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Shigella: The Bacterial Pathogen Responsible For Bacillary Dysentery

Shigella is a genus of bacteria that causes a diarrhoeal disease called shigellosis. It is sometimes also known as bacillary dysentery and generally speaking, this disease is not life-threatening as our immune system is usually able to fight off the infection fairly easily. However, more serious complications may arise amongst high-risk individuals, and that is definitely not a good sign.


Globally, there are around 80 to 165 million cases of shigellosis, whereby 99% of which are in developing countries. Besides that, shigellosis also has a significant mortality burden for it is responsible for around 600,000 deaths annually.


In this article, we will explore the four species that fall under the Shigella genus and discuss their distribution as well as the nature of the disease they cause.


Introducing the villain itself


There is a range of infectious agents that are capable of causing diarrhoeal disease. Such agents include bacteria (like Vibrio cholerae, Salmonella, and pathogenic E. coli), parasites (such as Giardia lamblia), and viruses (like rotavirus).


Of these pathogens, Shigella infection is one of the key contributors to the high prevalence of diarrhoea. In fact, it makes up around 5 to 15% of all the cases.


The classification of Shigella

Scientists use classification to arrange all living organisms into groups. These groups, which are known as taxa (or taxon, if singular), are hierarchically arranged. The highest and broadest taxon in the hierarchy is ‘domain’, and categories get progressively narrower as you move down towards ‘genus’ and then ‘species’. For example, humans are in the Eukaryote domain and Animalia kingdom, but they are also members of the much smaller taxonomic group, namely the Homo sapiens species.


Bacteria like Shigella can be classified in the same way too, as shown in Figure 1. To begin with, Shigella is a genus in the family Enterobacteriaceae. This family contains a range of important bacterial pathogens like Salmonella, Yersinia pestis (the pathogen responsible for the plague), as well as Escherichia coli.

Figure 1: The classification of Shigella species.


As we go into further detail, the Shigella genus contains four species - Shigella dysenteriae, S. flexneri, S. sonnei, and S. boydeii. All of these species cause disease in humans and are ‘host restricted’ for they can only infect humans. However, there are also some key differences between the species, such as molecular variation and the geographic regions that they are most common in or even endemic to.


In some cases of bacterial classification, a single species can be subdivided into serotypes due to differences in their virulence factors (proteins produced by pathogens involved in causing an infection). This is the case for all Shigella species except S. sonnei. For instance, one of the S. dysenteriae serotypes is S. dysenteriae serotype 1, which is a strain that is capable of producing the Shiga toxin, a virulence factor responsible for the most severe form of shigellosis.


Where can you find them?

Shigella dysenteriae was actually the first species to be discovered, where it was first isolated by Kiyoshi Shiga isolated from stool samples in 1897 during a dysentery outbreak in Japan. This particular variant of Shigella had been responsible for epidemic dysentery outbreaks that were historically very common. Though the good news is that they are, fortunately, much more infrequent now.


In contrast to the epidemic dysentery caused by S. dysenteriae, S. flexneri is endemic in many low-income countries where it is the most common cause of diarrhoea. On the other hand, Shigella sonnei causes the mildest form of shigellosis and is the dominant species in developed countries such as the USA and UK. Interestingly, as countries become more developed, a clear switch from dominance by S. flexneri to S. sonnei occurs. This unusual phenomenon has been observed in countries across Asia, Latin America, and the Middle East, though the reason for this switch in predominance remains unclear.


Finally, Shigella boydii is the least common of the four species, making up around only 5% of total Shigella infections. It is mainly confined to the Indian subcontinent and is very rarely found anywhere else.


Features of the Shigella bacteria

Essentially, all four species in the Shigella genus share several morphological and biochemical features - they are all Gram-negative, non-motile, and rod-shaped facultative anaerobes.


These are all pretty important terms that are widely used in the field of bacteriology, so let’s have a look at what they mean.


(i) Gram-negative bacteria

Prokaryotes, such as bacteria, are unicellular organisms that lack a nucleus or any other membrane-bound organelles. This particular trait thereby distinguishes them from eukaryotic cells such as those of plants and animals.


