Lecture 16 Neisseria

Question 1

What are the different species of Neisseria?

Answer 1

pathogens:

• N gonorrhoeae
• N meningitidis

Commensals:
Many (eg N lactamica)

Question 2

Neisseria are structurally identified by..?

Answer 2

• gram negative diplococci

- non-motile, non- sporeforming

Question 3

How is Neisseria grown in cx?

Answer 3

-requires enriched CO2 in medium
-oxidase-positive
-Pathogens utilize different sugars:
Gnonococcus: glucose
Meningococcus: maltose and glucose

Question 4

What is the host range?

Answer 4

• obligate human pathogens

- no good animal model to study

Question 5

What are structures found in both pathogens?

Answer 5

• G- cell wall

- Major antigens are pili, outer membrane proteins (Por, Opa), LOS (lipooligosaccharide)

Question 6

What are two host receptors that are utilized by pili?

Answer 6

• CD46 on male urogenital epithelial cells

- CR3 on female cervical epithelium

Question 7

How is the expression of pili controlled?

Answer 7

Phase variation (transcriptional)

Question 8

What is the antigenic variation in Pili?

Answer 8

• conserved regions and 6 immunodominant variable regions
• on antigenic type at a time, multiple present but are silent
• expression occurs at one active site

Question 9

What causes antigenic variation in pili?

Answer 9

-recombination (non-reciprocal) via intrachromosomal or via transformation.

Question 10

What are two outer membrane protein?

Answer 10

• Por

- Opa

Question 11

What is Por?

Answer 11

(OMP I)

• Por most abundant structural protein
• Trimers: porin function
• involved in attachment and invasion of host cells by binding to host CR3 receptor

Question 12

Why is serotyping scheme based on Por?

Answer 12

-each strain has one antigenic type, but there is variation
among strains
Por 1A - (disseminated infection)
Por 1B - (local genital infection)

Question 13

What is Opa?

Answer 13

(Omp II)

• compromises group of 12 genes (3-4 in meningiditis)
• 0-3 Opa proteins may be expressed in single strain
• expression determines colony phenotype: opaque or transparent
• functions in close attachment to host cells
• Phase switch depending on environment

Question 14

How is Opa genetically controlled?

Answer 14

• Multiple gene copies, all with promoters
• constitutively transcribed
• translationally controlled
• CTCTT repeats immediately proceeds genes, puts it in or out of phase

Question 15

What is LOS?

Answer 15

Similar to LPS, but lacks repeating sugar subunit.

• major role in production of inflammatory mediators
• plays a role in attachment

Question 16

What is Sialylated LOS?

Answer 16

confers serum resistance and attenuates the inflammatory response

Question 17

What is the pathogenesis in Male vs Female GC?

Answer 17

• infection of males leads to acute urethritis

- infection in females is asymptomatic

Question 18

What is the mechanism of male pathogenesis of GC?

Answer 18

• attachment to CD46 receptor in urethral epithelium
• Opa expression results in closer adhesion in gonococci and host cells
• GC multiply, reach submucosa, triggers inflammation, can have hematogenous extension.

Question 19

What is the mechanism of pathogenesis of GC in females?

Answer 19

-Pili and por bind to CR3 in epithelial cells, does not trigger inflammatory response

Question 20

What is the host immune response to Neiserria G?

Answer 20

• Natural abx develop from colonization with commensal Neisseria and other gram-negative organism
• results in ability of NHS + C to kill many strains
• Bactericidal abx (IgM, IgA, IgG).
• opsonic abx
• ingested, but not killed by neutrophils

Question 21

What is the epidemiology and transmission of GC?

Answer 21

• Mostly through sexual transmission, male to female.
• higher rates in non-whites
• asymptomatic (more in females) make it hard to eradicate

Question 22

What is the clinical spectrum manifestations of GC?

Answer 22

• Urethritis
• Cervicitis
• Salpingitis
• Disseminated Infection • Conjunctivitis (infants)
• Rectal

Question 23

What are the sx of Urethritis?

Answer 23

• Incubation period: 1-14 days; majority develop symptoms in 2-5 days
• Symptoms: dysuria and/or urethral discharge; variable degree of edema and erythema

Question 24

How does Urethritis affect males?

Answer 24

• Course: spontaneous resolution over several weeks without therapy; >95% are asymptomatic within 6 months.
• Complications:
–Epididymitis – unilateral testicular pain,
swelling
–Prostatitis – acute or chronic

Question 25

How does Urogenital infections affect women?

