Bacteria exist naturally on many biological surfaces, for example the skin or the lining of the intestines. Bacteria like these make up the body’s natural flora and have a range of symbiotic relationships; a good example would be the flora of the rumen in cattle which degrade food materials, providing energy for both the cattle and the bacteria. The three main types of symbiotic relationship are:
- Mutualism – Both members of the symbiotic relationship benefit
- Commensalism – No apparent harm/benefit occurs to either member of the relationship
- Parasitism – One member of the relationship is living at the expense of the other resulting in disease
The pathogenicity of a certain bacteria depends on its survival inside the host – how well is it able to resist or evade host defence mechanisms and immune response. The resulting disease/damage caused to tissue is due to either the pathogenicity of the bacteria or the immune response of the host itself.
Prokaryotes vs. Eukaryotes
Bacteria are prokaryotes, they differ from eukaryotic cells (such as those in humans) because the structures within prokaryotic cells are typically not compartmentalised. Prokaryotes also lack nuclear membranes, mitochondria, endoplasmic reticulum, a Golgi body, phagosomes and lysosomes (unlike eukaryotes). Also, prokaryotes only have a single, circular chromosome – unlike the nucleus of a eukaryotic cell.
Bacteria can be very broadly categorised into two groups, gram negative and gram positive. This describes whether or not the bacterial will stain when using a gram stain. Gram-negative bacteria do not take up the gram stain; this is due to an extra outer membrane. Gram-positive bacteria do not have this extra outer membrane and so will take up the gram stain.
- Plasmids – This is an extra-chromosomal strand of circular DNA, it is able to replicate independently from the main chromosome in the bacteria and the genes which the plasmid codes for aren’t typically essential for survival. The plasmid may be shared between bacteria which may be of concern as the plasmid often codes for pathogenesis and anti-bacterial resistance.
- Cell Envelope – This is the extra outer membrane seen in gram-negative bacteria
- Flagella – A protein organelle (consisting of flagellin) which is used for locomotion
- Pili (Fimbriae) – This is the organelle which allows adhesion to the epithelium of host cells.
- Capsules and ‘slime’ layers – These are layers outside of the cell envelope in some specialised bacteria. This extra layer allows the inhibition of ingestion by phagocytes as they are unable to detect the bacterium. A well-defined layer is known as a capsule, a lesser defined layer is known as a slime layer.
- Endospores – This is a term given to dormant forms of bacteria which are able to survive harsh conditions
A pathogen by definition is an organism capable of causing disease; there are four main types of pathogen:
- In some animals the natural flora are known as potential pathogens. This is because they are capable of causing disease but can live in the host in a parasitic relationship without causing disease; they can be transferred to between hosts asymptomatically. They will only become pathogenic if an opportunity arises to do so; this may be a weakening of the host due to malnutrition for example.
- Similar to potential pathogens, opportunistic pathogens typically only induce disease in unhealthy hosts. Disease would not normally occur in a similar but healthy host.
- Another type of pathogen is known as an obligate pathogen. This type of pathogen will not associate with the host except in the case of disease. Obligate pathogens must cause disease in order to be transmitted from one host to another. They must also infect a host in order to survive, in contrast to other bacteria that are capable of survival outside of a host.
- The final type of pathogens are known as accidental pathogens, pathogens whose induction of disease is accidental – their accidental induction of disease actually limits their transmission between hosts and so is not of benefit to them.
Bacteria pathogenicity can be due to a genetic trait, biochemical system or structural mechanism. Certain adaptations of these traits are how bacteria develop their pathogenicity or virulence and those who are better adapted are more potent pathogens. These determinants of virulence make up the total pathogenicity of the bacterium.
Bacteria can depend on one determinant of virulence or use a multitude to increase their effectiveness. For example, a gene expressed in a bacterial plasmid which codes for the production of toxin, this toxin is then used to cause disease in the host and allow the bacteria to thrive. This bacterium relies on a genetic determinant of virulence.
The efficiency of an immune response against bacteria can vary greatly, some are eliminated from the body rapidly resulting in no formation of symptoms in the host, however some are able to avoid the immune system for a longer period of time allowing them to progress well and cause disease.
The mechanisms which the host uses to fight off bacteria can be divided into two groups, innate and acquired.
Innate Host Immunity
The primary innate response to a bacterial infection is the production of vast amount of acute phase proteins (opsonins); these are produced by the liver during a number of types of infections. One such protein is C-reactive protein which can bind to damaged nuclei and bacterial capsules, once bound it acts as an opsonin. Some complement components are also acute phase proteins and can trigger the complement cascade using the alternative pathway. Heat shock proteins (HSPs) are bacterial products which act as good antigens making them a target for antibodies and t-cells.