Besides that, prokaryotic cells have a cell wall to maintain their shape and prevent osmotic lysis (i.e. the bursting of the cell when lots of water enters it), unlike animal cells. This cell wall surrounds a plasma membrane, which is a phospholipid bilayer that encloses eukaryotic and prokaryotic cells. Additionally, one of its key components is a polymer of sugars and peptides known as peptidoglycan.

Figure 2: Prokaryotic cells lack membrane-bound organelles, which are on the other hand, present in eukaryotic cells. Instead of a nucleus, prokaryotes have a region called the nucleoid which contains most of the cell’s genetic information. Unlike the eukaryotic animal cell shown, prokaryotic cells have a cell wall to prevent osmotic lysis. This figure was created using BioRender.


Despite all of these common features, the overall composition of cell walls may vary between different groups of bacteria. This can thus be used to broadly classify bacteria into two types. The first is Gram-negative bacteria, of which Shigella is a member, whilst the second is Gram-positive bacteria, which consist of members such as Staphylococcus aureus and Streptococcus pneumoniae.


These names come from a technique called ‘Gram staining’ which involves adding two dyes to samples of bacteria to determine which group they belong to. Firstly, crystal violet dye is added followed by iodine. Together, these form violet dye-iodine complexes which can get trapped in bacterial cell walls. After alcohol is applied to remove any excess dye, a pink-coloured one is applied.


Crucially, the cell wall of Gram-positive cells has a thick peptidoglycan layer that can retain the violet-iodine complexes. In contrast, the Gram-negative cell walls have a thinner peptidoglycan layer that can only retain the pink dye and not the violet dye-iodine complexes. Therefore, the result of this staining process is that Gram-positive cells will appear purple under a microscope, whilst Gram-negative cells will be pink.

Figure 3: Gram staining is used to differentiate between Gram-positive and Gram-negative bacteria. At the end of the experiment, Gram-positive bacteria will be purple whilst Gram-negative bacteria will appear in pink under the microscope. This figure was made using BioRender.

Figure 4: (a) The Gram-negative bacterial cell wall consists of a thin peptidoglycan layer surrounding the cytoplasmic membrane. Since its outer membrane is an additional lipid bilayer embedded with lipopolysaccharide molecules, the Gram staining of Gram-negative bacteria will lead to the cells appearing pink under the microscope. An example of this is shown for the Gram staining of Shigella dysenteriae. The image was obtained from the CDC PHIL. (b) Meanwhile, the cell wall of Gram-positive bacteria is made up of the cytoplasmic membrane surrounded by a thick peptidoglycan layer. After Gram staining, Gram-positive cells will appear purple in colour under the microscope, whereby an example of this is shown for Staphylococcus aureus. The image was contributed by Scott Jones (MD) and obtained from Sizar and Unakal (2020)’s ‘Gram positive bacteria’.


(ii) Rod-shaped

Bacterial cells can be one of three distinctive cell shapes.


Firstly, coccus cells such as Streptococcus species have a spherical shape. Alternatively, Shigella species are rod-shaped (sometimes known as bacillus-shaped), whilst other bacteria can be spiral-shaped.


(iii) Non-motile

Some bacteria have a flagellum on their cell surface that allows them to move around. However, Shigella bacteria lack such appendages and therefore, they can’t move around actively and swim towards a nutrient source, even if they wanted to (See Figure 5a).


In contrast, E. coli, which are members of the same family as Shigella, have around five to ten flagella distributed across their cell surface (See Figure 5b). These, in turn, can come together to form bundles that can rotate and move the cell in a certain direction. This is particularly useful in allowing the bacteria to, for example, move towards nutrients or away from toxic substances.

Figure 5: (a) A computer-generated image of a Shigella cell, which is non-flagellated. The thin, hair-like projections are fimbriae. (b) A computer-generated image of an E. coli cell. The long, whip-like structures extending out from the cell are flagellum. Besides that, E. coli also has fimbriae - these shorter projections give the cell a ‘furry’ appearance. These images were obtained from the CDC PHIL.


Obligate anaerobes are bacteria that cannot grow in the presence of oxygen, whereas obligate aerobes need oxygen to respire and survive.


In this case, facultative anaerobes like Shigella are a combination of the two - they can respire anaerobically (without oxygen) when necessary, but they usually opt for aerobic respiration (with oxygen) whenever they can.