Answer 25

* Asymptomatic in many * Symptoms range from minimal to severe * Increased vaginal discharge due to endocervical infection * Dysuria – urethral colonization is present in 70-90% of infected women

Question 26

What are the complications of Salpingitis?

Answer 26

* 10-20% of infected women * Symptoms: lower abdominal pain, abnormal menses * Can result in inflammation of fallopian tube, with scarring * Important cause of infertility, ectopic pregnancy

Question 27

What is disseminated gonohrea?

Answer 27

• Occurs in 0.5-3% of untreated patients • Manifested by acute arthritis – dermatitis syndrome • More common in females- may be associated with recent menstruation

Question 28

How is Gonorrhea dx?

Answer 28

- NA amplification test in urine (w/ CT) - Gram stain (G-) sensitive in male. Diplococci - Cx using Thayer-Martin media

Question 29

How is gonorrhea treated?

Answer 29

``` • Combination treatment: Ceftriaxone 250 mg IM PLUS Azithromycin 1g PO or Doxycycline 100 mg PO, twice daily X 7 days ```

Question 30

What are some distinguishable features of N Meningitidis?

Answer 30

* Commonly carried in nasopharynx as a commensal * Sometimes causes disease * Semi-typical gram negative cell wall * Same as N. gonorrhoeae except that N. meningitidis has a polysaccharide capsule

Question 31

What antigens are found on N meningitidis?

Answer 31

• Major antigens are capsular polysaccharide (CPS), LOS, pili, OMP’s -Antigenic diversity due partly through interspecies gene exchange

Question 32

How are capsule regulated?

Answer 32

—Capsule expression is down-regulated during carriage; up-regulated during invasion into bloodstream

Question 33

Which serotypes of Meningitidis cause the most infections in industrialized countries?

Answer 33

-B and C, recent clustered outbreaks of Y

Question 34

What is the asymptomatic carriage of Meningococci?

Answer 34

* 10-20% of individuals carry meningococci in throats * More common in adolescents, young adults * Usually transient: 75% clear within a few months * Serve as the primary reservoir of infection via droplets * Carriage is immunizing

Question 35

What is the immune response of MC?

Answer 35

-Maternal abx will protect you when you are born, but it will decrease and you will have to start to make your own.

Question 36

What is the pathogenesis of MC?

Answer 36

—Attachment to oropharynx – via pili — Most organisms remain as extracellular adherent pathogens —Dissemination from pharynx is via blood stream; invasion through blood brain barrier.

Question 37

What is the pathogenesis and immune response of MC?

Answer 37

* Susceptibility to infection is due to lack of bacteridical antibodies directed against Por, Opc, LOS. * Opsonic antibodies develop during carriage of N. lactamica and other cross-reactive organisms in childhood * Bactericidal antibodies develop during asymptomatic carriage of N. meningitidis.

Question 38

What is the meningitis belt?

Answer 38

-Region in Africa where there are seasonal outbreaks, 10 % of infected die. Usually form Type A.

Question 39

What are the type of vaccines for Meningococcus?

Answer 39

- CPS vaccines -effective against A, C, Y and W - Group B CPS is poorly immunogenic - MenB OMV vaccines are effective, targets PorA.

Question 40

What are some clinical spectrum and manifestations of MC?

Answer 40

• Meningitis • Meningococcemia —Fulminant Meningococcemia

Question 41

What are sx of Meningitis?

Answer 41

– Seen primarily in children 6 months – 10 years – Fever, vomiting, headache, confusion -Maybe hearing loss

Question 42

What are sx of Meningococcemia?

Answer 42

– Abrupt onset of illness: spiking fever, chills, arthralgias, myalgias – 75% develop petechial rash

Question 43

What are the sx of Fulminant Meningococcemia?

Answer 43

◦ Seen in 10-20% of patients (high levels of endotoxin circulating) ◦ LOS induces TNF and interleukins, leading to shock, hemorrhages of skin and organs, and influx of leukocytes (meningitis) ◦ 40-60% mortality ◦ Dramatic: healthy death in 6 hours

Question 44

How is MC dx?

Answer 44

• Gram stain of CSF (85% sensitivity) • Culture from blood, CSF; less commonly from skin lesions, joints • PCR for Neisseria meningitidis is most sensitive

Question 45

What is the treatment for MC?

Answer 45

* Penicillin G is drug of choice; adjunct steroid therapy is beneficial in children * Alternatives include newer cephalosporins * Antibiotic treatment of carrier state not warranted

Question 46

What is the type of binding from Opa?

Answer 46

• Promiscuous binding –Cell surface proteoglycans –Extracellular matrix proteins –Other cell surface adhesion molecules