In this episode, Lactic Acid Bacterium, washed away from Normal Cell in the last episode, is picked up and tended by Dendritic Cell. Meanwhile, Normal Cell, Neutrophil and NK Cell move to the small intestine, where they encounter Influenza Virus that mutates and becomes resistant to the immune cells’ attacks. Just as the immune cells fall into despair, the dressed-up NK Cell suddenly appears with Lactic Acid Bacterium. By consuming the biscuits produced by Lactic Acid Bacterium, Dendritic Cell is motivated to spread embarrassing photos of immune cells’ past lives, motivating the immune cells to eliminate Influenza Virus.
Influenza is an infection that I covered in a previous blog post as part of an episode in the last season of Cells at Work!. In that blog post, I talked about what the influenza virus is and how T cells are activated by dendritic cells to eliminate influenza-infected cells. This blog post builds on the previous blog post, where I first provide more information about the influenza virus itself. This will lead to the big mistake the anime makes in regards to the different ways influenza viruses can evolve. Following this, I will then explain what cytokines are and how they assist in immune responses against pathogens.
Further information on the influenza virus
Influenza is a respiratory infection caused by the influenza virus, an enveloped, RNA virus that infects respiratory epithelial cells in the lung. The influenza virus is made up of different parts on the surface and inside the virus. The surface of the influenza virus is studded with two proteins: haemagglutinin (HA) and neuraminidase (NA). HA assists in influenza virus attachment onto and entry into uninfected cells by binding to sialic acid on the cell surface. In contrast, NA releases the budding influenza virus from an infected cell by cutting the bond between HA and sialic acid. Being present on the viral surface, HA and NA are the most common proteins recognised by the immune system and laboratories. During influenza infection, the immune system produces antibodies that bind to HA and NA, neutralising their ability to infect and spread to uninfected host cells. HA and NA are also used to describe different influenza virus subtypes, with some subtypes being more common in specific animal species. For example, H1N1 and H3N2 are prevalent influenza subtypes in humans while H5N1 and H7N9 are the most common subtypes of avian (bird) influenza strains.
Inside the influenza virus is single-stranded RNA that codes for different influenza proteins. Unlike other viruses such as coronavirus and dengue virus which only have one huge RNA segment, the influenza virus has eight RNA segments, each coding for a different viral protein. This assists the influenza virus in exchanging genetic material from different influenza subtypes which can generate potentially virulent influenza strains. RNA polymerase is also present inside the virus which generates new RNA segments while influenza viruses are replicated inside an infected cell. This protein also plays an important role in producing new influenza strains.
The difference behind antigenic drift and antigenic shift: how the anime got it wrong
The anime defines antigenic shift as follows:
As influenza is prone to mutation, the nature of the antigen changes every year. This is why it can’t always be blocked by acquired immunity.
Content-wise, it is true that influenza viruses can mutate to evade recognition and destruction by the immune system. As it takes time for the immune system to recognise the new influenza virus, annually, people can be infected with influenza and influenza vaccines need to be updated. However, the above definition describes antigenic drift, not antigenic shift which is an altogether different process. To understand why, I will first describe what antigenic drift is before explaining what antigenic shift really is.
Antigenic drift
What actually happened in the anime was that Influenza Virus was undergoing antigenic drift to resist the immune cells’ attacks. Antigenic drift describes mutations in the HA and NA genes that result in changes in the resultant protein structures. These mutations arise as a result of errors in the replication of viral RNA, where the incorrect RNA base is added onto a growing RNA segment. RNA polymerase from the influenza virus is less likely to pick up these genetic errors, so the mistakes persist in the genomes of new influenza viruses.
Although most mutations have little to no effect on the structures of viral proteins, some mutations can substitute one amino acid with another amino acid or alter the amino acid sequence of HA or NA. This may result in vast changes to the protein structure of HA or NA which deviates from its original versions. Consequently, antibodies that can bind to HA or NA of the original influenza virus may not bind well to mutated HA or NA proteins of the new influenza virus. The new influenza virus thus escapes recognition and elimination by the immune system for some time, allowing it to replicate unimpeded and cause infection as it takes time to set up a new immune response against the virus.
Antigenic drift is the reason why we get global epidemics of seasonal influenza every year, and why influenza vaccines have to be updated annually with new influenza strains to keep up with mutations that appear due to antigenic drift.
Antigenic shift
In contrast to antigenic drift, antigenic shift is an altogether different process that is not shown in the anime. Antigenic shift involves the exchange of genetic material among influenza viruses of different animal strains inhabiting the same organism, producing a novel influenza strain that no human is previously immune to. This is possible due to the segmented nature of viral RNA in influenza viruses, where influenza strains from different animal sources can exchange RNA segments. This can result in the emergence of a new influenza virus that can spread rapidly due to its ability to infect human cells and causes severe tissue damage, similar to swine or avian influenza viruses.
