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National Center for Emerging and Zoonotic Infectious Diseases (proposed) 1 Selected Zoonotic Diseases  Conference Call January 6, 2010
Shauna L. Mettee, MSN, MPH EIS Officer, Enteric Diseases Epidemiology Branch, CDC 404-639-5277 smettee@cdc.gov Human Salmonella Associated with Aquatic Frogs Selected Zoonotic Diseases  Conference Call January 6, 2010
It’s Not Easy Being Green–A Multistate Outbreak of Human Salmonella Typhimurium Infections Associated with Aquatic Frogs–United States, 2009 Shauna L. Mettee, RN, MSN, MPH LTJG, United States Public Health Service Epidemic Intelligence Officer Outbreak Response and Prevention Branch Division of Foodborne, Bacterial and Mycotic Diseases  National Center for Zoonotic, Vector-borne and  Enteric Diseases  Centers for Disease Control and Prevention *All results are preliminary and subject to change*
Infections with the outbreak strain of Salmonella Typhimurium, by week of illness onset (n=83 for whom information was reported as of 12/31/09)* No. of cases Illnesses that began during this time may not yet be reported Week of Illness Onset *Some illness onset dates have been estimated from other reported information (Estimated onset dates range 4/9 – 12/11; Reported onset dates (n=48) range 5/24 – 11/30)
Case Counts by States reporting Salmonella Typhimurium cases in cluster 0909MAJPX-1, as of Thursday, December 31, 2009 WA 7 MN 1 MA 3 NY 2 WI 1 ID 1 SD 3 MI 4 PA 4 NE 1 OH 2 IN 1 NV 1 IL 5 UT 14 VA 3 CO 4 CA 5 MO 4 KY 1 NJ 2 TN 2 AZ 1 MD 3 NM 1 GA 1 AL 1 MS 1 LA 1 TX 4 FL 1 1-2 Cases 3-4 Cases  More than 4 Cases
Demographics for cases of Salmonella Typhimurium cases in cluster 0909MAJPX-1, as of Thursday, December 31, 2009
Results of Matched Case-Control Study Among 19 cases and 31 controls, illness was significantly associated with exposure to frogs (63% cases vs 3% controls, mOR=24.4, CI=4.0-infinity).  Among 6 case-patients who knew the frog type, all reported African Dwarf Frogs.
Results of Environmental Sampling Environmental samples from aquariums containing African Dwarf Frogs in 4 patients’ homes yielded Salmonella Typhimurium isolates matching the outbreak strain. (CO, UT, OH, NM) Common breeder in California identified during traceback investigation Environmental samples from breeder’s facility yielded outbreak strain
African Dwarf Frogs
Historical Case Investigation  Asking states to interview historical cases from Jan 1, 2008 - present with revised case questionnaire.   PLEASE CONTACT  Shauna Mettee at 404-639-5277 or smettee@cdc.gov to obtain case questionnaire
For more information CDC Web Update http://www.cdc.gov/salmonella/typh1209/index.html MMWR – Jan 8, 2009 Multistate Outbreak of Human Salmonella Typhimurium Infections Associated with Aquatic Frogs — United States, 2009 Contact: Shauna Mettee, smettee@cdc.gov
Acknowledgments CDC Samir Sodha, Casey Barton Behravesh, Linda Capewell, Gwen Ewald, Nancy Garrett, Brenda Le, Leslie Hausman, Ian Williams State and Local Health Departments:  Alabama, Arizona, California, Colorado, Florida, Georgia, Idaho, Indiana, Illinois, Kentucky, Louisiana, Massachusetts, Maryland, Michigan, Minnesota, Missouri, Mississippi, Nebraska, Nevada, New Jersey, New Mexico, New York, Ohio, Pennsylvania, South Dakota, Tennessee, Texas, Utah, Virginia, Washington, and Wisconsin
Julia Murphy, DVM, MS, DACVPM  Virginia Department of Health, 804-864-8113 Julia.murphy@vdh.virginia.gov Kim Mitchell, MPH Maryland Department of Health and Mental Hygiene, Center for Zoonotic and Vector-borne Diseases 410-767-6618 kmitchell@dhmh.state.md.us Peter Troell, MD, MPH Fairfax County Health Department 703-246-2411 peter.troell@fairfaxcounty.gov  Human Rabies Case in Virginia Selected Zoonotic Diseases  Conference Call January 6, 2010
Human Rabies, Virginia 2009 Julia Murphy, DVM, MS, DACVPM State Public Health Veterinarian Virginia Department of Health