In bacterial infections phagocytosis by neutrophils plays an important role. Neutrophils are released in large quantities (especially in response to gram-positive bacterial infections) and attracted to the sites of bacteria by chemical attractants exuded from the bacteria or by activated complement. The phagocytosis of bacteria is increased if the bacteria have been successfully opsonised by complement proteins or antibodies. The method by which phagocytes kill the bacteria is to consume glucose in a short burst of respiration which results in the formation of H2O2 which is then lethal towards most bacteria.
Acquired Host Immunity
Acquired host immunity has two methods of action, humoral and cell-mediated immunity. The humoral immunity generally involves the use of antibodies whereas cell-mediated immunity utilises cytotoxic cells and macrophages etc.
Antibodies are important in bacterial infection as they are able to neutralise toxins secreted by the bacteria. This is especially important where the primary determinant of virulence is the use of a toxin. Antibodies are also able to prevent the adhesion of bacteria to tissues, activate complement, opsonise bacteria (possibly using heat shock proteins as targets), give rise to passive immunity in new-borns and promote antibody dependent cell-mediated cytotoxicity (ADCC – Where the antibodies bind to targets to causing immune effector cells to destroy the target).
The role of cell-mediated immunity in bacterial infections is primarily the activation of T-helper 1 cells which induce cytotoxic t-cells, NK cells and macrophage activation which all aid in the destruction of the bacteria. T-helper 2 cells promote the production of antibodies to boost humoral immune responses.
The involvement of each type of immune response depends upon the bacteria causing infection.
Avoiding the Immune System
Before being phagocytosed, some bacteria are able to escape phagocytosis by having a capsule (as described earlier) surrounding them. This capsule prevents any immune cells from recognising foreign receptors/proteins on the bacterium surface. Some bacteria also express proteins on their surface which can block certain immune pathways:
- Protein A – This protein is able to bind to the IgG Fc component and activate the release of C3. The sudden release of large quantities of C3 depletes complement and blocks uptake by Fc receptor (FcR) on phagocytes
- M protein – This protein binds to fibrinogen thus blocking complement and reducing opsonisation.
Some bacteria are able to avoid antibody defences as well:
- Some can produce IgA protease, which cleaves the IgA antibodies found in mucosal secretions, making them perfect environments for bacteria
- By expressing different pili or ‘turning them on and off’ antigenic variation arises which ‘confuses’ the immune system lengthening the time taken to produce a response against the bacteria
- Some bacteria are also able to mimic the antigens of the host to avoid detection
In order to survive inside the host some bacteria are able to grow within macrophages. In order to aid their survival within the macrophage they can inhibit the phagolysosome production as well as exhibiting resistance to lysosomal enzymes. They are also able to initiate methods to escape from the phagosome and return to the cytoplasm.
Some species of bacteria are also able to manipulate the host’s cells, altering cytokine responses and production giving advantages to the survival of the bacteria. For example, mycobacteria are able to induce IL-6, 10 and TGF-β which suppresses T-cell mediated activation of macrophages and means less cytotoxic activity against infected cells.
Tissue injury can arise from toxins produced by the bacteria, or by the host attempting to remove the pathogen but causing self-injury.
Bacteria can produce different types of toxin:
- Endotoxins – Toxins which remain bound to the membrane. The two main types are Lipopolysaccharides (LPS) and lipid A.
- LPS – Activates macrophages to release inflammatory cytokines which leads to tissue degradation
- Lipid A – Toxic if it enters the bloodstream, it causes massive immune cell infiltration and activates coagulation
- Exotoxins – Toxins which can be secreted. They are a target for antibodies which are able to neutralise the toxin. However sometimes the toxin is so potent that before antibodies have been produced to neutralise the toxin, the toxin has proved fatal to the host.
As a result of some of the endotoxic mechanism, endotoxic shock can arise; this is due to the excessive release of cytokines (often triggered by LPS). This causes coagulation and defective clotting as well as changes in vascular permeability, loss of fluid (into tissues) and a fall in blood pressure.
Fungi differ from bacteria quite greatly; they are eukaryotic cells with rigid chitin cell walls. Fungi are typically too big to be phagocytosed so neutrophils attempt to cause damage to the fungal hyphae.
Once established though, fungal infections are effectively destroyed by T-cell mediated mechanisms activating macrophages.