Neisseria

Neisseria is a genus of bacteria commonly present on mucosal surfaces. Several species exist, but only 2 are pathogenic to humans: N. gonorrhoeae and N. meningitidis. Neisseria species are non-motile, gram-negative diplococci most commonly isolated on modified Thayer-Martin (MTM) agar. These pathogens have many virulence factors, including fimbriae, lipooligosaccharide envelope proteins, a polysaccharide capsule (unique to N. meningitidis), and IgA protease. Gonococcal infections are sexually or perinatally transmitted and include gonorrhea, pelvic inflammatory disease, septic arthritis, and neonatal conjunctivitis. Meningococcal infections are transmitted via respiratory and oral secretions. They most commonly cause meningococcemia with petechial hemorrhages and meningitis.

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General Characteristics

  • Many Neisseria species are normal inhabitants of the mucosal surfaces of many animals.
  • Of the 10+ species that infect humans, only 2 are strictly human pathogens: N. gonorrhoeae (gonococcus) and N. meningitidis (meningococcus).
  • Gram-negative diplococci (paired cocci)
  • Facultative intracellular organisms
  • Non-motile
  • Oxidase and catalase positive
  • Sugar fermentation:
    • N. meningitidis uses maltose and glucose.
    • N. gonorrhoeae uses glucose only.
  • Contain lipooligosaccharides (LOS) with strong endotoxin activity
  • Require special culture media to grow:
    • N. meningitidis is less fastidious and grows on sheep agar.
    • N. gonorrhoeae requires modified Thayer-Martin agar (MTM) for optimal growth: enriched chocolate agar with antimicrobial agents that selectively favor growth of Neisseria by inhibiting growth of other bacteria and fungi.
N. meningitidisN. gonorrhoeae
Encapsulated (polysaccharide capsule)Not capsulated
Ferments maltose and glucoseFerments glucose only
Colonizes nasopharynxColonizes genital mucosa
Rarely has plasmidsMost have plasmids

Neisseria Gonorrhoeae

Epidemiology

  • Worldwide distribution
  • Incidence of 583,405 cases in the United States in 2018, with a 5% increase from the year before and a higher rate in males than females (212.8:145.8 per 100,000 people)
  • A nationally notifiable disease

Transmission

  • Sexual contact with the penis, vagina, mouth, or anus of an infected individual
  • Perinatal transmission (during vaginal delivery)

Pathogenesis

  • Exclusively pathogenic for humans

General virulence factors: 

  • Pili (fimbriae): 
    • Enhance attachment to host cells
    • Furnish resistance to phagocytosis
    • Provide antigenic variation among different strains 
  • Por proteins in cell membrane: 
    • Components of the proteins of the outer membrane vesicles (OMVs)
    • May prevent intracellular killing by neutrophils by interfering with phagosome-lysosome fusion
  • Opacity-associated (Opa) proteins (outer membrane proteins): aid in attachment to host cell receptors
  • Lipooligosaccharide (LOS, endotoxin) envelope protein:
    • LOS is an oligosaccharide with a lipid A component. 
    • Responsible for most of the toxicity in gonococcal infections (e.g., causes fever, ciliary loss, and mucosal cell death in the fallopian tube)
    • Not to be confused with the capsular polysaccharide of meningococci
  • IgA1 protease: inactivates IgA1 immunoglobulin and reduces host’s defense

Mechanisms to evade immune recognition:

  • LOS mimics human cell membrane glycosphingolipids and can be sialylated, which renders them resistant to serum killing.
  • Can rapidly switch from 1 antigenic form of LOS, pilin, and Opa to another

Mechanisms of antimicrobial resistance:

  • Plasmids code for:
    • Penicillinase (similar to Haemophilus spp. and other gram-negative bacteria)
    • Resistance to tetracycline (from the conjugative streptococcal plasmid)
  • Most gonococci have plasmids, but meningococci rarely have them.
Neisseria gonorrhoeae pathogenesis

Pathogenesis of N. gonorrhoeae.
The bacterium adheres to the mucosal epithelium (1) where it competes with microbiota and colonizes to invade the epithelium (2). Peptidoglycans, LOS, and OMVs are released (3), activating TLR and NOD signaling in epithelial cells, macrophages, and dendritic cells (4). This leads to the production of cytokines and chemokines (5) which brings about a neutrophil-rich purulent exudate and phagocytosis of the harmful bacteria (6). Since N. gonorrhoeae has defense mechanisms that resist being killed, the bacteria-laden neutrophils can also act as agents of transmission to another host (7).

Selected abbreviation key:
LOS: lipooligosaccharide
OMV: outer membrane vesicles
TLR: toll-like receptor
NOD: nucleotide-binding oligomerization domain-containing protein

Image by Lecturio.

