Coxsackievirus B Persistence Modifies the Proteome and the Secretome of Pancreatic Ductal Cells

Abstract

Summary The group B Coxsackieviruses (CVB), belonging to the Enterovirus genus, can establish persistent infections in human cells. These persistent infections have been linked to chronic diseases including type 1 diabetes. Still, the outcomes of persistent CVB infections in human pancreas are largely unknown. We established persistent CVB infections in a human pancreatic ductal-like cell line PANC-1 using two distinct CVB1 strains and profiled infection-induced changes in cellular protein expression and secretion using mass spectrometry-based proteomics. Persistent infections, showing characteristics of carrier-state persistence, were associated with a broad spectrum of changes, including changes in mitochondrial network morphology and energy metabolism and in the regulated secretory pathway. Interestingly, the expression of antiviral immune response proteins, and also several other proteins, differed clearly between the two persistent infections. Our results provide extensive information about the protein-level changes induced by persistent CVB infection and the potential virus-associated variability in the outcomes of these infections.

Ins and Outs of Reovirus: Vesicular Trafficking in Viral Entry and Egress

“…In this way, IAV alkalinizes the lumen of the Golgi complex and the trans-Golgi network ( TGN ), preventing premature conformational changes in the viral hemagglutinin during exit of viral progeny [ 80 ] while directing trafficking of the hemagglutinin along the secretory pathway to the PM [ 81 ]. The CVB viroporin releases charged calcium ions and protons from the Golgi complex and ER into the cytosol [ 82 ], reducing cellular protein trafficking and promoting persistent CVB infection [ 82 , 83 ]. This process additionally inhibits glycosylation of proteins in the Golgi complex, resulting in dampened host cell immune responses [ 84 ].…”

Structures and Functions of Viral 5′ Non-Coding Genomic RNA Domain-I in Group-B Enterovirus Infections

“…These truncated viral populations displayed 5 NCR deletions in RNA domain-I disrupting secondary RNA structures, which could impair viral RNA sensing by RLRs and result in a modulation of type I IFN expression in target cells [17]. Given that 5 TD viruses are low replicating forms, the generation or maintenance of such variants could be an efficient process for EV-B to develop a chronic persistent infection in human target cells long after the acute infection phase [16,18,[144][145][146][147]. The combination of low-level replication and translation activities of naturally produced 5 TD viruses, associated with the capacity of these RNA forms to modulate type-I IFN response activation pathway could explain long-lasting detection of EV-B genome in some human target tissues such as heart and pancreas.…”

Exploring the Triple Interaction between the Host Genome, the Epigenome, and the Gut Microbiome in Type 1 Diabetes

“…The gut virome is known to be associated with the initiation of T1D, in which many in vitro and in vivo studies identified a positive correlation between the acute viral infection and the development of T1D [ 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 ]. T1D-associated viruses include enteroviruses such as coxsackievirus B4 ( CV-B4 ) which is known to mediate a low-grade pancreatic inflammation by enhancing viral replication, affecting the expression of β cell differentiation proteins, and lowering the expression of mitochondrial antiviral signaling proteins leading to persistent infection [ 130 ]. CV-B4 is also known to lower the expression of HLA class I molecules at the surface of the infected pancreatic beta cells which are then targeted by the activated NK cells leading to cytolysis [ 120 , 130 , 131 ].…”

“…T1D-associated viruses include enteroviruses such as coxsackievirus B4 ( CV-B4 ) which is known to mediate a low-grade pancreatic inflammation by enhancing viral replication, affecting the expression of β cell differentiation proteins, and lowering the expression of mitochondrial antiviral signaling proteins leading to persistent infection [ 130 ]. CV-B4 is also known to lower the expression of HLA class I molecules at the surface of the infected pancreatic beta cells which are then targeted by the activated NK cells leading to cytolysis [ 120 , 130 , 131 ]. A recent report from the TEDDY study indicated that young children with a genetic risk for T1D experienced a prolonged enteroviruses type B and adenovirus infections that precede the development of T1D [ 120 , 121 , 130 , 132 , 133 , 134 ].…”