In this episode, Red Blood Cell witnesses Monocyte doing a lot of weird things around the body such as sleeping in a hot spring and hiding behind lamp poles. Suddenly, Staphylococcus aureus (S. aureus) invades the human body to take revenge of her cousin who was killed in episode 2. Neutrophils appear in time to kill them, but the remaining bacteria fuse to form one giant monster that attacks the neutrophils. Just as the neutrophils get overwhelmed, the monocytes arrive and transform into macrophages. The macrophages beat up the S. aureus giant, breaking it off into individual bacteria that run away and get killed. Following this, macrophages and neutrophils thank each other for working together to eliminate S. aureus.

What happens during S. aureus infection and do macrophages really save neutrophils from being overwhelmed? Find out as we dive into S. aureus infection.

The biology of Staphylococcus aureus

Schematic	Microscopic	Anime

S. aureus is a Gram-positive, spherical bacterium with a capsule, thick cell wall and plasma membrane. They are found in grape-shaped colonies (hence the Greek words staphyle (for grapes) and kokkos (for berries)) that are yellow in colour (hence the Latin word aureus for gold). Like all bacteria, S. aureus has one chromosome, but it can exchange genetic material, allowing the bacteria to continually evolve.

S. aureus can also produce a variety of proteins that allow them to colonise and infect different parts of the body. In particular, they are able to release toxins, proteins that damage the human body. There are three types of toxins:

• Membrane-damaging toxins that form pores on the cell surface, leading to cell lysis and death. These include haemolysins (particularly α-haemolysins) which kill red blood cells and leukocidins (e.g., Panton-Valentine leucocidin) which kill white blood cells.
• Receptor-interfering toxins that bind to receptors on cells to interfere with its functions. A prime example is superantigens (e.g., toxic shock syndrome toxin (TSST)), a group of proteins that binds non-specifically to MHC class II complexes to trigger massive cytokine release and cell death from T cells.
• Secreted enzymes that can interfere with body processes or degrade host proteins. For example, coagulases such as staphylocoagulase and bacterial von Willebrand factor can activate the body’s coagulation cascade to form a fibrin mesh that protects the bacteria against the immune system.

How does Staphylococcus aureus cause disease?

S. aureus is normally present in the nostrils and skin of approximately 30% individuals. However, the bacteria can be invasive, particularly when the immune system is weakened, and can cause a variety of diseases around the body. The development of S. aureus infection can be split into five stages.

Adherence and colonisation

S. aureus can adhere onto a specific part of the body as well as medical devices and prosthetics. This is mediated by adherence proteins on bacteria that bind to human structural proteins. In addition, while colonising an unsterilised medical device or prosthetic. S. aureus can form a biofilm that protects them against antibiotics and the immune system. Once the biofilm is formed, it is very difficult to remove the bacteria, requiring replacement of the medical device or prosthetic.

Local infection

Colonisation of S. aureus bacteria in one specific organ or part of the body can produce local infection. Excessive S. aureus colonisation in the skin can produce lesions caused by excessive inflammation and cell death from the release of S. aureus toxins. S. aureus colonisation on bones and joints can cause osteomyelitis (bone infection) associated with bone degradation and improper bone formation. Rarely, S. aureus can also cause pneumonia (lung infection) and urinary tract infection.

Systemic spread

S. aureus can secrete enzymes such as collagenase to destroy tissue. This allows bacteria to enter the bloodstream, causing bacteraemia. While in the bloodstream, S. aureus can utilise the body’s blood clotting system by secreting two coagulases: staphylocoagulase and bacterial von Willebrand factor. These coagulases bind to prothrombin to form staphylothrombin. This protein functions similarly to thrombin in that it converts fibrinogen to fibrin. This forms a fibrin mesh that protects S. aureus against the immune system (which can be seen in the episode). In addition, S. aureus can secrete staphylokinase which degrades the host’s fibrin clots. This keeps any wounds open so that more bacteria can enter the body.