Patient Background 42 y.o. male with no significant past medical history Physician involved primarily in teaching and research Symptom onset October 23, 2009 Hot and cold flashes at work October 24 Leg pain and backaches  Spontaneous ejaculation Urinary incontinence
Patient Background Presented to local ED on October 26 MRI of lumbar spine Discharged and referred to PCP Evidence of hydrophobia Gagging while drinking and showering October 27 returned to same ED for evaluation of neurologic disorder / rabies Anxious and exhibited “bizarre” behavior Admitted
Hospitalization Agitated Required antipsychotic and 4 point restraints Cardiac arrest requiring intubation Frothing at mouth and spitting Multiple seizures
Hospitalization Rabies ante-mortem sampling Sent to CDC 10/29 early a.m. Rabies antigen detected in neck biopsy, 10/29 p.m. Sequenced as Indian canine virus, 10/30
Hospitalization Milwaukee protocol initiated Induced coma Samples sent daily to CDC to monitor viral load and antibody levels Frequent consultation with Dr. Willoughby Normal blood and intracranial pressures became increasingly difficult to maintain
Hospitalization Transcutaneous pacer, continuous renal dialysis and continual CSF draining required by November 12  Patient died November 20, 2009 after 24 days of hospitalization Postmortem performed by hospital and samples sent to CDC
Possible Rabies Exposures Travel to India July 3 – August 7, 2009 Father-in-law reported patient experienced scratch or bite from unknown dog while jogging No post-exposure prophylaxis pursued   Sequence consistent with Indian canine virus Potential bat exposure Rabid bat in his workplace, but not in his building
Public Health Investigation Potential exposure to others Hospital staff Wife and 2 children and family members Friends of the family Workplace exposures involving 3 clinical facilities 2 in Maryland 1 in Washington, DC Infectious period: October 8 forward
Public Health Investigation Two survey tools created Healthcare workers Coworkers, friends, family VDH, Fairfax Health District, MD DHMH and DCDOH conducted exposure assessments
Surveys Healthcare worker survey Contact with infectious materials Types of procedures performed PPE worn when performing procedures Household and coworker survey Contact with infectious materials Activities shared with patient
Results Hospital: Fairfax County HD (FHD) assessed 70 of 70 potentially exposed individuals 24 pursued PEP 17 met criteria for non-bite exposure 7 did not meet criteria but pursued PEP  Family: FHD assessed all family identified as having contact with the patient during the infectious period (n=6) 3 immediate and 3 additional family members All pursued PEP
Results DC: 34 of 40 contacts at patient’s worksite assessed 2 close friends pursued PEP MD: 63 of 63 contacts at patient’s worksites assessed Facility 1: 19/19 individuals assessed Facility 2: 44/44 individuals assessed No PEP pursued
PEP Summary, Human Rabies, Virginia, 2009
Challenges and Lessons Learned Public health involvement early in the process associated with potential human rabies cases is important Outreach to pathologists in regard to autopsy procedures is important Good to be familiar with the legal basis for information requested as part of a public health investigation
Acknowledgements Fairfax Health District Peter Troell Beth Miller-Zuber Bryant Bullock MD Dept. of Health and Mental Hygiene Katherine Feldman Kim Mitchell Erin Jones
Acknowledgements DC Department of Health Chevelle Glymph Garret Lum Maria Hille Florida Department of Health Carina Blackmore New York City Department of Health Sally Slavinski
Acknowledgements CDC Charles Rupprecht Jesse Blanton Sergio Recuenco Richard Franka
