mucosal surfaces - a barrier against the outside world

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2.0INTRODUCTION

2.1The mucosal surface – a barrier against the outside world

Most pathogens cause disease by disrupting and/or penetrating mucosal surfaces, and in order to be successful they have to circumvent the host defence. The first barrier the pathogen encounters is the highly hydrated mucus gel that covers the mucosal surface and protects the epithelial cells against chemical, enzymatic, microbial and mechanical insult. The mucus gel is formed by high-molecular-mass oligomeric glycoproteins (mucins) and protection is reinforced by a number of ‘defence factors’ (Table 1) trapped in the gel matrix. The thickness of the mucus layer is highly variable depending on, for example, tissue location. In addition, the mucus gel is found to consist of a firmly adherent layer with a thickness of 15- 154 μm and a loosely adherent one of 108-714 μm.2 The functional significance of the two layers has not yet been established, but their presence may be explained by differences in mucin concentration.2 Underneath the mucus layer, the cells present a dense forest of highly diverse glycoproteins and glycolipids, which form the glycocalyx (Figure 1). Again, the thickness is highly variable. In the electron microscope, the glycocalyx appears as filaments attached to the plasma membrane. The oligosaccharide moieties of the molecules forming the glycocalyx and the mucus layer are highly diverse and the average turnover time of the human jejunum glycocalyx is 6-12 hours.6 Consequently, the mucosal surfaces presented to the outside world are constantly renewed and could potentially be adjusted to changes in the environment, e.g. microbial attacks. Alteration in glycosylation has been proposed to influence cell adhesion, receptor activation, cell differentiation, and tissue morphogenesis.

2.2Mucins – an integral part of the barrier

The mucus polymer matrix is formed by large secreted mucins, which confer viscoelastic properties. Each mucin gene contains unique tandem repeat (TR) motifs coding for regions with a high density of serine, threonine and proline. The TR region varies in length between the mucins, and there is a genetic polymorphism in the number of repeats referred to as Variable Number of Tandem Repeats (VNTR) polymorphism. The VNTR polymorphisms cause mucin size to differ between individuals. The serine and threonine residues can be Oglycosylated and more than 50% (often 70-80%) of the mucin molecular mass is due to carbohydrate. Each mucin carries in the order of 100 different oligosaccharide structures.15 These carbohydrate chains are often clustered into highly glycosylated domains, giving the mucin a ‘bottle-brush’ appearance. To date, at least 14 human mucins have been described, and the expression profile of mucins varies between tissues. The secreted gel-forming mucins are oligomeric structures formed by subunits linked by disulfide bridges. The mucins are produced by cells in the epithelial surface and/or by glands located in the submucosal connective tissues and secretion occurs via both constitutive and a regulated pathways.16

The membrane-associated mucins provide a barrier that limits access of other cells and large molecules to the cell surface. These glycoproteins have a hydrophobic membrane-spanning domain, a C-terminal cytoplasmic ‘tail’ with putative sites for serine and tyrosine phosphorylation, SEA modules located in the extracellular region (possibly for signaling through dimerization18) and EGF–like domains.19-23 The membrane-associated mucins can occur in secreted, non-membrane bound forms as a result of alternative splicing or proteolysis.24, 25

2.3 Helicobacter pylori – A Successful Pathogen

Helicobacter pylori previously known as Campylobacter pyloridis was first cultured about 30 years ago by Barry Marshall and Robin Warren from a gastric biopsy. Since then, the bacteria have provoked interests of several biologists, pharmaceutical scientists and infectious disease specialists. H. pylori represent Gram negative bacterium, 2 to 4µm long with a diameter of 0.5 to 1 µm. The bacteria are highly motile due to its flagella and generally colonises in the mucus layer of gastric epithelium of human. Even though, H. pylori is not as harmful as other bacteria, it is one of the most successful pathogen that infects half of the world’s population. In the developing countries, the rate of infection is as high as 60%. The major risk factor of the infection is the country’s socioeconomic condition and hygiene. However, in the developed nations the rate of infection lies between 6 to 10%. Some investigators suggest that the common routes of infection includes oral to oral and faecal to oral contacts. In addition, parents to sibling transmission also plays major role in H.pylori infection. However, the exact route of infection is still elusive.

