In the first episode of the anime series Cells at Work!, Pneumococcus bacteria suddenly invade the human body. The neutrophils eliminate most Pneumococcus, but one of them runs away, intent on attacking the lungs. White Blood Cell rescues Red Blood Cell during the attack and accompanies her to the lungs as the former searches for the stray Pneumococcus and the latter drops off the carbon dioxide. After White Blood Cell leaves; however, Red Blood Cell is terrified by the stray Pneumococcus that emerges from her package. Realising this, White Blood Cell corners Pneumococcus into a trap in the lungs where he is captured and sent in a rocket to be sneezed out.

How true are the events of the anime episode? Join us as we learn more about Pneumococcus and how it can cause serious damage to the human body.

The biology of Pneumococcus

Schematic	Microscopic	Anime

Pneumococcus (scientific name Streptococcus pneumoniae) is a Gram-positive, extracellular bacterium with three layers: a polysaccharide capsule, a cell wall (made of peptidoglycan and teichoic acid) and the cell membrane. The capsule protects Pneumococcus against the immune system, particularly in preventing phagocytosis by white blood cells and binding of immune proteins such as complement and antibodies to the cell wall.

Did you know? There are at least 97 serotypes (subtypes) of Pneumococcus that vary by the capsule they carry. The capsule determines how invasive and virulent the Pneumococcus is. Pneumococcus of different serotypes can swap capsules to become more virulent.

Pneumococcus possesses a lot of virulence factors (parts of pathogens that cause disease) that are bound to the cell wall. For example, CbpA (choline-binding protein A) on the cell wall allows Pneumococcus to bind to epithelial cells in the nasal cavity so that it can grow and divide in the nose. Inside the Pneumococcus is the virulence factor pneumolysin, an important bacterial toxin that forms pores on cell membranes to lyse and kill host cells.

The pathology of Pneumococcal infection

Unlike the anime episode, Pneumococcus are restricted in where they enter the body. They normally enter the body via the nose (i.e., the upper respiratory tract), colonising there by binding to epithelial cells in the nasal cavity. In a healthy person, the immune system is strong enough to either contain or eliminate Pneumococcus in the nose.

However, if the immune system is weak such as in the young and elderly, Pneumococcus can migrate down the respiratory tract to the lungs where it can infect epithelial cells in alveoli, causing pneumonia (lung infection). Here, Pneumococcus releases pneumolysin and hydrogen peroxide (H₂O₂) to damage the blood-air barrier of the lung. This causes tissue fluid to leak into the alveolus, producing oedema which leads to breathing difficulties.

Pneumococcus can also go through the broken blood-air barrier to enter the blood, producing bacteraemia. This allows Pneumococcus to spread around the body to infect various organs, producing different diseases. Most notably, Pneumococcus can stick to the blood-brain barrier to cross over and cause meningitis. This is where Pneumococcus infects the meninges, the layers covering the spinal cord and brain, and divides in cerebrospinal fluid (CSF). Here, Pneumococcus releases toxins such as pneumolysin and hydrogen peroxide to kill neurons and host cells. The resultant inflammatory response in the brain worsens the damage, causing permanent brain damage and possibly death. Hence, Pneumococcal infection can be devastating to the human body, something that is accurately described in the anime.

Did you know? Pneumococcus can also infect the middle ear, producing the disease otitis media.

Similar to how Pneumococcus concealed himself in Red Blood Cell’s package before she arrived in the lungs, real-life Pneumococcus can hide in red blood cells to remain undetected by the immune system. Being α-haemolytic cells, they don’t directly kill cells. Instead, they undertake incomplete haemolysis, releasing hydrogen peroxide which converts haemoglobin (which can bind to oxygen) to green methaemoglobin (which cannot bind to oxygen). This not only reduces oxygen transport but also changes the cell colour to green which can be seen when bacteria is grown on blood agar.

The epidemiology of Pneumococcal infection

Pneumococcus spreads via air droplets that are coughed or sneezed from infected people as well as contaminated materials (called fomites) such as blankets and clothing. Pneumococcal infection is a huge problem worldwide, infecting 197 million people and killing 1.2 million globally in 2016, particularly in developing countries. Infants, children under the age of five, the elderly over the age of 60, immunocompromised patients and smokers have a high risk of developing Pneumococcal infection. Hence, even if it is not widely-publicised, Pneumococcal infection is an important global disease and something that is still being intensively researched.

How the body responds to Pneumococcus

The end of the anime episode is quite dramatic in that the trapped Pneumococcus travels through a series of tubes before it is loaded in a rocket and sneezed out. A similar process, albeit less dramatic, is seen in real-life: mucociliary clearance. This process is essential for clearing the airways of pathogens and foreign particles so that the lungs can keep breathing in and out to enable gas exchange. In mucociliary clearance, goblet cells in the respiratory epithelium secrete mucus which traps pathogens and foreign particles. From there, cilia on epithelial cells beat in a synchronised rhythm to sweep mucus up the respiratory tract to the pharynx where it is either swallowed or spat out.

If mucociliary clearance is insufficient for clearing pathogens and foreign particles out of the lungs, the body has two additional reflexes. Coughing expels pathogens or foreign particles from the throat (trachea) and lungs (bronchi and airways) while sneezing removes foreign particles from the nose. Coughing and sneezing can release droplets containing live Pneumococcus which is how the bacteria spreads between people. Hence, it is important that you cover your mouth when you cough or sneeze and to wash your hands afterwards.

Did you know? Smoking impairs mucociliary clearance. Not only does it increase the smoker’s risk of developing Pneumococcal infection but they also cough more often to clear the airways of trapped mucus that are not swept away (a phenomenon known as smoker’s cough).

If the Pneumococcus reaches the lungs to divide and cause disease, the immune response is activated. Initially, neutrophils migrate to the lungs to contain the Pneumococcal infection. They engulf the bacteria and break them down using defensins to disrupt the bacterial cell membrane and enzymes to degrade the bacteria. Macrophages appear later to engulf and kill Pneumococcus and secrete cytokines to recruit and activate other immune cells.

The adaptive immune system is activated later in infection. This involves helper T cells that strengthen physical barriers against infection, recruit neutrophils and promote antibody responses against Pneumococcus. B cells are also involved, releasing antibodies that bind to bacteria to mark them for phagocytosis. Specifically, IgA antibody targets Pneumococcus in the lungs while IgG antibody targets the bacteria in the bloodstream.

Contrary to the anime, killer T cells are not involved in Pneumococcal infection as the bacteria infects and kills host cells by releasing virulence factors extracellularly. Hence, there are no infected host cells that killer T cells can target to kill them.

Conclusion

Pneumococcus is an interesting pathogen to talk about. If mucociliary clearance is working and the immune system is strong, Pneumococcus would not pose a problem. If either of these processes are impaired; however, Pneumococcus can remain in the body to divide and infect organs. Left unchecked, Pneumococcus can cause a wide array of diseases, most notably pneumonia, bacteraemia and meningitis. That is why Pneumococcal infection is such a serious problem globally and one that is still being researched today.

In the next blog post, I will talk about blood clotting and how this helps maintain the integrity of the skin against the external environment. See you then!