Metastatic infection

S. aureus can spread in the bloodstream to colonise and infect other organs and parts of the human body. In most organs, S. aureus can form abscesses where a fibrin capsule and rings of dead white blood cells protect the bacteria. These abscesses can be pushed out to the surface where they burst, releasing bacteria back into the bloodstream. S. aureus can also cause various organ-specific diseases. A prime example of this is infective endocarditis where S. aureus infects the heart valves and inside lining of the heart chambers. This can disrupt blood flow in the heart and damage heart valves which can lead to organ failure and death.

Toxinosis

S. aureus can release toxins into the bloodstream such as superantigens. This can lead to toxic shock syndrome, where circulation of toxins dilates blood vessels, reducing blood pressure, and induces sudden fever. Toxins can also act on other parts of the body such as the digestive system to cause symptoms such as vomiting and diarrhoea and organ failure.

Did you know? S. aureus infection is a huge public health problem worldwide, being spread in hospitals (as more invasive, medical device and prosthetic operations are being performed) and communities (driven by ageing populations). S. aureus is also resistant to common antibiotics such as penicillin and methicillin, making it more difficult to treat infection.

The immune response to Staphylococcus aureus infection

Neutrophils are white blood cells that initially respond to S. aureus infection. They act to limit the spread of S. aureus infection, buying time for other white blood cells to arrive at the infected site. Without them, the human body would be quickly overwhelmed by S. aureus infection. How neutrophils kill bacteria is explained in a previous post. In summary, neutrophils can engulf and degrade S. aureus with reactive oxygen species (ROS) and neutrophil granules. They can also trap and degrade S. aureus outside the cell by releasing neutrophil extracellular traps (NETs).

Macrophages arrive later in infection and function similarly to neutrophils in that they engulf and degrade S. aureus via phagocytosis. However, how macrophages kill S. aureus is slightly different to neutrophils. Firstly, phagosomes containing S. aureus inside macrophages can acidify, decreasing the pH which makes it more difficult for bacteria to survive. Phagosomes can also fuse with lysosomes to form phagolysosomes, where enzymes such as cathepsin, lysozyme and LL-37 degrade S. aureus. Similar to neutrophils, macrophages can also produce ROS to degrade S. aureus. Hence, macrophages can save neutrophlis from being overwhelmed by providing alternative ways to capture and degrade S. aureus, allowing the infection to be contained.

Staphylococcus aureus can evade the immune response

Despite neutrophils and macrophages working together to eliminate S. aureus infection in the episode, the bacteria has evolved to possess a variety of tools to dodge the immune response. Some of the ways in which S. aureus can evade the immune response include:

• Producing factors (e.g., chemotaxis inhibitory protein) to stop neutrophils and macrophages from migrating to the infection site;
• Secreting proteins (e.g., protein A) to stop antibodies from binding to bacteria, preventing engulfment of bacteria by neutrophils and macrophages;
• Producing leukocidins to kill neutrophils and macrophages;
• Releasing enzymes (e.g., superoxide dismutase and catalase) to neutralise ROS and enzymes while inside a neutrophil or macrophage; and
• Producing proteins on the surface to protect bacteria against macrophage enzymes, allowing them to keep living inside macrophages.

Conclusion

In the anime episode, macrophages, which have evolved from monocytes, save the neutrophils’ day in eliminating S. aureus infection. Similar to neutrophils, macrophages can engulf and degrade S. aureus bacteria. However, S. aureus has a variety of ways to dodge the actions of macrophages and neutrophils in eliminating them. Combined with the increasing resistance of these bacteria to antibiotics, S. aureus is becoming an increasingly problematic pathogen with the potential to cause a variety of diseases and even death. Research into novel S. aureus infection and vaccines is ongoing with the hope that the infection can be controlled, giving the immune system a chance to more easily eliminate the bacteria.

In the next blog post, we will discover how the body reacts to a hot day. See you there!