Antigenic shift is more problematic than antigenic drift as it can produce a new influenza strain that cannot be readily contained and eliminated by existing treatments and vaccines. As it takes time to sequence and characterise the new influenza virus and develop new treatments and vaccines against it, the influenza virus can spread quickly and produce severe infection, precipitating an influenza pandemic. An example where antigenic shift of an influenza virus caused a pandemic is the 2009 swine flu pandemic. The pandemic was caused by a H1N1 influenza strain (H1N1pdm09) produced by mixing different swine influenza strains in pigs, with different RNA segments coming from human, swine and avian influenza strains. The result was an influenza strain that replicated quickly and produced more severe infection in animals. In humans, the H1N1pdm09 influenza strain caused 60.8 million cases in the US and killed an estimated 284,500 people, with 80% of these deaths occurring in people younger than 65 years (not typical for a seasonal influ3enza strain). This speaks to the potential impact antigenic shift of influenza viruses can cause compared to antigenic drift.
Cytokines
What are cytokines?
Cytokines (from the Greek words cyto = cell and kinos = movement) are protein messengers that promote, direct and control immune responses to many stimuli, including pathogens. These protein messengers are secreted by a variety of immune and non-immune cells in response to various stimuli such as a pathogen, cell damage or environmental changes. Acting on the same cell it was released from or travelling to distant cells, cytokines bind to receptors on the cell surface. This interaction stimulates a signalling pathway inside cells, producing a variety of cellular responses such as growth, differentiation or death. Cytokines can also promote the production and secretion of proteins that can boost or inhibit immune responses around the body. Besides cytokines that direct immune responses around the body, there are also chemokines that attract white blood cells to infected sites around the body and interferons that stimulate cells to become more resistant to viral infection.
IL-12: an example of a pro-inflammatory cytokine
In the anime episode, the box where Dendritic Cell was storing the embarrassing photos was labelled IL-12. IL-12 is a prime example of a cytokine that can promote immune responses against bacterial and viral pathogens. IL-12 is produced by dendritic cells, macrophages, neutrophils and B cells upon interaction of a pathogen with receptors called pattern recognition receptors (PRRs). This interaction turns on signalling pathways inside the cell that switch on the production and secretion of IL-12.
IL-12 acts on the IL-12 receptor (IL-12R) on T and NK cells, activating a signalling pathway that produces a variety of effects. Firstly, IL-12 activates the naïve, inactive T cell. The activated T cell adopts a Th1 phenotype that promotes immunity against pathogens, particularly those that infect cells such as viruses. Th1 cells can boost immune responses to eliminate pathogens from the body. For example, Th1 cells are able to increase the antimicrobial activities of macrophages so that they can more efficiently kill the engulfed pathogens. IL-12 can also act on NK cells to stimulate its proliferation and enhance its cytotoxicity, making it more capable in killing infected cells.
IL-12 also stimulates the production of various cytokines from T and NK cells to further promote immune activity. The most notable cytokine whose production is induced by IL-12 is IFN-γ. IFN-γ can augment the activities of Th1 cells, increasing its capacity in promoting immune responses around the body and eliminating pathogens. IFN-γ can also act on dendritic cells, macrophages and B cells to further promote IL-12 secretion. This drives a positive feedback loop where IL-12 and IFN-γ can promote the secretion of each other from different cells, strengthening immune responses.
The role of lactic acid bacteria in promoting cytokine responses
In the anime episode, Lactic Acid Bacterium produced a biscuit that Dendritic Cell ate. This stimulated Dendritic Cell to produce and release IL-12 to motivate the other white blood cells to kill the influenza-infected cells. In reality, lactic acid bacteria can play a role in boosting cytokine responses and secretion, particularly IL-12. Studies have shown that lactic acid bacteria can induce IL-12 secretion from macrophages and DCs. This has a biological effect, slowing down tumour growth in a mouse model of cancer and inhibiting influenza infection in mouse lungs.
The immune-promoting effects of lactic acid bacteria are derived from the cell walls of lactic acid bacteria which are released when lactic acid bacteria die. The cell walls of lactic acid bacteria have been shown to induce IL-12 productionfrom mice macrophages. Hence, lactic acid bacteria has the potential to enhance immune responses in humans and animals by stimulating the release of pro-inflammatory and pro-immune cytokines.
Conclusion
Influenza viruses have two different ways to evade the immune system. The virus can mutate to change the conformation of its surface proteins via antigenic drift, or it can obtain RNA segments from influenza strains of other animals to produce different influenza proteins via antigen shift. Both processes allow influenza viruses to mount annual influenza epidemics and the rare pandemic. Nevertheless, cytokines can help control immune responses against pathogens such as influenza viruses, with IL-12 an example of an important cytokine. Moreover, lactic acid bacteria can help augment cytokine secretion and responses, allowing them to play a role in boosting immune responses against pathogens such as influenza.
In the next blog post, I will talk about the importance of the gut microbiota in maintaining the integrity of the gut epithelium, and what happens when the composition of the gut microbiota is compromised. See you then!