Jennifer House, DVM, MPH Indiana State Department of Health 317-233-7272 jhouse@isdh.in.gov  John Poe, DVM, MPH Kentucky Department for Public Health 502-564-3418 john.poe@ky.gov Human Rabies – A Joint Investigation with CDC, Indiana and Kentucky Selected Zoonotic Diseases  Conference Call January 6, 2010
Human Rabies – A Joint Investigation with CDC, Indiana and Kentucky Jennifer House, DVM, MPH  Indiana State Department of Health John Poe, DVM, MPH  Kentucky Department for Public Health Indiana Logo
Case Report 43 year old white male No history of previous severe illness Resident of Southern Indiana Died in a Kentucky hospital
October 2009 PCP: Muscle fasc., signs of sepsis Admitted to  Local Hospital-Placed on Resp Support ED: Chest pain, spasms in back, and chills Left hospital against medical advice Employee HCP: Fever, Chills, Chest pain, arm numbness Employee HCP: Fever & Cough Condition continues to deteriorate Patient has minor arm pain attributed to previous car accident but otherwise seems fine Transferred to tertiary care facility in KY ED: Chest Pain Mechanical Ventilation Mechanical Ventilation Patient died after being removed from life support Mechanical Ventilation Autopsy performed
Investigation Family, friends, co-workers interviewed for history and exposure to patient No history of animal bites Told neighbor he ‘saw’ a bat (end of July) Did not mention a bite Worked as a mechanic/welder May not have recognized a bite or unaware of the importance of being bitten
Investigation cont… Use standardized form One for family/friends/co-workers Different form for HCP Asked specific questions about potential saliva exposures Included a one page summary of risks and non-risks specific to exposures to human cases Also provided handouts and brochures on rabies virus
Rabies Post-Exposure Prophylaxis 159 close contacts- 100% counseled 147 individually interviewed- 92.5% 23 identified that MAY have been exposed to saliva   18 started/completed PEP
Normal Human Brain –  Ventral View Patient  X  10.25.2009
Negri bodies in neuron: hematoxylin and eosin stain IHC stain for rabies virus
Kentucky-Indiana 2009, rabies autopsy
Lessons Learned Rabies diagnosis is extremely difficult to obtain Rabies is not high on the list of differential                  diagnoses for encephalitis Human encephalitides often go undiagnosed Many pathologists are reluctant to perform autopsies on possible rabies cases Rabies is interpreted as an “animal disease” in a             primary care setting Joint federal, state and local health department collaboration is critical for successful diagnosis and disease mitigation
Mary Grace Stobierski, DVM, MPH, DACVPM Michigan Department of Community Health 517-335-8165 stobierskim@michigan.gov Kim Signs, DVM Michigan Department of Community Health 517-335-8165 signsk@michigan.gov Human Rabies Case in Michigan Selected Zoonotic Diseases  Conference Call January 6, 2010
William H. Wunner, PhDProfessor and Director of Outreach Education and Technology Training The WistarInstitute 215-898-3854 wunner@wistar.org Overview of special collections on papers on rabies appearing in the journals Vaccine and PLoS NTD Selected Zoonotic Diseases  Conference Call January 6, 2010
D. Craig Hooper, PhD Associate Director, WHO Center for Neurovirology, Associate Professor, Departments of Cancer Biology and Neurological Surgery, Thomas Jefferson University 215-503-1774 douglas.hooper@jefferson.edu The Production of Antibody by Invading B Cells Is Required for the Clearance of Rabies Virus from the Central Nervous System  Selected Zoonotic Diseases  Conference Call January 6, 2010
Rabies virus clearance from the CNS requires antibody production in  CNS tissues D. Craig Hooper Thomas Jefferson University
Attenuated RV that spread to the CNS induce limited, therapeutic BBB permeability changes BBB fails to “open” during lethal RV infections – few immune effectors reach the CNS and the virus is not cleared  Antibodies are the major effector in rabies immunity; how important is the BBB?
