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MICR 454L
Emerging and Re-EmergingInfectious Diseases
Lecture 4:N. meningitidis
(Chapter 8)Dr. Nancy McQueen & Dr. Edith Porter
Overview
N. meningitidis Morphology Growth and metabolic characteristics Virulence factors Diseases Host defenses Diagnosis
Culture and biochemical identification Membrane-based dot immunoassay Latex agglutination PCR
Therapy and Prevention Threats
Neisseria meningitidis
Neisseria meningitidis
Gram-negative aerobic diplococci Capnophil Capsule - only some serotypes
are associated with epidemics Serotypes A, B, C, W-135, Y
US: C, Y, and W-135 (infants: B)
10% of people are healthy nasopharyngeal carriers Humans only known host Transmission via respiratory droplets
Major N. meningitidis Virulence Factors and Their Roles in Host-Pathogen Interaction
http://zdsys.chgb.org.cn/cgi-bin/VFs/genus.cgi?Genus=Neisseria
N. meningitidis Virulence Factors: Surface Proteins
Pili - attachment to nonciliated columnar epithelial cells
Class 5 protein (Opa) - attachment and invasion
Opc protein - attachment and invasion
Class 1, 2 and 3 proteins (por) - porins; invasion; intracellular survival
Class 4 protein (rmp) - elicits formation of ineffective blocking antibodies
Proteins that detoxify NO
Outer membrane proteins
Induced Uptake of N. meningitidis
http://zdsys.chgb.org.cn/cgi-bin/VFs/genus.cgi?Genus=Neisseria
N. meningitidis: Virulence Factors (2) Lipooligosaccharide (LOS)
Comparable to LPS of Gram negative bacilli: endotoxin, but limited sugar residues
Adherence and invasion Molecular mimicry of host
structures Released in membrane blebs Lipid moiety strongly induces
TNF- Capsule - antiphagocytic;
protection from antimicrobial peptides
Pili, Opa,LOS, and to a lesser extent, Opc, undergo antigenic variation
IgA1 protease
N. meningitidis Virulence Factors: Iron Acquisition and Uptake
http://zdsys.chgb.org.cn/cgi-bin/VFs/vfs.cgi?VFID=VF0272#VF0272
Active learning exercise
There is a multivalent capsular polysaccharide vaccine currently available for types A, C, Y, and W-135. It has not been possible to develop a capsular vaccine for type B. If you were to try to develop a vaccine to protect individuals from type B infections, what would you target and why?
N. meningitidis: Pathogenesis and Diseases Pathogenesis
Attachment to epithelial cells Invasion - bacteria cross the
mucosal barrier Bacteria enter the bloodstream ? Entrance into central nervous
system Most symptoms are due to the toxic
effects of the LOS Diseases
Meninogococcal sepsis Abrupt onset High fever Shaking and chills Nausea and vomiting Myalgias and weakness Petechial rash (hallmark of
MGC infections).
N. meningitidis: Pathogenesis and Diseases
More severe skin lesions as the disease progresses
Headache Disease may or may not
be accompanied by meninigitis
Disease may be chronic, moderate, or fulminant
The fulminant form of the disease = Waterhouse Friderichsen Syndrome
Waterhouse-Friderichsen Syndrome• Disseminated intravascular
coagulation and multiorgan failure (due to released blebs)
• Septic Shock and bleeding into adrenal glands
• Widespread purpuric and ecchymotic skin lesions (bleeding into skin and surrounding tissue)
• Pulmonary insufficiency
• Death usually within 12 – 48 hours
• Patients that survive may lose their limbs from tissue necrosis (gangrene of the skin and soft tissues)
N. meningitidis: Pathogenesis and Diseases
Bacterial meningitis Abrupt or insidious onset High fever Petechial rash Headache and stiff neck Followed by nausea and
vomiting In severe cases there is
severe cerebral hyperemia (accumulation of blood) and tissue swelling.