Clinical Presentation

  • The incubation period ranges from 1–14 days (usually < 7).
  • The clinical presentation can vary greatly depending on the age and immunologic state of the host, as well as the mode of transmission. 
  • Some patients can present asymptomatically.
    • More common in young women
    • Higher risk of spreading the infection and developing long-term complications
Type of presentationClinical features
Gonorrhea (acute gonococcal infection; commonly referred to as “the clap”)
  • Sexually transmitted infection (STI)
  • Presentation varies depending on the mode of transmission:
    • Can be asymptomatic, especially in women
    • Urethritis: purulent, yellow-green discharge through urethra with painful urination
    • Cervicitis: purulent, yellow-green (or blood-tinged) with foul smell, abdominal pain, or pain during pelvic exam
    • Pharyngitis: sore throat, difficulty swallowing, swollen lymph nodes of the neck, and purulent exudante
    • Proctitis: pain and mucosal swelling of the rectum with purulent, yellow-green discharge
    • Prostatitis: fever, painful and difficult urination and ejaculation, with foul-smelling urine
    • Orchitis and epididymitis: unilateral pain and swelling of the scrotum
Pelvic inflammatory disease (PID)
  • Infection of the uterus, fallopian tubes (salpingitis), and/or ovaries that began as an asymptomatic case, urethritis, or cervicitis
  • Presents as:
    • White, purulent discharge
    • Cervical motion tenderness
    • Fever
    • Abdominal/pelvic pain/dyspareunia
    • Abnormal menstrual bleeding
  • Complications:
    • Infertility
    • Ectopic pregnancy
    • Chronic pelvic pain
    • Fitz-Hugh-Curtis syndrome: spreads to the upper peritoneal cavity with infection of the liver capsule and characteristic “violin string” peritoneal adhesions
    • Ovarian or cervical cancer
Neonatal conjunctivitis (gonococcal ophthalmia neonatorum)
  • Presents as purulent conjunctivitis 2–5 days after birth
  • Due to perinatal transmission during vaginal delivery
  • Can be prevented by the local application of 0.5% erythromycin or 1% tetracycline to the conjunctivae of newborns (mandatory in the United States)
Disseminated gonococcal infection
  • More common in women (ratio, 4:1)
  • Presents as a mixture or any of the following:
    • Septic arthritis: swelling of multiple joints (up to 4)
    • Dermatitis-arthritis syndrome: vesicular, pustular, or maculopapular lesions on the trunk and extremities with necrotic or hemorrhagic centers
    • Bacteremia
    • Endocarditis

Diagnosis

  • Specimens used: 
    • Pus/secretions from various sites 
    • First-catch urine, without pre-cleansing, for genitourinary tract lesions
    • Blood and joint fluid for culture (only 30% sensitivity) needs a special transport medium.
    • Smears: Sensitivity and specificity vary among sites.
      • > 90% in urethral exudates from men
      • 50% sensitivity for endocervical exudates 
      • < 10% for joint fluid
      • Gram stain is not helpful for throat or rectum samples because non-pathogenic Neisseria often colonize these sites. 
  • Culture on modified Thayer-Martin medium:
    • Not routinely used because nucleic acid amplification test (NAAT) is much faster and reliable
    • Used to determine antibiotic resistance if patient failed initial therapy
    • Identification by:
      • Positive oxidase test, only glucose is oxidized
      • Immunologic (coagulation) testing
      • MALDI-TOF (matrix-assisted laser desorption ionization-time of flight) mass spectrometry for same-day identification
Histopathology in an acute case of gonococcal urethritis using g

N. gonorrhoeae are gram-negative diplococci that provoke a marked neutrophilic response, as seen in this image, with several neutrophils containing many phagocytized bacteria.

Image: “Gonorrhea Neisseria gonorrhoeae” by Joe Miller. License: CC0

Neisseria Meningitidis

Epidemiology

  • Meningococcal meningitis occurs in 2 settings:
    • Epidemic waves, associated with crowding
      • Military bases/encampments
      • School dormitories
      • Religious pilgrims
      • Sub-Saharan Africa (the “meningitis belt,” from Senegal to Ethiopia)
    • Sporadic “interepidemic” cases
      • Older infants, children, and adolescents have the highest incidence in developed countries.
  • In the United States, the annual incidence is approximately 1/100,000.

Transmission

  • Transmission occurs via respiratory droplets and oral secretions, and requires close contact.
  • Factors that increase the risk of infection: 
    • Complement component deficiencies
    • Anatomic or functional asplenia
    • HIV positivity
    • Clinical microbiologists have a higher risk of becoming infected
    • Children exposed to secondhand smoke

Pathogenesis

Virulence factors:

  • Capsular polysaccharides are antigenic and form 6 important serogroups, responsible for most invasive meningococcal disease (IMD): 
    • A, B, C, X, Y, W (formerly W-135)
    • Serogroup A causes most meningitis in sub-Saharan Africa.
    • Serogroup B causes most sporadic meningitis.
  • Other virulence factors are similar to those of N. gonorrhoeae.
    • Lipooligosaccharide (LOS, endotoxin) envelope protein
      • LOS mimics human cell membrane glycosphingolipids.
      • Can be sialylated→ resistant to serum killing
      • Lipid A disaccharide (endotoxin) component causes much of the toxicity.
    • IgA protease: inactivates IgA1 immunoglobulin and reduces host’s defense
    • Can rapidly switch antigenic forms of LOS, pilin, Opa
Pathogenesis Haemophilus influenzae

N. meningitidis pathogenesis.
The bacteria enter the respiratory system to invade mucous membranes, then enter the bloodstream. In the blood, proliferation occurs and the pathogen releases endotoxin, which causes fever, increased vascular permeability, shock, and petechiae. The antiphagocytic capsule enables the pathogen to evade destruction by the immune system.

