Let's Get Physical: Flavivirus-Host Protein-Protein Interactions in Replication and Pathogenesis

Abstract

Flaviviruses comprise a genus of viruses that pose a significant burden on human health worldwide. Transmission by both mosquito and tick vectors, and broad host tropism contribute to the presence of flaviviruses globally. Like all viruses, they require utilization of host molecular machinery to facilitate their replication through physical interactions. Their RNA genomes are translated using host ribosomes, synthesizing viral proteins that cooperate with each other and host proteins to reshape the host cell into a factory for virus replication. Thus, dissecting the physical interactions between viral proteins and their host protein targets is essential in our comprehension of how flaviviruses replicate and how they alter host cell behavior. Beyond replication, even single interactions can contribute to immune evasion and pathogenesis, providing potential avenues for therapeutic intervention. Here, we review protein interactions between flavivirus and host proteins that contribute to virus replication, immune evasion, and disease.

Keywords: autophagy; flavivirus; protein–protein interactions; virus host interactions; virus pathogenesis; virus replication.

Figure 1

Flavivirus replication cycle. Flavivirus infection begins by receptor-mediated binding to the host cell and entry via clathrin-mediated endocytosis. Decreases in endosome pH trigger virion envelope fusion with the endosome membrane, releasing the genome into the host cytosol. After uncoating, the viral RNA genome is translated by host ribosomes into the viral polypeptide, which is co-translationally processed, including insertion of transmembrane proteins into the ER and cleavage of the polypeptide by host and viral proteases into individual proteins. Non-structural viral proteins form replication complexes, which replicate viral RNA genomes within invaginated ER compartments. Structural viral proteins are assembled and loaded with viral genetic material in the ER prior to entering the trans-Golgi network. In the Golgi, immature virions are processed by furin protease cleavage of prM, resulting in mature, infectious virions. These virions exit the cell by exocytosis and continue the replication cycle by initiating infection of other host cells.

Figure 2

Summary of host proteins used by flaviviruses for entry. Flaviviruses recognize and bind plasma membrane host factors to initiate entry into the host cell. Different flaviviruses utilize a similar pool of host proteins for entry.

Figure 3

Flaviviruses co-opt host proteins to remodel the ER. Flaviviruses dramatically alter the morphology of the host ER to create a niche that maximizes the efficiency of genome replication and virion packaging. Replication compartments are formed by the involution of the ER membrane by both viral and host proteins. Viral replication complexes reside within these compartments and carry out RNA replication. These complexes also physically associate with host proteins. Viral single-stranded RNA (ssRNA)+ genomes are translated on the ER by host ribosomes. The resulting viral polyprotein is co-translationally processed to ensure its stability, insertion into the ER membrane, and proper cleavage into individual viral proteins. *TMEM41B is known to interact with either ZIKV NS4A or YFV NS4B and may facilitate ER remodeling.

Figure 4

Host innate immune response is antagonized by flavivirus protein interactions. Upon entry, flaviviruses are sensed by different pattern-recognition receptors (PRRs) such as TLR-3 and RIG-I. The signaling induced by these sensors converges on a common cascade that induces the production of interferon (IFN) and downstream genes stimulated by IFN called interferon-stimulated genes (ISGs). Flaviviruses have evolved invasive strategies to interfere with host immune response by antagonizing different protein components of innate immune signaling pathways associated with IFN production and IFN signaling. The DENV NS2B3 protease is shown as NS2B and NS3 interacting together to antagonize STING.