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Tularemia Natural History of Francisella tularensis.

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1 Tularemia Natural History of Francisella tularensis

2 History Leviticus 11:6-7 – But you shall not eat any of the following that only chew the cud or only have hoofs... the hare, which indeed chews the cud, but does not have hoofs and is therefore unclean for you Wherry WB, Lamb BH. Infection of man with Bacterium tularense. J Infect Dis 1914l 15: – first description of human tularemia with culture of causative organism Francis E. A summary of the present knowledge of tularemia. Medicine (Baltimore) 1928;7: – clinical and epidemiological study of >600 human cases

3 Pathogen – Francisella tularensis Gram negative non-motile non-sporulating cocco-bacillus Reservoir unknown – free living protozoa? Infects small mammals – ground squirrels, rabbits, hares, voles, muskrats, water rats and other rodents Arthropod vectors – ticks, biting flies, mosquitoes Uncommon zoonosis – 125 cases/year in USA – farmers, hunters, walkers, forest workers – kills less than 50 people a year worldwide

4 Bioterrorism (1) Category A agents – bacterial Francisella tularensis (tularemia) Bacillus anthracis (anthrax) Yersinia pestis (plague) Clostridium botulinum (botulism) – viral Variola major (smallpox) Viral hemorrhagic fever (ebola, marburg, lassa, argentine)

5 Bioterrorism (2) Tested by Japan in WWII as potential bioweapon Weaponised and stockpiled by USA and USSR during Cold War Epidemics (probably natural causes) – Battle of Stalingrad – Kosovo 1999 (327 cases, no fatalities) – Recurrent outbreaks on Martha's vineyard (cause unknown)

6 Microbiology

7 Subspecies F. tularensis subsp. tularensis (Type A) – LD 50 ~ 1 (mice) – LD 50 < 10 2 (humans) F. tularensis subsp. holarctica (Type B) – LD 50 > 10 6 (rabbits) F. tularensis subsp. mediasiatica F. tularensis subsp. novicida

8 Taxonomy

9 Transmission Highly infectious – inhalation of 10 bacteria can cause disease Avenues – ingestion (water and food) – inhalation – direct contact – arthropod intermediates – animal bites No person to person spread

10 Vectors in America Biting fly Utah, Nevada, California Tick East of Rocky Mountains

11 Disease Forms Ulceroglandular (<5% mortality untreated) Oculoglandular Typhoidal syndrome (30-60% mortality untreated) Oropharyngeal Gastrointestinal Secondary pneumonia Primary inhalational pneumonia

12 Clinical Disease Ulceroglandular – Incubation period 3-6 days – Sudden onset flu like symptoms – Ulcer at site of infection – Enlargement of draining nodes Typhoidal syndrome – septicemia without ulcer or lymphadenopathy Oropharyngeal – sore throat, enlarged tonsils, yellow-white pseudomembrane Gastrointestinal – persistent diarrhea, bowel ulceration -> acute fatal disease Pneumonia

13 Ulceroglandular Tularemia

14 Diagnosis Culture – high risk to laboratory personnel Non-culture methods – Serology ELISA micro-agglutination Western blot flow cytometry indirect immunofluorescence – PCR

15 Treatment Recommended – Streptomycin – Gentamicin Oral medication – Fluroquinolones (Ciprofloxacin) Mortality -> 0 Reduce debilitating features of disease

16 Vaccines Live vaccines – F. tularensis LVS – water rat -> USSR -> USAMRIID (1956) – Use halted by FDA 2001 Problems – protects against inhalational but not cutaneous disease – protective response not well understood – basis of attenuation not known – potential for reversion No effective killed bacterial or subtype vaccine

17 Model Organism Animal models available Cell culture models available Live vaccine strain available Grows rapidly in vivo and in vitro Genome sequencing in progress Public health interest

18 Host-pathogen (0) Intracellular living 1. Cell Entry 2. Replication cytoplasmic phagosomal phagolysosomal 3. Cell Exit

19 Host-Pathogen (1) Obligate intracellular pathogen – macrophages, hepatocytes, endothelial cells, fibroblasts Entry pathway unknown – no respiratory burst – complement/complement receptor dependent? Intracellular residence – first 4 hours -> non-acidified phagosome – after 8 hours -> cytoplasm Doubling time in macrophages is 4-6 hours

20 Host-Pathogen (2) Inhibits NF- B and MAPK activation by TLR ligation Evade phagosome-lysosome fusion No evidence for secreted toxins Induces apoptosis in murine macrophages

21 Virulence Factors Atypical LPS – elicits 1000-fold less TNF and IL-1 than E. coli Capsule – prevents serum-mediated lysis Pili – adherence, cell-cell interactions, biofilm formation Proteins – pathogenicity island (FPI) recently discovered – mglA, mglB transcriptional regulator – mglA positively regulates pdpA, pdpD, iglA, iglC, and iglD genes – iglC (23 kD protein) disrupts TLR signaling Other components – 'phosphoantigens' expand -T cells (significance unknown)

22 Francisella Pathogenecity Island (FPI) kb cluster of genes encoding virulence factors 2. flanked by transposable elements 3. G+C content significantly different from rest of chromosome

23 Immunology (1) Early (<3 days) response is T cell independent – infected macrophages -> TNF- – TNF- -> NK cells -> IFN- – IFN- -> infected macrophage -> NO Late (>3 days) and secondary response is T cell dependent – Th1 response – CD4+, CD8+ and Thy1 + CD4 - CD8 - T cells cells important – IFN-g, TNF-a, RNS, ROS – Role of perforin, Fas-FasL cell killing unknown Others – -T cells expanded – Antibodies probably minor role – Neutrophils can phagocytose opsonized bacteria but poor killing

24 Immunology (2) Infection confers long-lasting immunity – may be partial – Edward Francis infected at least 3 times Each immune individual recognises a mosaic of antigens No immunodominant antigens identified – Orchestration of the protective immune response to intracellular bacteria: Francisella tularensis as a model organism. FEMS Immunol Med Microb, 1996, 13:

25 Genome 1 partial annotation published – Preliminary analysis and annotation of the partial genome sequence of Francisella tularensis strain Schu 4. J Appl Microbiol Oct;91(4): – Predicted ORFs with no match in GenBank much higher than other microbial genomes – No matches with known virulence genes in other pathogens 2 preliminary genome sequences completed – (Lawrence Livermore National Laboratory) – (Uppsala University)

26 Transcriptome Samrakandi MM et al, Genome diversity among regional populations of Francisella tularensis subspecies tularensis and Francisella tularensis subspecies holarctica isolated from the US, FEMS Microbiol Lett Aug 1;237(1):9-17. Broekhuijsen M et al, Genome-wide DNA microarray analysis of Francisella tularensis strains demonstrates extensive genetic conservation within the species but identifies regions that are unique to the highly virulent F. tularensis subsp. tularensis, J Clin Microbiol Jul;41(7):

27 Proteome Papers – Hubalek M et al, Proteomics Oct;4(10): – Hubalek M et al, J Chromatogr B Analyt Technol Biomed Life Sci Apr 5;787(1): – Havlasova J et al, Proteomics Jul;2(7): – Kovarova H et al, Proteomics Jan;2(1): – Hernychova L et al, Proteomics Apr;1(4): D PAGE Databases – 3D protein structure –

28 References J Infect Dis, 2004, 189: Clin Microb Rev, 2002, 15: Trends Microb, 2003, 11: Curr Opin Microb, 2003, 6:66-71 Lancet, 2000, 356: Infect Immun, : J Bacteriol, 2004,186:

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