Peak circulating rabies-specific antibody levels occur after the restoration of BBB integrity
BBB permeability detected during rabies virus clearance is limited to fluid phase markers
CVS-F3 clearance correlates with antibody synthesis in the CNS
B cells in the CNS during CVS-F3 clearance
B cells infiltrate the CNS tissues and produce antiviral antibodies in situ B cells (CD19) Immunoglobulin (anti-Ig) T helper cells (CD4)
Rabies virus-specific antibodies produced by B cells infiltrating the CNS differ from those produced in the periphery
B cell growth/differentiation/maturation factors in the RV infected CNS
Germinal centers and Ig affinity maturation in the CNS? Peanut agglutinin Activation-induced cytidine deaminase (AID)  control d10 d18 d24
Conclusions The clearance of attenuated rabies viruses from CNS tissues is associated with limited fluid phase BBB permeability  Serum rabies virus-specific antibody titers peak after BBB integrity has largely been restored B cells enter the CNS during the response to attenuated rabies viruses B cell growth/differentiation/maturation factors are produced in the CNS and B cells transiently display germinal center markers Rabies virus-specific antibodies produced in the CNS may differ from those produced in periphery (isotype, specificity?) Are antibodies capable of clearing rabies virus from infected CNS tissues more commonly produced in CNS tissues?
National Center for Emerging and Zoonotic Infectious Diseases (proposed) 59 Selected Zoonotic Diseases  Conference Call January 6, 2010

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January 2010 Selected Zoonotic Diseases Conference Call

  • 1. National Center for Emerging and Zoonotic Infectious Diseases (proposed) 1 Selected Zoonotic Diseases Conference Call January 6, 2010
  • 2. Shauna L. Mettee, MSN, MPH EIS Officer, Enteric Diseases Epidemiology Branch, CDC 404-639-5277 smettee@cdc.gov Human Salmonella Associated with Aquatic Frogs Selected Zoonotic Diseases Conference Call January 6, 2010
  • 3. It’s Not Easy Being Green–A Multistate Outbreak of Human Salmonella Typhimurium Infections Associated with Aquatic Frogs–United States, 2009 Shauna L. Mettee, RN, MSN, MPH LTJG, United States Public Health Service Epidemic Intelligence Officer Outbreak Response and Prevention Branch Division of Foodborne, Bacterial and Mycotic Diseases National Center for Zoonotic, Vector-borne and Enteric Diseases Centers for Disease Control and Prevention *All results are preliminary and subject to change*
  • 4. Infections with the outbreak strain of Salmonella Typhimurium, by week of illness onset (n=83 for whom information was reported as of 12/31/09)* No. of cases Illnesses that began during this time may not yet be reported Week of Illness Onset *Some illness onset dates have been estimated from other reported information (Estimated onset dates range 4/9 – 12/11; Reported onset dates (n=48) range 5/24 – 11/30)
  • 5. Case Counts by States reporting Salmonella Typhimurium cases in cluster 0909MAJPX-1, as of Thursday, December 31, 2009 WA 7 MN 1 MA 3 NY 2 WI 1 ID 1 SD 3 MI 4 PA 4 NE 1 OH 2 IN 1 NV 1 IL 5 UT 14 VA 3 CO 4 CA 5 MO 4 KY 1 NJ 2 TN 2 AZ 1 MD 3 NM 1 GA 1 AL 1 MS 1 LA 1 TX 4 FL 1 1-2 Cases 3-4 Cases More than 4 Cases
  • 6. Demographics for cases of Salmonella Typhimurium cases in cluster 0909MAJPX-1, as of Thursday, December 31, 2009
  • 7. Results of Matched Case-Control Study Among 19 cases and 31 controls, illness was significantly associated with exposure to frogs (63% cases vs 3% controls, mOR=24.4, CI=4.0-infinity). Among 6 case-patients who knew the frog type, all reported African Dwarf Frogs.