Image by Lecturio.

Pathogenesis:

  • The nasopharynx is the portal of entry, attaching to mucosal cells with the aid of pili.
  • Organisms reach the bloodstream → IMD, which has a rapid course and manifests as sepsis (meningococcemia) and meningitis.
  • Bacteria may also reach the meninges from nearby infected structures or through a congenital or acquired defect in the skull or spine. 
  • Much of the neurologic injury is caused by the immune response to the endotoxin and other bacterial components rather than direct bacteria-induced tissue injury.
    • Inflammatory cytokines and chemokines → intense acute inflammatory response, vasogenic edema, and purulent exudate (visible on the brain surface)
    • Interstitial and cytotoxic edema, vasculitis, and thrombosis → ischemia, infarction, and cerebral herniation

Clinical Presentations

Type of presentationClinical features
Meningitis
  • N. meningitidis is the most common cause of meningitis in children from 1 month to 18 years of age.
  • The classic meningitis triad may not always be present:
    • Fever
    • Headache
    • Nuchal rigidity or “stiff neck”
  • Other signs and symptoms include:
    • Decreased level of consciousness
    • Nausea and/or vomiting
    • Photophobia
    • Seizures (usually focal)
    • Elevated ICP that can lead to cerebral herniation and death
Meningococcemia (meningococcal septicemia) Acute meningococcemia:
  • Septicemia with or without meningitis
  • Presents as:
    • Fever
    • Septic shock
    • Fever
    • Generalized hemorrhagic state that leads to a diffuse erythematous maculopapular rash that becomes petechiae and/or purpura
  • Progresses rapidly and is highly fatal without treatment

Chronic meningococcemia:
  • Milder disease
  • Presents as:
    • Persistent bacteremia (for weeks)
    • Fever
    • Arthritis
    • Splenomegaly
    • Petechial skin lesions
    • Can progress to acute meningococcemia
Waterhouse-Friderichse syndrome
  • A complication of meningococcemia
  • Presents as:
    • DIC
    • Bilateral hemorrhagic adrenal infarctions
    • Septic shock
Other presentations
  • Rare, usually as a result of meningococcal meningitis or septicemia that disseminates:
    • Pneumonia
    • Pharyngitis
    • Arthritis
    • Urethritis
ICP: intracranial pressure
DIC: disseminated intravascular coagulation

Identification

  • Specimens used:
    • Blood: culture (50%–60% sensitive) and real-time polymerase chain reaction (RT-PCR) if available (96% sensitivity and 100% specificity)
    • CSF: smear and culture and RT-PCR
    • Petechiae: smear or biopsy for culture and RT-PCR
    • Nasopharyngeal swab: for culture and RT-PCR: for carrier surveys but not for stand-alone diagnosis as many healthy carriers are in population
  • Lumbar puncture: if no contraindications (elevated ICP, coagulation disorders, thrombocytopenia, uncorrected shock)
  • Culture: N. meningitidis is less fastidious than N. gonorrhoeae but special transport media should still be used, as well as culture on modified Thayer-Martin medium.

Prevention

Prevention is done by quadrivalent meningococcal polysaccharide conjugate vaccine:

  • Contains A, C, Y, and W 
  • Recommended for individuals 11–18 years, with a booster dose 3 years later
  • A single dose only if > 16 years of age
  • Vaccination at 2 months and older for at-risk groups of people
  • Efficacy: 82% first year after vaccination, waning to 59% at 3–6 years

References

  1. Riedel, S., Hobden, J.A. (2019). In Riedel, S, Morse, S.A., Mietzner, T., Miller, S. (Eds.), Jawetz, Melnick, & Adelberg’s Medical Microbiology (28th ed, pp. 295–305).
  2. Textor, S. (2018). In Jameson, J.L., et al. (Ed.), Harrison’s Principles of Internal Medicine (20th ed. Vol 1, pp. 1114–1129). 
  3. Secondhand smoke linked to childhood meningitis. (2018, October 3). Nhs. Uk. https://www.nhs.uk/news/pregnancy-and-child/secondhand-smoke-linked-to-childhood-meningitis/
  4. Apicella, M. (2020). Treatment and prevention of meningococcal infection. UpToDate. Retrieved November, 1, 2020, from https://www.uptodate.com/contents/treatment-and-prevention-of-meningococcal-infection?search=Meningococcal%20meningitis&source=search_result&selectedTitle=1~45&usage_type=default&display_rank=1#H2603449448
  5. Rosenthal, K.S. & Tan, M.J. (2010). Rapid Review Microbiology and Immunology (Goljan, E.F.) (3rd ed.). Mosby/Elsevier.

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