What kind of disease does Shigella cause?


Now you are much more familiar with this pathogen, let’s look at the nature of the infamous disease it causes.


The incubation period for shigellosis - meaning the time taken for disease symptoms to emerge after the person has been exposed to it - is normally around three days. Generally speaking, shigellosis is associated with two distinct clinical presentations that occur at different stages of infection.


The first is watery diarrhoea with vomiting and dehydration, whilst the second is dysentery, which is characterised by bloody, mucoid stools, and abdominal pain. Oftentimes, dysentery occurs at a later stage of infection and it isn’t seen in all Shigella-infected individuals.


During an infection, shigellosis causes the patient to lose serum proteins (i.e. the protein in our blood) through their faeces. This, in turn, leads to malnutrition as the loss of this protein depletes the individual’s nitrogen stores. And over the long term, the patient may also suffer from long-term health effects such as having stunted growth.


Under normal circumstances, our body is able to get rid of this infection without much trouble within five to seven days. However, clinical complications can occur, particularly among high-risk individuals. And these are often responsible for the Shigella-associated mortality.


To give you an example, did you know that S. dysenteriae can enter the bloodstream of malnourished infants? In this scenario, this infection would lead to a condition known as ‘bacteraemia’, which can be life-threatening if no action were to be taken.


Another serious complication affecting 13% of those infected with S. dysenteriae serotype 1 is haemolytic-uremic syndrome. In fact, it is actually the most common cause of acute renal failure in children.


This clinical syndrome is caused by the Shiga toxin and is characterised by a triad of disorders. The first of these is thrombocytopenia, which essentially means having a low platelet count (these are blood cells that mediate clotting). Moving on, we also have haemolytic anaemia, which occurs when blood cells are destroyed faster than the rate at which bone marrow can produce them. And finally, renal dysfunction can also affect individuals with haemolytic-uremic syndrome, often resulting in long-term consequences.


The epidemiology of Shigella infection

Whilst diarrhoea in developed countries is rare and generally not dangerous, this disease remains a significant cause of mortality worldwide. For instance, the global mortality rate due to diarrhoea in 2015 was 34.3% in children and 20.8% in adults.


The prevalence of this disease is at its highest in South Asia and Africa due to poor sanitation as well as inadequate access to adequate healthcare and clean water by the general public.


Oftentimes, Shigella is endemic in low-income regions, where children under five years of age are most susceptible to infection. And to make matters worse, diarrhoea in these children is both a cause and effect of malnutrition. This is because malnourished children are more vulnerable to diarrhoeal disease, whilst each diarrhoeal episode that they suffer from worsens pre-existing malnutrition. In short, this cycle means that malnourished children often die from diarrhoea and therefore explains how deadly this disease can be.


How does Shigella infect us?


Transmission

As mentioned earlier, Shigella is mainly spread by the faecal-oral route. So, you can expect this route of transmission to involve the spread of food or water-borne pathogens from contaminated faeces of an infected individual to the oral cavity of an uninfected individual.


Although less common, outbreaks of S. flexneri and S. sonnei have also been associated with men who have sex with men. As a result, shigellosis has also been classified as a sexually transmitted disease.


Figure 6: The Shigella infection cycle. [1] When Shigella is ingested, it travels to the stomach where it is able to resist the low pH environment. [2] Next, it travels to the small intestine where the release of enterotoxins leads to watery diarrhoea in infected individuals. [3] Shigella then enters the large intestine, where it [4] crosses from the apical to basolateral side of the intestinal epithelium via M cells. Once released, it is [5] phagocytosed by macrophages which subsequently undergo apoptosis. [6] The bacteria are now free to invade the basolateral membrane of enterocytes in the colon. [7] Intracellular bacteria can now replicate and spread intercellularly to neighbouring enterocytes. Shigella dysenteriae serotype 1 produces and secretes the Shiga toxin which enters the bloodstream. Once in the circulation, it travels to other organs, such as the kidneys and those in the central nervous system, where it causes serious complications. The Shiga toxin protein structure was obtained from Hughes et al., (2020) ‘Structural and functional characterization of Stx2k, a new subtype of Shiga toxin 2. Additionally, this figure was adapted from Mattock and Blocker (2017), ‘How Do the Virulence Factors of Shigella Work Together to Cause Disease?’ and created using BioRender.


