by Malak Sadek and Rana Elyamany

Introduction

Neisseria gonorrhoeae is the causative agent of the sexually transmitted infection gonorrhea which is is the second most prevalent bacterial sexually transmitted infection worldwide. Its formal identification was in 1879 by the German bacteriologist Albert Neisser. Gonorrhea grows mainly in the warm, moist areas of the reproductive tract for both men and women. It can also grow in the mouth, throat, eyes, and anus.

Disease

Neisseria gonorrhoeae infections are acquired in humans by sexual contact. It is able to infect the lower genital tract, urethra in men and cervix in women (see Figure 1 and 2). Infected women may be asymptomatic (show no symptoms), but up to 50% show nonspecific symptoms including odorless mucopurulent, vaginal discharge and vaginal bleeding. Even infections without symptoms can also result in severe consequences. On the other hand, 90% of men with urethral infection have symptomatic mucopurulent penile discharge and dysuria. Gonococci can ascend to the upper genital tract, leading to serious diseases, such as epididymitis in men and cervicitis, endometriosis, and pelvic inflammatory disease in women. When N. gonorrhoeae infects the urogenital tract, it interacts with a variety of cells, including Polymorphonuclear leukocytes (PMNs or neutrophils). PMNs are professional cells of the immune system which often serve as the first line of host defense against the bacterial infection. N. gonorrhoeae can survive and replicate inside PMNs and this interactions likely play a critical role in the pathogenesis of infection (see Figure 3).

Figure 1: This illustration depicts a urethral exudate containing Neisseria gonorrhoeae from a patient with gonococcal urethritis. N. gonorrhoeae appears as typical intracellular (pink) diplococcic. Source: Public Health Image Library, Center for Disease Control. Dr. Norman Jacobs (1974).

Figure 2: This illustration depicts Neisseria gonorrhoeae in a cervical smear using the Gram-stain technique.. N. gonorrhoeae appears as typical intracellular (pink) diplococcic. Source: Public Health Image Library, Center for Disease Control. Dr. Joe Miller (1975)

Figure 3: Microscopic image the presence of intracellular Neisseria gonorrhoeae amongst numerous white blood cells (WBCs) known as polymorphonuclear leukocytes, or PMNs. N. Gonorrhoeae cells are pink diplococcal. Source: Public Health Image Library, Center for Disease Control. Dr. Bill Schwartz (1971).

Epidemiology

Gonorrhea is a very common infectious disease. It is the second most prevalent sexually acquired infection in the United States, with more than 300,000 reported cases per year. The Center for Disease Control and Prevention (CDC) estimates that annually more than 700,000 people in the United States get new gonorrhea infections. The most recent data provided by the (CDC) indicate that reported cases have increased by almost 10% over the last 5 years. In 2013, 106.1 cases of N. gonorrhoeae per 100,000 persons were reported, representing an 8.2% increase in incidence from 2009. Approximately 75 percent of all reported cases of gonorrhea are found in younger persons 15 to 29 years of age. The prevalence of this infection has strong economic effects, as in 2008, the total lifetime direct medical cost of N. gonorrhoeae infections in the United States was estimated to be $162.1 million.

Virulence systems

Neisseria gonorrheae express a set of common mechanisms that allow its adaptation to the immune system and immune evasion. .Gonorrheae first attaches itself to the cells and the tissues using a rod shaped protein structure called Type IV pili that recognizes a molecule of the host and bind to it (the host is the human in whom the bacteria live and cause infection). Therefore Type IV pili is essential for virulence in N. gonorrhoeae because it mediates specific attachment to human mucosal cells, initiating the infectious process. It is known that type IV pili is formed from subunits of a protein called pilin, and a gene called pilE in the genome of N. gonorrhoeae, is responsible for encoding the pilin subunit. Notably, Type IV pili in gonorrhoeae is a surface antigen, an antigen is a substance that causes the immune system to produce large proteins called antibodies to identify and neutralize the bacteria. Because N. gonorrhoeae undergoes antigenic variation, the capacity to generate much more diversity in its surface antigens, it has the ability to resist the killing cells in the host. A mechanism called gene shuffling or gene conversion allows N. gonorrhoeae undergoes antigenic variation events.Through DNA recombination (DNA exchange between genes),pilE gene can exchange a part of itself with pilS gene copy. Subsequently a new variant of pilE protein will be produced which is not the same as the original one (see Figure 4). Producing different types of pili increases the chance of evading the immune system especially the antibodies response. Antibodies should bind to adhesions such as typeIV pili and prevent the attachment of the bacteria to the host cells. Furthermore antibodies increase the attachment of the bacteria to phagocytes (immune system cells that pick up and kill the bacteria by a process called phagoctosis) .Therefore, it is assumed that antibodies reacting with pili type IV could block the infection. However, switching of pili expression states alters bacterial interactions with host cells. Thus varying the antigens that are presented to the host immune system prevents antibodies binding to the bacterial surface and subsequently phagocytosis.

Figure 4: Antigenic variation in Neisseria gonorrhoeae by gene shuffling. The white boxes represent the conserved regions of pilE and pilS. The variable sequences (mc1-mc6) are represented by the yellow boxes for pilS and the pink boxes for pilE. Sma/Cla is DNA sequence that is involved in pilin recombination.

Treatment

N. gonorrhoeae has developed resistance to mainly all antibiotics introduced for treatment of gonorrhea. These drugs include: cefixime (an oral cephalosporin), ceftriaxone (an injectable cephalosporin), azithromycin, and tetracycline. N. gonorrhoeae is able to use number of mechanisms for antibiotics resistance including enzymes to degrade antibiotics. Recently, Centers for Disease Control and Prevention (CDC) recommends only ceftriaxone plus either azithromycin or doxycycline as first-line treatment for gonorrhea.

References:

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