Viruses are intracellular parasites that rely on the host cellular machinery to replicate and survive. Their life cycle is divided into entry, replication and exit. To sustain this life cycle, viruses take over cellular signaling pathways, including NF-κB, MAPK, PI3K/AKT and Wnt/β-catenin signaling.

FAQs About Viral Signaling

What are the common signaling pathways hijacked by viruses?
Viruses hijack the host’s signaling pathways to use the host's cellular machinery and ensure their replication and survival (1). These signaling pathways, including NF-κB, MAPK, PI3K/AKT and Wnt/β-catenin signaling, regulate cellular functions, including gene expression, cell proliferation, cell differentiation, immune response, homeostasis, inflammation, apoptosis, cell survival, cell motility and more (2).
How do cells respond to viral entry?
When cells detect viral entry, they respond by activating signaling pathways and processes with antiviral activity. They produce interferons, which prevent viral replication within the cell, and activate pathways like the NF-κB pathway, which induces inflammatory genes, cytokines and chemokines to stimulate an immune response. Additionally, cells present pieces of viral proteins on their surface using Class I major histocompatibility complex proteins, allowing immune cells to detect the viral infection. However, viruses have developed ways to manipulate NF-κB signaling to evade antiviral responses and promote viral infection and survival. This is the case for viruses such as Kaposi sarcoma-associated herpesvirus, Epstein–Barr virus, Human immune-deficient virus 1 (HIV-1) and herpes simplex virus 1 (HSV-1) (3, 4).
What are the viral entry pathways?

Viral entry occurs in four steps, including virus attachment to the target cells, penetration into the cytoplasm, transportation within the cytoplasm to the replication site and uncoating, where the virus sheds its capsid to be exposed to cellular machinery for viral gene expression and replication (1).

Most viruses enter cells through a process called receptor-mediated endocytosis that allows them to penetrate deep into the cytoplasm and bypass plasma membrane barriers and cytoplasmic crowding (5, 6). Endocytosis occurs when a cell picks up an extracellular material by engulfing them within the cell membrane so that they enter the cell contained within a membrane bound vesicle. This occurs by several different methods, including caveolin or clathrin-mediated endocytosis, bulk-phase endocytosis and phagocytosis.

Some viruses, however, enter directly into the cell with the fusion of the viral envelope and plasma membrane.

How do viruses interact with host cells during endocytic entry?

Virus entry through endocytosis is a multi-step process that starts with the virus attaching to the cell surface, followed by receptors clustering. This clustering activates various signaling pathways, such as the PI3K-Akt and Src-JNK pathways, which are essential for initiating endocytosis and vesicle formation. These pathways lead to the formation of endocytic vesicles and vacuoles, which then deliver the viral cargo to endosomal compartments, where it is sorted and eventually escapes into the cytosol. (7)

Viruses use the host cell's molecular machinery to initiate endocytosis and prime the host cell for invasion from the plasma membrane. For instance, with the Japanese encephalitis virus (JEV), the viral envelope protein binds to the cell receptor to trigger the EGFR-PI3K-RhoA-ROCK-CFL1 signaling cascade. The activation of this cascade results in F-actin polymerization and CAV-1 phosphorylation, which then helps in the virus's entry into the cell through caveolae-mediated endocytosis. (7, 8)

What are the viral replication pathways?

Genome replication is unique to each virus family and is a key differentiating factor of virus families (1). Some viruses rely completely on host cell machinery to replicate, while others can replicate more independently. However, all viruses depend on the host cellular machinery for protein synthesis.

The Baltimore classification system groups viruses into seven classes depending on the type of nucleic acid and replication strategy: dsDNA, ssDNA, dsRNA, +ssRNA, -ssRNA, RNA viruses that reverse transcribe and DNA viruses that reverse transcribe. For example, because viruses with dsDNA genomes have the most similar nucleic acid to the genetic material of their eukaryotic hosts, they tend to use the enzymes and proteins used by the host cell for DNA replication and transcription.

When the ssDNA virus enters the host cell's nucleus the DNA polymerase converts the ssDNA genome dsDNA during the S phase of the cell cycle. Once the ssDNA genome is converted into dsDNA, RNA polymerase II can transcribe the viral genes. These genes are then translated into viral proteins, and DNA polymerase replicates the genome to enable the assembly of new virions (9).

What are the viral exit pathways?
Viral exit occurs with virion release from the cell. Enveloped viruses exit through a process called budding, where the virus takes on an envelope from the host cell membrane (10). It occurs in stages that include capsid assembly, release and maturation. On the other hand, non-enveloped viruses exit through cell lysis, where the virus ruptures from the host cell, killing it (1).

References and further reading

  1. Ryu WS. Virus Life Cycle. Molecular Virology of Human Pathogenic Viruses. 2017;31-45.
  2. Moens U. Role of Signaling Pathways in the Viral Life Cycle 2.0. Int J Mol Sci. 2022;23(14):7857. Published 2022 Jul 16.
  3. Zhao J, He S, Minassian A, Li J, Feng P. Recent advances on viral manipulation of NF-κB signaling pathway. Curr Opin Virol. 2015;15:103-111.
  4. Zinatizadeh MR, Schock B, Chalbatani GM, Zarandi PK, Jalali SA, Miri SR. The Nuclear Factor Kappa B (NF-kB) signaling in cancer development and immune diseases. Genes Dis. 2020;8(3):287-297. Published 2020 Jul 18.
  5. Kalia M, Jameel S. Virus entry paradigms. Amino Acids. 2011;41(5):1147-1157.
  6. Barrow E, Nicola AV, Liu J. Multiscale perspectives of virus entry via endocytosis. Virol J. 2013;10:177. Published 2013 Jun 5.
  7. Cossart P, Helenius A. Endocytosis of viruses and bacteria. Cold Spring Harb Perspect Biol. 2014;6(8):a016972. Published 2014 Aug 1.
  8. Xing Y, Wen Z, Gao W, Lin Z, Zhong J, Jiu Y. Multifaceted Functions of Host Cell Caveolae/Caveolin-1 in Virus Infections. Viruses. 2020;12(5):487. Published 2020 Apr 26.
  9. Louten J. Virus Replication. Essential Human Virology. 2016;49-70.
  10. Rheinemann L, Sundquist WI. Virus Budding. Encyclopedia of Virology. 2021;519-528.