Gonorrhoea - How Is It Caused And What Are The Possible Complications?

Gonorrhoea is a sexually transmitted infection that is caused by the bacteria Neisseria gonorrhoeae. N. gonorrhoeae is an obligate human pathogen meaning it only causes infections in humans and cannot live symbiotically with humans. Around 44,500 people contract gonorrhoea each year in the UK, making it the second most common STI after chlamydia; its global incidence is 78 million cases each year. The organism itself is a gram-negative, oxidase-positive kidney-shaped diplococcus which can often be seen inside polymorphonuclear leukocytes (specific types of white blood cells) or extracellularly under a microscope. It is transmitted from person to person by unprotected vaginal, oral or anal sex and is found in secretions of the penis and vagina. Gonorrhoea can have many complications if left untreated from pelvic inflammatory disease (PID), salpingitis (inflammation of the fallopian tubes), infertility, ectopic pregnancy as well as other more serious infections such as disseminated gonococcal infections.

So how does N. gonorrhoeae infect the human host?

Once the bacteria reach the mucosal epithelium, they utilise type IV pili and Opa proteins on their membrane to bind to the epithelial cells and interact with them. The type IV pili contract which pulls the bacteria closer to the cell surface; it is here where they form microcolonies. The Opa proteins mediate cellular adhesion. In order for N. gonorrhoeae to proliferate, there is a requirement for iron as a nutritional growth factor. However, after infection, the host has many mechanisms that aim to sequester iron molecules in order to prevent the growth of the pathogen through nutritional immunity. Unlike most bacteria, N. gonorrhoeae do not produce siderophores – molecules that bind iron and transport it into the bacterial cell for their metabolism. Because of this, they have evolved to utilise other methods to obtain iron such as transferrin binding proteins. These are expressed on their cell membrane and can bind to human transferrin (a molecule responsible for transporting iron molecules around the body which can be found in body fluids and on the mucosal surface) and deliver it to the intracellular site for growth purposes. A similar mechanism is employed by the bacteria for the acquisition of iron molecules from free haem and haem bound to haemoglobin which are presented to the bacteria periodically as part of the female menstrual cycle.

Upon colonisation of the epithelium, another membrane-bound molecule interacts with the host’s cells. This molecule is lipooligosaccharide (LOS). LOS is found on the outer membrane of N. gonorrhoeae and when infection occurs, LOS interacts with specific receptors on the host cell’s membranes triggering a process known as transcytosis. After invasion has occurred, the LOS acts as a pathogen-associated molecular pattern which is recognised by pattern recognition receptors such as Toll-like receptor 4 on surveying white blood cells known as neutrophils and macrophages. Through signal transduction, the transcription factor NF-kB is activated which upregulates the production of pro-inflammatory cytokines and chemokines such as TNF-a, IL-6, IL-8, IL-1b which amplify the immune response and the recruitment of more white blood cells with the aim of ridding the host of the infection. It is the recruitment of further white blood cells that causes the purulent discharge seen in symptomatic infections. However, N. gonorrhoeae has developed several mechanisms to evade removal and destruction by the host’s immune response. One of the most interesting ways is the bacteria’s mechanism of surviving within the macrophages after they have engulfed them in a process known as phagocytosis. Once the white blood cells recognise the bacteria, they phagocytose and encapsulate the bacteria within a phagosome. In normal circumstances, the white blood cells create reactive oxygen species (ROS) via the enzyme NADPH oxidase which act on the bacteria to kill them, however, N. gonorrhoeae have a cytoplasmic enzyme called superoxide dismutase which converts the reactive oxygen species hydrogen peroxide to water and oxygen. They also possess a cytoplasmic enzyme known as catalase which has the same effect on hydrogen peroxide. In cases where oxidative damage by these ROS occurs, they possess enzymes that reverse the oxidation of proteins that would usually kill the bacteria. Mechanisms like these are key to the pathogenesis of an infection caused by N. gonorrhoeae. Their survival within white blood cells allows them to be carried around the body thus the neutrophil infiltration that occurs during infection works primarily in the bacteria’s favour by facilitating transmission and acting like the Trojan horse of the bacterial world.

What are the possible implications of an infection caused by N. gonorrhoeae?

There are many potential complications of an untreated infection with N. gonorrhoeae, one of which is disseminated gonococcal infection whereby the bacteria gain entry into the bloodstream through transcytosis through epithelial cells as discussed earlier. This occurs in only 0.4-3% of cases, however, if this occurs, the bacteria can reach joints and cause gonococcal arthritis. In the same antagonistic mechanisms employed by components of the bacterial cells such as LOS, proinflammatory cytokines are produced in large concentrations at the joints. This causes a recruitment of more white blood cells which release proteolytic enzymes that degrade proteins such as the intra-articular cartilage. The high cytokine concentrations also cause an increase in the release of host matrix metalloproteinases. These are enzymes that degrade proteins such as collagen. An overall effect of these processes is the destruction of the joint structure and clinical presentation of arthritis.

A more serious consequence of disseminated gonococcal infection is gonococcal meningitis. After the bacteria enter the bloodstream, they can gain access to the central nervous system via well-vascularised sites of the brain such as the choroid plexus. N. gonorrhoeae break through the tight junctions of the blood-brain and blood-CSF barrier causing inflammation of the meninges of parts of the brain such as the arachnoid and the pia mater. Here, they recruit highly activated white blood cells into the CSF which ultimately causes swelling of the meninges which can spread to and along the spinal cord putting pressure on nerves as well as releasing molecules from the recruited white blood cells causing nerve damage. Very quickly, meningitis can become fatal.

One of the more common complications of untreated gonorrhoea infections is PID. During infection, the bacteria can ascend into the upper genital tract and adhere to cells including those of the fallopian tubes. As a result, the usually ciliated epithelial cells of the fallopian tubes become non-ciliated and begin to slough. The immune response in the infected area of the fallopian tubes can result in scarring and permanent damage. The scarring of the fallopian tubes can lead to a blockage of the tube whilst the removal of the cilia from the epithelial cells which usually serve to help move the egg to the uterus for implantation results in an increased risk of infertility by 16%. The scarring also contributes to an increased risk of ectopic pregnancy by 9% as the fertilised egg is blocked from getting to the uterus. As a result, it implants itself in the fallopian tubes.

To conclude, gonorrhoea is a highly prevalent and serious infection that can cause long-lasting health problems if undiagnosed or untreated. The increasing infection rate around the world and in the UK is leading to multi-drug resistant strains of N. gonorrhoeae that are resistant to the main first-line antimicrobial therapies such as ceftriaxone and azithromycin – the last available first-line treatment options. This is mainly due to asymptomatic individuals being unaware that they are infected and passing it on to others in combination with the highly transmissible property of N. gonorrhoeae, people being afraid to get diagnosed, the increasing incidence of unprotected sex, and the over-prescription of antibiotics. If the spread of gonorrhoea continues, the risk of the bacteria becoming ‘super gonorrhoea’ is increased. This then leaves us with potentially no possible treatment options leaving the patient at the submission of this ‘microscopic menace’ until new treatment options become available.