BMS2037 Neisseria PDF

Neisseriaceae: Gram-negative cocci of clinical importance Neisseriaceae Classification of the Neisseriaceae Key questions What are the microbiological characteristics of Neisseria? What are the key differences between Neisseria meningitidis (meningococcus) and Neisseria gono...

Neisseriaceae: Gram-negative cocci of clinical importance Neisseriaceae Classification of the Neisseriaceae Key questions What are the microbiological characteristics of Neisseria? What are the key differences between Neisseria meningitidis (meningococcus) and Neisseria gonorrhoea (gonococcus)? What are the important challenges posed by these pathogens in terms of infection control?  NEISSERIACEAE: PHYLOGENY The family Neisseriaceae are Gram- negative aerobic rods or cocci. Contains 5 genera: Neisseria: cocci Neisseria meningitidis Pathogens Simonsiella spp. Top: Electron Neisseria gonorrhoea micrograph. Below – light micrograph Neisseria lactamica Commensal Kingella: rods Rare pathogens Eikenella: rods Simonsiella: multicellular filaments Alysiella: multicellular filaments General characteristics of the Neisseriaceae Gram-negative cocci, (often diplococci) with adjacent sides flattened (like coffee beans) Top: N. gonorrhoea within Associated with mucous membranes of neutrophils – Gram stain, x warm-blooded animals. 1000 magnification Twitching motility via Type IV pili Below: electron micrograph of Oxidase positive diplococci formation Capnophilic, requiring 5-10% CO2 for growth Acid from oxidation of carbohydrates, Weichselbaum identified N. not fermentation meningitidis from cerebral spinal fluid of a meningitis patient in 1887  Lifestyles versus disease Have genetic and antigenic similarities BUT very different lifestyles N. meningitidis N. gonorrhoeae Asymptomatic commensal Usually sexually transmitted of the human upper Primarily infects the urogenital respiratory tract (URT) epithelia: epididymitis, cervicitis, Accidental human pathogen, endometriosis, PID (a major cause of causing meningitis and infertility) septicaemia Persistent, asymptomatic disease Very high morbidity and common but NOT a commensal mortality Rare cases of disseminated infection, Sporadic or epidemic arthritis and endocarditis outbreaks Rare cause of pharyngitis and conjunctivitis (neonates)  Carriage versus invasion of N. meningitidis The human nasopharynx is sole ecological niche Spreads via saliva – direct contact / droplet spread Proliferation / horizontal gene exchange, and genetic reassortment during carriage results in many phenotypes For genetically primed strains, invasion can occur Mostly, carriage is not associated Overview of N. meningitis transmission and carriage state. with disease Caugant and Brynildsrud, 2020. Nature. Understanding of carriage (10-35% (some university students Carriage offers some immunity up to 55%) is crucial to understanding meningococcal disease and prevention.  Pathogenesis of N. meningitidis Invasive phenotypes express the factors needed to invade the bloodstream Pathogenicty factors: Lipooligosaccharide (LOS) Type IV pili Surface proteins NadA and Opa Invasins Iron-acquisition Polysaccharide capsule protects against host phagocytes Meningococcal meningitis Signs and symptoms Vomiting Excruciating intense headache (escalated cerebrospinal fluid pressure). Other symptoms may include: confusion, drowsiness, fever, sensitivity to light, and a skin rash. Eventually the neck stiffens (nerves along the spine become increasingly irritated) Convulsions Meningitis = inflammation of If untreated fluid build-up in the the meninges ventricles of the brain, which can result in a loss of consciousness or even death.  Meningococcal disease - Clinical signs You need to be VERY quick as meningococcal disease can kill within 4 hours! The “glass test” for petechial rash Meningococcal disease Meningococcal Vaccines Surface variation poses a BIG problem in vaccine development Multicomponent vaccines exist but fall short of combating all virulent strains. Quadrivalent A, C, Y, W-135 polysaccharide, for subcutaneous injection. Useful in outbreak control in meningo belt. Conjugate C vaccine introduction in UK reduced cases The controversial and difficult B vaccine (most commonest cause in UK). Invasive meningococcal disease, by age in years Bexsero B Vaccine (4CmenB) Developed by reverse vaccinology. Bexsero (Novartis) is licensed for use in the UK and the EU. Initially, not adopted by NHS as part of routine childhood vaccinations because insufficient ‘quality-adjusted life years (QALY)’ per cost. After extensive lobbying introduced in March 2014 Possible protection against serogroup W and cross-protection against Neisseria gonorrhoeae infection  Trotter et al. / WHO / Lancet, 2019 The available conjugate vaccines are too expensive for low-income countries. WHO