  • 8. Results of Environmental Sampling Environmental samples from aquariums containing African Dwarf Frogs in 4 patients’ homes yielded Salmonella Typhimurium isolates matching the outbreak strain. (CO, UT, OH, NM) Common breeder in California identified during traceback investigation Environmental samples from breeder’s facility yielded outbreak strain
  • 10. Historical Case Investigation Asking states to interview historical cases from Jan 1, 2008 - present with revised case questionnaire. PLEASE CONTACT Shauna Mettee at 404-639-5277 or smettee@cdc.gov to obtain case questionnaire
  • 11. For more information CDC Web Update http://www.cdc.gov/salmonella/typh1209/index.html MMWR – Jan 8, 2009 Multistate Outbreak of Human Salmonella Typhimurium Infections Associated with Aquatic Frogs — United States, 2009 Contact: Shauna Mettee, smettee@cdc.gov
  • 12. Acknowledgments CDC Samir Sodha, Casey Barton Behravesh, Linda Capewell, Gwen Ewald, Nancy Garrett, Brenda Le, Leslie Hausman, Ian Williams State and Local Health Departments: Alabama, Arizona, California, Colorado, Florida, Georgia, Idaho, Indiana, Illinois, Kentucky, Louisiana, Massachusetts, Maryland, Michigan, Minnesota, Missouri, Mississippi, Nebraska, Nevada, New Jersey, New Mexico, New York, Ohio, Pennsylvania, South Dakota, Tennessee, Texas, Utah, Virginia, Washington, and Wisconsin
  • 13. Julia Murphy, DVM, MS, DACVPM Virginia Department of Health, 804-864-8113 Julia.murphy@vdh.virginia.gov Kim Mitchell, MPH Maryland Department of Health and Mental Hygiene, Center for Zoonotic and Vector-borne Diseases 410-767-6618 kmitchell@dhmh.state.md.us Peter Troell, MD, MPH Fairfax County Health Department 703-246-2411 peter.troell@fairfaxcounty.gov Human Rabies Case in Virginia Selected Zoonotic Diseases Conference Call January 6, 2010
  • 14. Human Rabies, Virginia 2009 Julia Murphy, DVM, MS, DACVPM State Public Health Veterinarian Virginia Department of Health
  • 15. Patient Background 42 y.o. male with no significant past medical history Physician involved primarily in teaching and research Symptom onset October 23, 2009 Hot and cold flashes at work October 24 Leg pain and backaches Spontaneous ejaculation Urinary incontinence
  • 16. Patient Background Presented to local ED on October 26 MRI of lumbar spine Discharged and referred to PCP Evidence of hydrophobia Gagging while drinking and showering October 27 returned to same ED for evaluation of neurologic disorder / rabies Anxious and exhibited “bizarre” behavior Admitted
  • 17. Hospitalization Agitated Required antipsychotic and 4 point restraints Cardiac arrest requiring intubation Frothing at mouth and spitting Multiple seizures
  • 18. Hospitalization Rabies ante-mortem sampling Sent to CDC 10/29 early a.m. Rabies antigen detected in neck biopsy, 10/29 p.m. Sequenced as Indian canine virus, 10/30
  • 19. Hospitalization Milwaukee protocol initiated Induced coma Samples sent daily to CDC to monitor viral load and antibody levels Frequent consultation with Dr. Willoughby Normal blood and intracranial pressures became increasingly difficult to maintain
  • 20. Hospitalization Transcutaneous pacer, continuous renal dialysis and continual CSF draining required by November 12 Patient died November 20, 2009 after 24 days of hospitalization Postmortem performed by hospital and samples sent to CDC
  • 21. Possible Rabies Exposures Travel to India July 3 – August 7, 2009 Father-in-law reported patient experienced scratch or bite from unknown dog while jogging No post-exposure prophylaxis pursued Sequence consistent with Indian canine virus Potential bat exposure Rabid bat in his workplace, but not in his building
  • 22. Public Health Investigation Potential exposure to others Hospital staff Wife and 2 children and family members Friends of the family Workplace exposures involving 3 clinical facilities 2 in Maryland 1 in Washington, DC Infectious period: October 8 forward
