Gonorrhea is a sexually transmitted infection (STI) caused by the bacterium Neisseria gonorrhoeae. It is spread through unprotected vaginal, anal, or oral sex with an infected partner. Gonorrhea can infect the genitals, rectum, and throat. In women, it can also spread to the uterus and fallopian tubes, causing pelvic inflammatory disease (PID) (1).
Gonorrhea often causes no symptoms, especially in women. As a result, many infections go undiagnosed and untreated. Over time, untreated gonorrhea can lead to serious complications like infertility and increased risk of HIV infection (2).
The key to treating gonorrhea is antibiotics. But in recent years, certain strains of N. gonorrhoeae have developed resistance to most available antibiotics (3). This makes gonorrhea much harder to treat. Researchers are looking for new antibiotics and alternative treatment options.
Some research has explored whether our immune systems can clear gonorrhea infections on their own, without antibiotics. This article reviews what we know so far about the immune response to N. gonorrhoeae and the prospects for developing a gonorrhea vaccine.
The immune response to N. gonorrhoeae infection
When N. gonorrhoeae first infects the genital tract or rectum, it triggers an inflammatory response. Immune cells like neutrophils rush to the site of infection. These cells attempt to phagocytize (engulf and destroy) the invading gonococci bacteria (4).
N. gonorrhoeae has evolved multiple strategies to evade destruction by neutrophils and other immune cells:
Antigenic variation
The outer surface of N. gonorrhoeae is coated in molecules called outer membrane proteins. These proteins can vary greatly between strains. By altering its outer membrane proteins, N. gonorrhoeae can avoid detection by the immune system (5).
Resistance to complement-mediated killing
The complement system is part of the innate immune response. When activated, it creates proteins that coat pathogens and mark them for destruction. But N. gonorrhoeae uses surface molecules like porin to block attachment of complement proteins (6).
Suppression of oxidative burst in neutrophils
Neutrophils kill bacteria by producing reactive oxygen species through oxidative burst. But N. gonorrhoeae expresses surface molecules that suppress this oxidative burst (7).
Resistance to antimicrobial peptides
Antimicrobial peptides are small proteins made by immune cells that poke holes in bacterial membranes. But N. gonorrhoeae modifies the charge of its cell envelope to repel cationic (positively charged) antimicrobial peptides (8).
Through these and other mechanisms, N. gonorrhoeae can persist and replicate even in the presence of local immune responses. Over time, untreated infections disseminate from the initial site and spread to other tissues.
Does prior infection with N. gonorrhoeae produce immunity?
Natural infection with many pathogens leads to acquired immunity mediated by B and T cells. This often provides long-term protection against reinfection. However, for unclear reasons, this is not the case with N. gonorrhoeae.
Individuals infected with gonorrhea do develop B cells that secrete IgM and IgG antibodies against N. gonorrhoeae outer membrane antigens. But these antibodies provide weak and short-lived protection that wanes after just a few months (9).
Individuals with prior gonorrhea also develop antigen-specific CD4+ T cells. But these T cell responses tend to be disorganized and ineffective at providing long-term immunity (10). As a result, individuals remain susceptible to reinfection after recovering from gonorrhea.
Developing a gonorrhea vaccine
Given the ongoing threat of antibiotic-resistant N. gonorrhoeae, researchers are interested in developing a protective vaccine against gonorrhea. An effective vaccine could reduce transmission and prevent complications like PID in women.
However, developing a gonorrhea vaccine poses major challenges:
– The high genetic variability of N. gonorrhoeae makes it a moving target for vaccine developers (11). Surface antigens that elicit an immune response in one strain may not be effective against others.
– Immunity against N. gonorrhoeae appears to wane quickly after infection or exposure. A vaccine will need to overcome this and induce long-lasting immune memory.
– As a strictly human pathogen, N. gonorrhoeae has evolved multiple ways to suppress human immune responses. These mechanisms will interfere with vaccine-induced immunity.
Despite these difficulties, researchers have identified some promising vaccine candidates using genomic and proteomic screens (12):
PorB
The PorB outer membrane protein is expressed in nearly all clinical isolates of N. gonorrhoeae. It triggers bactericidal antibody responses and may be a good vaccine candidate. However, PorB can undergo antigenic variation which could limit its effectiveness (13).
Factor H binding protein (FHbp)
FHbp helps N. gonorrhoeae evade complement-mediated killing. Vaccines targeting FHbp protect mice from gonorrhea and elicit bactericidal antibodies (14). But individual variation in human FHbp responses may affect efficacy (15).
Lipooligosaccharide (LOS)
LOS is a glycolipid on the N. gonorrhoeae surface. LOS antigens can elicit complement-mediated killing. LOS immunotypes that are conserved across strains may serve as vaccine targets (16). However, LOS variation between strains may limit breadth of protection.
Biofilm proteins
N. gonorrhoeae can form biofilms on epithelial surfaces. Vaccines targeting biofilm proteins like AniA, NorB, and NorM may limit biofilm formation and dissemination (17).
Researchers are also working on vaccine delivery methods to induce sustained mucosal immunity against N. gonorrhoeae. Potential options include live attenuated vaccines, protein/adjuvant combinations, and nucleic acid vaccines (18).
Conclusion
So in summary:
– Gonorrhea infection does provoke immune responses against N. gonorrhoeae. But the bacterium has evolved clever ways to avoid elimination by the immune system.
– Natural infection with gonorrhea leads to weak, short-lived immunity that fails to protect against reinfection.
– Developing a protective vaccine is challenging but may be possible by targeting conserved bacterial antigens.
– Overcoming N. gonorrhoeae immune evasion and inducing sustained immunity will be key for an effective gonorrhea vaccine.
– With antibiotic options dwindling, a vaccine may be our best hope for gaining the upper hand against this stubborn STI.