joined with the Program for Appropriate Technology for Health to create the Meningitis Vaccine Project (MVP). In 2001, the Bill and Melinda Gates Foundation provided core funding A serogroup A meningococcal polysaccharide–tetanus toxoid conjugate vaccine -licensed 2009  ▪ Roughly 1·8 million individuals vaccinated with PsA–TT in three regions of Chad ▪ No case of serogroup A meningococcal meningitis was reported in the vaccinated regions. ▪ 32 serogroup A carriers were identified living in a rural area near the capital 2–4 months before vaccination, whereas only one serogroup A meningococcus was isolated in people living in the same community 4–6 months after vaccination ▪ PSA–TT was highly effective at ▪ Introduction of MenAfriVac (serogroup A meningococcal prevention of serogroup A invasive conjugate vaccine) for Africa has been a massive public health meningococcal disease and carriage in success with virtual elimination of serogroup A meningitis and epidemics. Chad. ▪ Must introduce MenAfriVacR into the national childhood ▪ How long this protection will persist immunization program needs to be established ▪ However there are still > 25,000 suspected cases of meningitis reported each year from 2015 to 2017.  Neisseria gonorrhoea: The gonococcus Discovered in 1879 by Albert Neisser Type IV pili is major virulence factor Non-capsulated (unlike N. meningitidis) Outer membrane: Lipooligosaccharide (LOS) Surface protein OPA Via unprotected vaginal, oral or anal sex  Discharge from the genitals Burning when peeing Men usually get symptoms (or do they?) Women asymptomatic (or are they?) Versus reality…. Gonorrhoea - conjunctivitis Transmitted from mother to baby during birth May rapidly perforate the cornea URGENT REFERRAL for intensive IV & topical treatment Gonorrhoea mainly affects people in their 20s Age group 2014 2015 2016 2017 2018 13-14 73 73 48 78 80 15-19 4,780 4,501 4,146 5,476 6,805 20-24 9,536 10,165 9,111 11,041 13,648 25-34 13,552 15,706 13,729 16,626 20,759 35-44 5,834 6,937 5,871 7,049 8,826 45-64 3,145 3,701 3,422 4,225 5,725 65+ 172 193 180 236 336 Other 80 106 70 81 80 Total 37,172 41,382 36,577 44,812 56,259 >78 million cases worldwide each year Increasing incidence in the UK Increases transmission of HIV Lack of understanding of the complex transmission routes and reservoirs Gonorrhoea – antibiotic resistance Increased azithromycin resistance in the UK, leading to the possibility that gonorrhoea may become untreatable Dual antimicrobial therapy (Azithromycin and ceftriaxone) Increased surveillance of strains and resistance required How has this resistance developed? Sub-therapeutic dosing mainly in Asia and also in the UK due to the Chlamydia screening programme (low dose azithromycin). Laboratory Diagnosis Meningococcal disease CSF and blood samples Microscopy Culture (takes too long!) PCR Detection of soluble bacterial polysaccharides in CSF by Gonococcal disease latex agglutination Endocervical, cervical, anal and eye swabs, and urines Nucleic amplification tests (strand displacement amplification assay) QRT PCR Culture Treatment – to be discussed in a further lecture! Meningococcal disease Gonnococcal disease IV antibiotics – benzyl penicillin or Developed resistance rapidly to all amoxicillin. antibiotics introduced for treatment. – 3rd generation cephalosporins First line treatments now extended – Drug resistance is rare spectrum e.g. cefixime or IM Maintenance therapy for shock ceftriaxone (fluids, etc.) Gonococcal superbugs now id’ed Vasoactive treatments IV adrenaline which have R to ceftriaxone Steroids (preferably before first of Dual treatments now recommended – Ceftriaxone and Azithromycin antibiotic – why?) Experimental therapies, such as anti-cytokine and anti-endotoxin have been investigated. Shared signatures: What’s similar and what’s different? Revision exercise: After you have revised the topic see how much of table you can complete from memory. Then check your answers against your notes Feature Gonococcus Meningococcus Microbiology Disease Symptoms Treatment Prevention Control  References Caugant, D.A., Brynildsrud, O.B. Neisseria meningitidis: using genomics to understand diversity, evolution and pathogenesis. Nat Rev Microbiol 18, 84–96 (2020). https://doi.org/10.1038/s41579-019-0282-6 Quillin & Seifert (2018) Neisseria gonorrhoeae host adaptation and Pathogenesis. Nat Rev Microbiol. 2018 Apr;16(4):226-240. doi: 10.1038/nrmicro.2017.169. Unemo (2015) Current and Future antimicrobial treatment of gonorrhoea-the rapidly evolving Neisseria gonnorrhoeae continues to challenge. BMC Infectious Diseases 15:364 Russell (2018) Could vaccination against Neisseria gonorrhoeae be on the horizon Future Microbiology 13(5)., 495-497. Gottfedsson (2016). Unveiling aspects of meningococcal carriage and disease prevention. JCM 542-4