  • 23. Public Health Investigation Two survey tools created Healthcare workers Coworkers, friends, family VDH, Fairfax Health District, MD DHMH and DCDOH conducted exposure assessments
  • 24. Surveys Healthcare worker survey Contact with infectious materials Types of procedures performed PPE worn when performing procedures Household and coworker survey Contact with infectious materials Activities shared with patient
  • 25. Results Hospital: Fairfax County HD (FHD) assessed 70 of 70 potentially exposed individuals 24 pursued PEP 17 met criteria for non-bite exposure 7 did not meet criteria but pursued PEP Family: FHD assessed all family identified as having contact with the patient during the infectious period (n=6) 3 immediate and 3 additional family members All pursued PEP
  • 26. Results DC: 34 of 40 contacts at patient’s worksite assessed 2 close friends pursued PEP MD: 63 of 63 contacts at patient’s worksites assessed Facility 1: 19/19 individuals assessed Facility 2: 44/44 individuals assessed No PEP pursued
  • 27. PEP Summary, Human Rabies, Virginia, 2009
  • 28. Challenges and Lessons Learned Public health involvement early in the process associated with potential human rabies cases is important Outreach to pathologists in regard to autopsy procedures is important Good to be familiar with the legal basis for information requested as part of a public health investigation
  • 29. Acknowledgements Fairfax Health District Peter Troell Beth Miller-Zuber Bryant Bullock MD Dept. of Health and Mental Hygiene Katherine Feldman Kim Mitchell Erin Jones
  • 30. Acknowledgements DC Department of Health Chevelle Glymph Garret Lum Maria Hille Florida Department of Health Carina Blackmore New York City Department of Health Sally Slavinski
  • 31. Acknowledgements CDC Charles Rupprecht Jesse Blanton Sergio Recuenco Richard Franka
  • 32. Jennifer House, DVM, MPH Indiana State Department of Health 317-233-7272 jhouse@isdh.in.gov John Poe, DVM, MPH Kentucky Department for Public Health 502-564-3418 john.poe@ky.gov Human Rabies – A Joint Investigation with CDC, Indiana and Kentucky Selected Zoonotic Diseases Conference Call January 6, 2010
  • 33. Human Rabies – A Joint Investigation with CDC, Indiana and Kentucky Jennifer House, DVM, MPH Indiana State Department of Health John Poe, DVM, MPH Kentucky Department for Public Health Indiana Logo
  • 34. Case Report 43 year old white male No history of previous severe illness Resident of Southern Indiana Died in a Kentucky hospital
  • 35. October 2009 PCP: Muscle fasc., signs of sepsis Admitted to Local Hospital-Placed on Resp Support ED: Chest pain, spasms in back, and chills Left hospital against medical advice Employee HCP: Fever, Chills, Chest pain, arm numbness Employee HCP: Fever & Cough Condition continues to deteriorate Patient has minor arm pain attributed to previous car accident but otherwise seems fine Transferred to tertiary care facility in KY ED: Chest Pain Mechanical Ventilation Mechanical Ventilation Patient died after being removed from life support Mechanical Ventilation Autopsy performed
  • 36. Investigation Family, friends, co-workers interviewed for history and exposure to patient No history of animal bites Told neighbor he ‘saw’ a bat (end of July) Did not mention a bite Worked as a mechanic/welder May not have recognized a bite or unaware of the importance of being bitten
  • 37. Investigation cont… Use standardized form One for family/friends/co-workers Different form for HCP Asked specific questions about potential saliva exposures Included a one page summary of risks and non-risks specific to exposures to human cases Also provided handouts and brochures on rabies virus
  • 38. Rabies Post-Exposure Prophylaxis 159 close contacts- 100% counseled 147 individually interviewed- 92.5% 23 identified that MAY have been exposed to saliva 18 started/completed PEP
  • 39.
