and source records attributed to Altindis, E..

3 recordsLinked to original sources

bioRxiv2024

Sex-Specific Cytokine, Chemokine, and Growth Factor Signatures in T1D Patients and Progressors

While studies have reported altered levels of cytokines in type 1 diabetes (T1D) patients, the results are inconsistent, likely because of variable factors. This study tests the hypothesis that there are sex-based differences in cytokine levels in T1D, prior to and after disease onset. We analyzed 48 blood cytokine, chemokine, and growth factor levels using a multiplex assay. We found only two cytokines, M-CSF and IL-6, with significant differences between T1D patients (n=25) versus controls overall (n=25). However, we identified notable alterations when comparing sex-age-matched controls and T1D samples. Inflammatory cytokines (TNF-, IL-6, IL-1a), Th2 cytokines (IL-4, IL-13), and chemokines (MIP-1, RANTES, MIP-3) were lower in female T1D patients compared to female controls, but not in males. IL-22 was lower in female T1D patients compared to female controls, while it was higher in male T1D patients compared to male controls. In contrast, growth factors (EGF, PDGF-AB/BB) were higher in male T1D patients compared to male controls. In T1D progressors (children who developed the disease years after the sample collection, n=16-21), GROa was lower compared to controls in both sexes. Our findings underscore the importance of understanding sex-specific differences in T1D pathogenesis and their implications for developing personalized treatments.

immunology↗

bioRxiv2024

Viral Insulin/IGF-like Peptides Selectively Activate Host Insulin/IGF Signaling pathways during Grouper Iridovirus Infection

Until our recent discovery of viral insulin/IGF-1-like peptides (VILPs), examples of viral mimicry were mostly limited to immunomodulatory proteins and growth factors. We previously showed that six viruses in the Iridoviridae family encode genes mimicking insulin and IGF-1. While VILP-carrying viruses are isolated from fish, the role of VILPs in host-pathogen interactions remain elusive. In this study, we used the Grouper Iridovirus (GIV), one of the VILP-carrying viruses, to examine the impact of the GIV-VILPs on the host IGF-1R/IR system during infection. Our structural analysis revealed that GIV-VILP is 35% identical to both zebrafish insulin and 35 IGF-1. We also showed that GIV-VILPs are early viral transcripts and resulting peptides are secreted during viral infection. Both single-chain (sc, resembling IGF-1) and double chain (dc, resembling insulin) forms of chemically synthesized GIV-VILPs can stimulate insulin receptor (IR) and IGF-1 receptor (IGF1R) phosphorylation. They could also stimulatepost-receptor signaling in both grouper kidney (GK) and zebrafish AB.9 cells as potently as insulin. Notably, supernatants obtained from GIV-infected cells could stimulate insulin/IGF system in a dose dependent manner. Interestingly, GIV-VILP was able to selectively activate the Akt/PI3K pathway while had no or minimal effect on Erk/MAPK pathway. Using either IR, IGF1R or dual inhibitors, we illustrated that inhibition of IR signaling suppressed GIV viral replication while inhibition of IGF1R enhanced viral replication. Consistent with selective signaling action of PI3K/Akt pathway, inhibition of the Akt reduced GIV viral replication however Erk pathway inhibition did not affect it. In summary, GIV-VILP is produced during GIV infection and manipulates host insulin/IGF signaling in a selective manner. Our findings reveal a previously unknown viral strategy in which viruses mimic a host hormone to exploit the hosts endocrine system. This discovery unveils a novel viral pathogenesis mechanism, broadens our understanding of viral mimicry, and opens a new avenue to better understand viral strategies to manipulate the host.

microbiology↗

bioRxiv2020

Characterization of Viral Insulins Reveals White Adipose Tissue Specific Effects in Mice

Members of the insulin/IGF superfamily are well conserved across the evolutionary tree. We recently showed that four viruses in the Iridoviridae family possess genes that encode proteins highly homologous to human insulin/IGF-1. Using chemically synthesized single chain (sc), i.e. IGF-1-like, forms of the viral insulin/IGF-1 like peptides (VILPs), we previously showed that they can stimulate human receptors. Because these peptides possess potential cleavage sites to form double chain (dc), i.e. more insulin-like, VILPs, in this study, we have characterized dc forms of VILPs for Grouper iridovirus (GIV), Singapore grouper iridovirus (SGIV) and Lymphocystis disease virus-1 (LCDV-1). GIV and SGIV dcVILPs bind to both isoforms of human insulin receptor (IR-A, IR-B) and to the IGF1R, and for the latter show higher affinity than human insulin. These dcVILPs stimulate IR and IGF1R phosphorylation and post-receptor signaling in vitro and in vivo. Both GIV and SGIV dcVILPs stimulate glucose uptake in mice. In vivo infusion experiments in awake mice revealed that while insulin (0.015 nmol/kg/min) and GIV dcVILP (0.75nmol/kg/min) stimulated a comparable glucose uptake in heart, skeletal muscle and brown adipose tissue, GIV dcVILP stimulated ~2 fold higher glucose uptake in white adipose tissue (WAT) compared to insulin. This was associated with increased Akt phosphorylation and glucose transporter type 4 (GLUT4) gene expression compared to insulin. Taken together, these results show that GIV and SGIV dcVILPs are active members of the insulin superfamily with unique characteristics. Elucidating the mechanism of tissue specificity for GIV dcVILP will help us to better understand insulin action, design new analogues that specifically target the tissues, and provide new insights into their potential role in disease.

cell biology↗