Type B coxsackieviruses and their interactions with the innate and adaptive immune systems

Abstract

Coxsackieviruses are important human pathogens, and their interactions with the innate and adaptive immune systems are of particular interest. Many viruses evade some aspects of the innate response, but coxsackieviruses go a step further by actively inducing, and then exploiting, some features of the host cell response. Furthermore, while most viruses encode proteins that hinder the effector functions of adaptive immunity, coxsackieviruses and their cousins demonstrate a unique capacity to almost completely evade the attention of naive CD8(+) T cells. In this artcle, we discuss the above phenomena, describe the current status of research in the field, and present several testable hypotheses regarding possible links between virus infection, innate immune sensing and disease.

Figure 1. Proposed intersections between type B coxsackievirus RNA, Toll-like receptors, RIG-I-like receptors, mitochondria and autophagy

This representation of the hypotheses presented in the text helps explain cellular innate responses to CVB infection. Viral RNA (blue lines) releases the CARD domains of the cytosolic RNA sensors (RIG-I and MDA5) from their RD. By binding to MAVS (yellow bar), a signal transduction cascade is triggered, leading to induction of type I IFNs etc (lower right of cartoon). However, we speculate that MAVS binding has additional effects. We propose that mitochondria act as a bridge (green arrow) between the cytosolic RNA sensors (RIG-I, MDA5) and the intravesicular TLRs, as follows: mitochondrial depolarization occurs, upregulating autophagy; this increases the uptake of viral RNA into the autophagy pathway, thereby introducing this RNA to the nucleic acid-sensing TLRs (red ovals) in acidified autolysosomes. A positive-feedback loop (yellow arrow) ensures the rapid amplification of these RLR-initiated, TLR-propagated innate responses. Finally, we suggest that, as infection progresses within the cell, viral proteins may become sufficiently abundant to obviate the feedback loop by inhibiting autophagosomal maturation (┴), thereby limiting the amount of viral RNA that encounters TLRs. CARD: Caspase-recruitment domain; CVB: Type B coxsackieviruses; MAVS: Mitochondrial antiviral signaling; RD: Repressor domains; RLR: RIG-I-like receptor; TLR: Toll-like receptor.

Figure 2. Mitochondrial degradation in a type B coxsackievirus-infected pancreatic acinar cell in vivo

Transmission electron microscopy image (magnification: ×10,500) of a pancreatic acinar cell from a mouse, 48 h after infection with Type B coxsackieviruses 3. A mitochondrion in the process of degradation is shown. Z: Zymogen granules.