1. Entering the human host

When bacteria are ingested, they travel down into the stomach, where the low pH environment normally kills many pathogens. Unfortunately for us, Shigella has special adaptations which allow it to resist these harsh conditions and proceed to the small intestine. These survival mechanisms result in Shigella having a minimum infectious dose (the lowest dose needed to cause infection) of around ten to 100 bacteria.


This is a very low value relative to other diarrhoeal pathogens like enterotoxigenic E. coli (ETEC), which requires at least 108 bacteria, or Vibrio cholerae, which needs at least 104 bacteria. Because Shigella can pass through the stomach relatively easily, very few bacterial cells are needed for an infection to be established in the intestines.


In contrast, pathogens such as ETEC and V. cholerae aren’t very good at surviving in the stomach, so they require lots of bacteria to be ingested as only a few will actually reach the small intestine alive.


2. Enterotoxin production in the small intestine

Watery diarrhoea, an earlier symptom in infected individuals, happens as a result of Shigella releasing enterotoxins in the small intestine. Enterotoxins are basically proteins secreted by a range of pathogenic bacteria that target the intestines.


For example, Shigella enterotoxins (ShET1 and ShET2) are produced and released by some Shigella flexneri serotypes.


3. From the small to large intestine

Next stop, we have Shigella entering the large intestine (or colon).


4. Crossing the intestinal epithelium

In the large intestine, the bacteria’s main objective is to invade intestinal epithelial cells, or more specifically, enterocytes. Enterocytes are the most abundant variant of the many cell types that make up the intestinal epithelium, which is a single layer of cells lining the small and large intestine.


As you can see in Figure 6, the apical side faces the intestinal lumen and is specialised for absorbing nutrients from digested food as it passes through. On the other hand, the opposite end is known as the basolateral side - it faces the bloodstream and releases nutrients into it. This is important to understand because Shigella can only enter its target cell, enterocytes, from the basolateral side.


To do that, Shigella would need a mechanism to cross the intestinal epithelium, and they do so by entering M cells.


In essence, M cells are another type of intestinal epithelial cell that are specialised to carry out ‘trans-epithelial transport’. This process involves taking up any antigens or pathogens from the lumen of the gut and then transporting anything it finds to immune cells on the other side of the epithelium. After that, depending on what has been transported from the lumen, these immune cells will then mediate an appropriate response against these pathogens as soon as possible.


5. Macrophage invasion

Once Shigella has reached the basolateral side, it is phagocytosed by macrophages. However, once that happens, the macrophage quickly undergoes cell death.


6. Intracellular enterocyte invasion

Upon the unfortunate fate of the macrophage, the bacteria are now free to invade the basolateral membrane of colonic enterocytes.


7. Intercellular spread between enterocytes

Once inside, the intracellular bacteria replicate and move adjacent cells. This process, in short, is known as intercellular spread.


As you can see, this multi-step infection process in the large intestine results in lots of inflammation and cell damage. This, in turn, can result in dysentery in some patients.


Moving forward in time, all sorts of pandemonium can break loose. For instance, the Shiga toxin could cause further damage to the colon, thereby leading to severe dysentery. Other than that, it could also enter the bloodstream and exert its toxic effects on various other organs such as our kidneys.


Why is this important?


In this article, we have looked into the huge burden that Shigella pathogens could present, particularly amongst younger children from low-income countries.


All in all, it is pretty clear that shigellosis is an important disease to eradicate and the only way we can effectively diagnose, treat, and prevent it is by understanding the pathogen and how it causes disease. And, unfortunately, we have yet been able to apply our knowledge to develop a vaccine that prevents Shigella infection.


Therefore, until and even after we have a vaccine, public health measures are the best way to control the disease, so having a sound understanding of the Shigella’s faecal-oral and sexual transmission routes as well as the disease is prevalent means the most effective control methods can be implemented wherever they are needed most.


Author


Ambar Khan

BSc Biological Sciences

Imperial College London



Disclaimer: All figures created using BioRender are intended solely for educational purposes and not for profit. This article’s cover photo was obtained from the CDC PHIL.

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