Flavivirus

Basic information and current topics regarding Flaviviridae

Virus Attachment, Entry, and Uncoating

Welcome to the first stage of the flavivirus life-cycle

In this section, we will be looking at everything from the Entry label to the endosome label in this diagram:


Flavivirus Life-cycle Image from: Chambers, T. J.,  et. al. The Flaviviruses: Structure, replication, and evolution (see references for full citation)


The attachment of any virus to the cell surface is a critical and determinant characteristic. After all, if phages could attach to human cell lines, we’d all be dead just from the massive amounts of viruses attached to us! Thankfully, this is not the case. And, in the same manner, not all Flaviviruses share the same tropism.

Saying that the Flaviviridae family infects only vertebrates doesn’t really limit the matches down a readable list, so we must describe their tropism backwards—that is, we must generalize about what enables these viruses to infect a cell. So, let’s take a look at what doors Flaviviridae holds the key to.

Flaviviruses have only thee structural proteins to work with when creating more viruses. As a result, the surface of the finished viral particle is a simple mix of nucleocapsid (C), membrane proteins (prM/M), and cell surface recognition proteins (E). Although it might not seem like much, these proteins are used to their full potential, and many perform multiple functions throughout the virus life-cycle.

The most determinant protein which affects a flavivirus’s tropism is the E glycoprotein, which acts as a binding factor and initiates membrane fusion. Phagocytic cells which express the immunoglobulin gamma (IgG) receptors on their cell-surface—specifically, the Fc-gamma-receptor—have a greater affinity for binding most flaviviruses due to opsonization with GpE and the complement IgG.1

It is important to note that flaviviruses enter the cell via receptor-mediated endocytosis, and that membrane fusion only occurs between the E protein and the endosomal membrane, not the cell membrane.3,4 Below is a figure which–rather artfully–shows the internalization of Dengue Virus into cancerous, human liver cells (Huh7 cell line). This figure simplifies and provides a visual basis for the attachment and entry of flaviviruses–I strongly suggest you take a look at the original published figure by clicking on the image! Be sure to note how the virus starts out being spatially stratified, but then centralize their location after entering the cell.

Click to navigate to the original diagram.

Figure 2. Internalization of Dengue Virus by the endosome.5
Image from Ang, F (2010). (see references for full citation)

So, in general, the E protein holds two specific functions: Binding to the cell-surface (attachment), and inducing fusion with the endosomal membrane (release).How the E protein is signaled to fuse with the membrane is still unknown, though it is widely accepted that the low pH of the endosome plays the main role in this phenomenon.2,3

Figure 3. The conformational change (C) that the E protein undergoes when in an acidic environment.
Image from: Chambers, T. J.,  et. al. The Flaviviruses: Structure, replication, and evolution. pp. 27

This conformational change is critical to the fusion activity between the viral proteins and the endosomal membrane, which allows the nucleocapsid to be released into the cytoplasm.

Following the fusion of the membrane, a flavivirus will then have its nucleocapsid released into the cytoplasm where it is ready for the next stage of the life-cycle, replication and biosynthesis.


References

1.       Peiris, JS (11/29/1979). “Antibody-mediated enhancement of Flavivirus replication in macrophage-like cell lines.”. Nature (London) (0028-0836), 282 (5738), p. 509.

2.       Nawa, M (1998). “Effects of bafilomycin A1 on Japanese encephalitis virus in C6 36 mosquito cells”. Archives of virology (0304-8608), 143 (8), p. 1555.

3.       Allison, SL (05/2001). “Mutational evidence for an internal fusion peptide in flavivirus envelope protein E.”. Journal of virology (0022-538X), 75 (9), p. 4268.

4.       Chambers, T. J., & Monath, T. P. (January 1, 2003). The Flaviviruses: Structure, replication, and evolution. p. 27, 65.

5.       Ang, F (2010). Small interference RNA profiling reveals the essential role of human membrane trafficking genes in mediating the infectious entry of dengue virus. Virology journal (1743-422X), 7, p. 24.