The bug is ubiquitously found in nature and infects both males and females. The bacterial infection occurs mostly at young age and is expressed with other gastrodeodenal diseases when the individual is in adulthood. As mentioned, the bacteria cause chronic gastritis. However, 85% of the infected population cohort remains asymptomatic throughout life. In rare cases, gastric inflammation leads towards other severe diseases including gastric mucosa-associated lymphoid tissue (MALT) lymphoma or non-cardia gastric carcinoma. In 1994, World Health Organisation (WHO) classified H. pylori infection as type 1 carcinogen. Moreover, the International Agency for Cancer Research report suggests that H. pylori infection includes the major risk factor for 92% of gastric cancer with the mortality rate of 740,000 per year.

2.4Colonisation - Bug’s first Step towards Infection

One of the most critical features of the bug is not to damage the host tissues but rather its survival within the host for decades. Once the bug enters the stomach, there are three vital steps for infection:

  1. Colonisation
  2. Evading the host innate and adaptive immune system.
  3. Invading the gastric mucosa.

The process of colonisation consists of four stages:

  1. Transmission to new host.
  2. Adherence to specific niche within the host.
  3. Avoidance of host’s immune system.
  4. Acquisition of nutrients resulting in successful replication.

Fig:

Initial colonisation of the bacteria in human stomach is through adherence to the mucus layer of gastric epithelium. Therefore, adhesion is one of the crucial steps in colonisation. Adhesins are mainly composed of bacterial protein, glycoconjugates or lipids. These bacterial proteins mostly help the bug to stick with the host cell surface and also render 100 to 1,000 times more resistance towards antibiotics as compared to nonadherent bacteria. In addition, adherence also protects the bacteria from being washed out from the host system. However, there are several other factors that influence the persistence of the bacteria in gastric mucosa.

Bacterial colonisation triggers both humoral and cellular immune responses. However, in most of the cases these elevated immune responses fail in the clearance of the bug. H. pylori is one of the most diverse bacterial species that constitutes a valuable advantage to successfully evade the immune system. According to various studies, every isolates from unrelated patients have its unique ‘fingerprint’. Moreover, colonisation with multiple strains is also a common scenario found within infected individuals. It is also quite common for the bug to undergo genetic alteration. This is mainly due to high mutation rate and exchange of genetic materials.

2.4.1Urease

Urease is produced by several bacterial species including H. pylori. Urease tends to catalyse the hydrolysis of urea to yield ammonia and carbamate. Later, carbamate spontaneously decomposes to yield ammonia and carbonic acid. Once the bacteria is introduced in the stomach, it prefers neutral pH for survival and colonisation. Therefore, to maintain a neutral surrounding, the bug produces extraordinary amount of urease that converts urea to amino ions thereby neutralising the gastric pH. The size and the structure of the urease molecule vary among different bacterial species. The molecular weight of H.pylori urease is approximately > 300 Kd. The urease of H.pylori consists of two different subunits UreA and UreB. Apart from urease there are several other enzymes such as aliphatic amines (AMiE and AmiF) that help the bacteria to survive by neutralising the acidic pH. Therefore, knocking out the urease gene leads towards failure of colonisation.

2.4.3 Motility

H.pylori is a highly motile organism. Motility is mainly due to its bundle of two to six sheathed flagella. These flagella allow motility and also act as an important factor for the bug to penetrate through the mucin layer. The flagella mainly consist of two flagellins i.e. FlaA and FlaB. Due to its motility and shape, H.pylori is the only bacteria that colonises in the gastric mucosa. The bacteria successfully colonises in the stomach by attaching itself to the gastric epithelium. Once the bug attaches to the epithelium, it produces several outer membrane proteins (OMP). These proteins adhere to the corresponding receptors on the gastric epithelium. As a result, the bacteria evade the host immunity and are successful in delivery of toxins into the epithelium.

2.4.4 Adhesins

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