  • 40.
  • 41. Normal Human Brain – Ventral View Patient X 10.25.2009
  • 42. Negri bodies in neuron: hematoxylin and eosin stain IHC stain for rabies virus
  • 44. Lessons Learned Rabies diagnosis is extremely difficult to obtain Rabies is not high on the list of differential diagnoses for encephalitis Human encephalitides often go undiagnosed Many pathologists are reluctant to perform autopsies on possible rabies cases Rabies is interpreted as an “animal disease” in a primary care setting Joint federal, state and local health department collaboration is critical for successful diagnosis and disease mitigation
  • 45. Mary Grace Stobierski, DVM, MPH, DACVPM Michigan Department of Community Health 517-335-8165 stobierskim@michigan.gov Kim Signs, DVM Michigan Department of Community Health 517-335-8165 signsk@michigan.gov Human Rabies Case in Michigan Selected Zoonotic Diseases Conference Call January 6, 2010
  • 46. William H. Wunner, PhDProfessor and Director of Outreach Education and Technology Training The WistarInstitute 215-898-3854 wunner@wistar.org Overview of special collections on papers on rabies appearing in the journals Vaccine and PLoS NTD Selected Zoonotic Diseases Conference Call January 6, 2010
  • 47. D. Craig Hooper, PhD Associate Director, WHO Center for Neurovirology, Associate Professor, Departments of Cancer Biology and Neurological Surgery, Thomas Jefferson University 215-503-1774 douglas.hooper@jefferson.edu The Production of Antibody by Invading B Cells Is Required for the Clearance of Rabies Virus from the Central Nervous System Selected Zoonotic Diseases Conference Call January 6, 2010
  • 48. Rabies virus clearance from the CNS requires antibody production in CNS tissues D. Craig Hooper Thomas Jefferson University
  • 49. Attenuated RV that spread to the CNS induce limited, therapeutic BBB permeability changes BBB fails to “open” during lethal RV infections – few immune effectors reach the CNS and the virus is not cleared Antibodies are the major effector in rabies immunity; how important is the BBB?
  • 50. Peak circulating rabies-specific antibody levels occur after the restoration of BBB integrity
  • 51. BBB permeability detected during rabies virus clearance is limited to fluid phase markers
  • 52. CVS-F3 clearance correlates with antibody synthesis in the CNS
  • 53. B cells in the CNS during CVS-F3 clearance
  • 54. B cells infiltrate the CNS tissues and produce antiviral antibodies in situ B cells (CD19) Immunoglobulin (anti-Ig) T helper cells (CD4)
  • 55. Rabies virus-specific antibodies produced by B cells infiltrating the CNS differ from those produced in the periphery
  • 56. B cell growth/differentiation/maturation factors in the RV infected CNS
  • 57. Germinal centers and Ig affinity maturation in the CNS? Peanut agglutinin Activation-induced cytidine deaminase (AID) control d10 d18 d24
  • 58. Conclusions The clearance of attenuated rabies viruses from CNS tissues is associated with limited fluid phase BBB permeability Serum rabies virus-specific antibody titers peak after BBB integrity has largely been restored B cells enter the CNS during the response to attenuated rabies viruses B cell growth/differentiation/maturation factors are produced in the CNS and B cells transiently display germinal center markers Rabies virus-specific antibodies produced in the CNS may differ from those produced in periphery (isotype, specificity?) Are antibodies capable of clearing rabies virus from infected CNS tissues more commonly produced in CNS tissues?
  • 59. National Center for Emerging and Zoonotic Infectious Diseases (proposed) 59 Selected Zoonotic Diseases Conference Call January 6, 2010