May progress to convulsions and coma
10%-14% of cases are fatal For patients who recover
11%-19% have permanent hearing loss or mental retardation
N. meningitidis - Host Defenses
Systemic infections occur in individuals lacking serum bactericidal antibodies against the capsular or other outer membrane antigens (Opc).
Systemic infections occur in individuals lacking late-acting complement components (C5-C8) or individuals lacking a spleen.
Chronic irritation or damage to the respiratory mucosa may be predisposing factors.
N. meningitidis: Diagnosis Plate immediately
Is sensitive to temperature extremes and drying
Gram stain Often seen intracellularly
Identification Culture and biochemicals
Plating on selective media Incubation in increased CO2
Oxidase + Catalase + Oxidative use of glucose and
maltose Nitrate -
Membrane-based dot immunoassay
Latex agglutination PCR
Latex agglutination
+
Specific antibody bound to latex particles
+
Specific antigen
Agglutination
N. meningitidis: Therapy and Prevention
Therapy Ceftriaxon Prophylaxis with rifampin, ciprofloxacin, or ceftriaxone for
household and other close contacts
Prevention A capsular polysaccharide vaccine to protect disease from
groups A, C, Y and W135 is available. A group B vaccine consisting of OM antigens has been
developed, but is not available in the United States.
Threats by N. meningitidis
Massive epidemic outbreaks in sub-Saharan Africa in the 1990's
Emergence since 1995 of serogroups Y, W-135 and X Risk groups
Infants and young children Refugees Household contacts of case patients Military recruits College freshmen who live in dormitories microbiologists who work with isolates of N. meningitidis
Patients without spleens or with terminal complement component deficiencies
Meningitis Belt in Africa
http://www.nathnac.org/ds/c_pages/documents/mening_belt.gif
Take Home Messages
N. meningitis is a pathogen that resists phagocytosis, is capable of intracellular survival, and can induce a major LOS mediated inflammatory response with a rapidly fatal outcome.
10% of the populations are carriers. Capsule serotypes A, B, C, W-135, Y can
cause epidemics.
Resources The Microbial Challenge, by Krasner, ASM Press, Washington DC, 2002. Brock Biology of Microorganisms, by Madigan and Martinko, Pearson Prentice
Hall, Upper Saddle River, NJ, 11th ed, 2006. Microbiology: An Introduction, by Tortora, Funke and Case; Pearson Prentice Hall;
9th ed, 2007. Immunobiology, by Janeway,, Travers, Walport, and Shlomchik, Garland Science,
6th ed, 2005. Malak Kotb Genetics of Susceptibility to Infectious Diseases Volume 70, Number
10, 2004 / ASM News Y 457-463 Bernard Dixon MicrobeLibrary Article: Microbe
2005 Tsai CM, 2001. Molecular mimicry of host structures by lipooligosaccharides of
Neisseria meningitidis: characterization of sialylated and nonsialylated lacto-N-neotetraose (Galbeta1-4GlcNAcbeta1-3Galbeta1-4Glc) structures in lipooligosaccharides using monoclonal antibodies and specific lectins. Adv Exp Med Biol 491:525-542.
Gray-Owen SD, et al., 2001. Neisseria In Groisman EA (ed.), Principles of Bacterial pathogenesis. Academic Press. San Diego, Calif. pp. 559-618.
Bentley SD, et al., 2007. Meningococcal genetic variation mechanisms viewed through comparative analysis of serogroup C strain FAM18. PLoS Genet 3(2):e23.
Resources Hauck CR, Meyer TF, 2003. 'Small' talk: Opa proteins as mediators of
Neisseria-host-cell communication. Curr. Opin. Microbiol. 6(1):43-49. Spinosa MR, Progida C, Talà A, Cogli L, Alifano P, Bucci C. (2007) The
Neisseria meningitidis capsule is important for intracellular survival in human cells. Infect Immun. Jul;75(7):3594-603. Epub 2007 Apr 30.