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pPst

pPst. 9.5 kb- smallest plasmid Found only in Y. Pestis Encodes for plasminogen activator ( pla) Cell surface protease Has coagulase activity evident only at temperatures below 30°C, which initiates blockage in flea and forms fibrin matrix that anchors bacteria to proventiculus of flea

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pPst

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  1. pPst • 9.5 kb- smallest plasmid • Found only in Y. Pestis • Encodes for plasminogen activator (pla) • Cell surface protease • Has coagulase activity evident only at temperatures below 30°C, which initiates blockage in flea and forms fibrin matrix that anchors bacteria to proventiculus of flea • At 37°C exhibit fibronolytic activities, lyses fibrin at bite site and allows dissemination of bacterium

  2. pPst • Other possible functions of Plasminogen activator • Produces excess plasmin that causes ineffective structures between inflammatory cells and fibrin • Reduces chemoattractants at the infection site possibly via inhibition of IL-8. • Encodes bacteriosin pesticin (pst) and its immunity protein (pim)

  3. pCD1 • 68-75 kb (depending on the strain) • Responsible for encoding anti-host genome • Y.Pestis, Y.pseudotuberculosis, and Y. Enterocolitis both possess this plasmid • Encodes the Low Calcium Response System (LCRS)- controlled by Temperature and Calcium concentration • Low Calcium response V antigen-LcrV • Yersinia Outer membrane proteins- Yops • Specific Yop chaperones- Syc • Yop secretion proteins/Type III secretion system- Ysc

  4. pCD1LcrV/V antigen • LcrV protein plays a role in regulating the LCRS • It is a protective antigen that is associated with resistance to phagocytosis • May play an immunosuppressive role, by inhibiting cytokine production • Induces IL-10 production by macrophages this downregulates host’s immune response

  5. pCD1Yop proteins • Altogether there are 29 Yop proteins • Yop effector proteins protect Y.pestis from macrophages by destroying phagocytic signaling capabilities • There are 6 Yops which directly or indirectly cause disease: • Yop E, Yop H, Yop J, Yop O, Yop M, Yop B and D

  6. How Yops Thwart Host Immune System ■ Yop E ■ Indirectly depolymerizes actin microfilaments ■ Yop H ■ a protein tyrosine phosphatase capable of dephosphorylating host proteins such as p125FAK and p130Ca at focal adhesions, inhibiting signal transduction necessary for phagocytosis ■ Yop J ■ Binds to MAP kinase family-downregulating TNF-

  7. More Yops • Yop O/YpkA • Ser/Thr kinase that probably interferes with signaling pathways • Yop M • Prevents thrombin platelet aggregation • Mutes inflammatory response by sequestering thrombin • Yop B and D • Translocate effectors across cell membrane

  8. Yops RegulationTemperature and Ca2+ • When placed in 37°C and in a medium deprived of Ca2+,Y. Pestis ceases growth and expression of Yops is induced. • Yops expression and secretion is induced in Ca2+-containing media by a local signal that occurs at the site of contact between the pathogen and the eukaryotic cell. This leads to the polarized transfer of at least five Yops into the target cell.

  9. pCD1Syc proteins • Small Yop binding proteins • Not all Yops are syc associated • Act as chaperones by preventing Yop degradation • Act as “secretion pilots” leading the Yops to their location of secretion

  10. pCD1Ysc/ Type III secretion system • Yops is mediated by Type III secretion system called Ysc • Ysc Type III secretion system consists of: • the core Ysc mechanism for secretion through the two bacterial membranes • a delivery apparatus (YopB, YopD, YopK, LcrV) • control elements (LcrE also called YopN and TyeA at the surface and LcrG in the cytosol) • anti-host effector proteins (YopE, YopH, YopM, YpkA and YopJ).

  11. Ysc/Type III secretion system

  12. Yersinia’s Deadly Kiss

  13. All Together Now!

  14. Clinical AspectsFocus on Bubonic Plague Signs and symptoms Complications Differential Diagnosis Diagnosis Treatment Prognosis Prevention Vaccine Development

  15. Presenting Plague Patients %

  16. Signs & Symptoms Within 2-7 days of Infection: ■ Severe malaise or prostration ---75% ■ High fever, headache ---20%-85% ■ Chills --- 40% ■ Vomiting ---25%-49% ■ Altered mentation ---26%-38% ■ Abdominal pain --- 18% ■ Other: bladder distention, apathy, confusion, fright, anxiety, oliguria, anuria, tachycardia, hypotension, leukocytosis

  17. Signs & Symptoms 6-8 hours following onset of symptoms: ■ Pain/tenderness at regional lymph nodes enlarge to be called buboes - extremely painful - occur in groin*, axilla or cervical areas - usually occur in 1 region, but multiple can be seen - may drain pus if left untreated ■ ulcer or skin lesions at site of flea bite <10% of cases

  18. Complications ■ 2Septicemic Plague due to hematogenous spread (23% of patients) - Purpuric Lesions - Acral Necrosis - DIC disseminated intravascular coagulation - Convulsions - Shock Purpuric lesions diffuse, hemorrhagic changes in skin (darkened skin changes ="black death”) Acral necrosis

  19. Complications ■ 2Pneumonic Plague (5-15% of patients) - begins as interstitial pneumonitis;  bacteria in interstitium - show signs and symptoms prior to developing advanced pneumonitis: High fever Severe bronchopneumonia Chest pain Coughing or spitting up blood Difficulty breathing ■ Infection of Buboes ■ Meningitis (< 5%) ■ Death

  20. Distinguishing 1 from 2 Pneumonic Plague ■ no buboes ■ 1-3 day incubation period ■ infectious pneumonitis from onset of symptoms ■ sputum production common ■ less severe evidence of disease in organs other than lungs ■  bacteria in alveoli ■ tracheal & bronchial mucosal hemorrhages ■ can lead to 2 Septicemic Plague symptoms Sudden onset of fever, chills, headache, body pains, weakness, chest discomfort & tightness; Coughing with sputum production; Difficulty breathing; Coughing or spitting up blood; GI symptoms; Pharyngitis

  21. Distinguishing 1 from 2 Septicemic Plague ■ no buboes ■ 1-4 day incubation period ■ more GI symptoms ■ can also lead to 2 Pneumonic Plague (25%) ■ meningitis is 4x more common symptoms Fever and chills Extreme exhaustion Bleeding disorder Necrosis of small vessels Hemorrhagic Skin lesions (purpuric lesions, acral necrosis) Gangrene of extremities (nose or digits) DICConvulsions Shock

  22. Differential Diagnosis Bubonic Plague ■ Chancroid ■ Primary genital herpes ■ 1 or 2 syphilis ■ Strangulated inguinal hernias ■ Streptococcal or staphylococcal adenitis ■ Tularemia ■ Cat scratch disease ■ Mycobacterial infection ■ Lymphogranuloma venereum

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