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Glendie Marcelin, PhD 3 rd World Congress on Virology November 21, 2013

Mechanisms of Severity of Pandemic H1N1 2009 Influenza A Virus Infection During Pregnancy, A Mouse Model. Glendie Marcelin, PhD 3 rd World Congress on Virology November 21, 2013. Tetramer Core Facility Scott Brown, PhD Animal Resource Center David Carey Beth Little.

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Glendie Marcelin, PhD 3 rd World Congress on Virology November 21, 2013

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  1. Mechanisms of Severity of Pandemic H1N1 2009 Influenza A Virus Infection During Pregnancy, A Mouse Model Glendie Marcelin, PhD 3rd World Congress on Virology November 21, 2013

  2. Tetramer Core Facility Scott Brown, PhD Animal Resource Center David Carey Beth Little Richard J. Webby, PhD Jerry R. Aldridge, PhD Adrianus C.M. Boon, PhD Jerold Rehg, PhD Henju Marjuki, PhD Susu Duan, PhD Jonathan A. McCullers, MD Hazem H. Ghoneim Veterinary Pathology Core Pamela Johnson Dorothy Bush NIH NIAID WHO Global Surveillance Network Centers of Excellence for Influenza Research and Surveillance ALSAC Flow Cytometry and Cell Sorting Ann-Marie Hamilton-Easton, PhD Perry Scott, PhD Trudeau Institute Marcelin et al, J Virol PMID: 21865394

  3. * * Compared to non-pregnant Louie et al, N Eng J Med 2010

  4. T cell-Helper Responses During Pregnancy Th1/Th2 Basal Th1/Th2 Fetal tolerance Pregnancy Th1/Th2 Fetal rejection

  5. Lung Injury and alterations in immune responses responsible for severity?

  6. Severity of Pandemic H1N1-09 in Pregnant Mice P NP E13 Influenza A/California/04/2009 (H1N1): “pH1N1” Virus Replication Innate /Adaptive Lung, Upper Respiratory, Liver, Kidney, Brain, Spleen Pathology CD8+, CD4+ T cells T regulatory cells Antibody Cytokines Lung Repair Pathology

  7. pH1N1 is More Severe in Pregnant Mice *p= 0.01 106EID50

  8. Severity Not Due to Increase in Virus Replication L L Pregnant Not Pregnant Pregnant Not Pregnant N N 200 200 400 400 Lung homogenate *p>0.120 days 3,5,7 3 dpi L: lung N: nasal cavity % Nucleoprotein Positive cells (Image Scope)

  9. Cellular Recruitment Factors Are Increased in Lungs of Pregnant Mice pg/ml (log10) Days Post Infection Luminex, Multiplex beads *p<0.05 Dotted line: mean value mock infected mice

  10. Th2 Cytokines Are Elevated in Pregnant Mice Pregnant Not Pregnant pg/ml (log10) Days Post Infection Luminex, Multiplex beads *p<0.05 Dotted line: mean value mock infected mice

  11. Elevated Immune Cells in Lungs of Pregnant Mice *p<0.05 Dotted line: mock infected

  12. Elevated Neutrophils in Alveolar Spaces & Interstitium Not Pregnant Pregnant Mock Mock 220 220 Virus Virus 220 220

  13. Elevated Macrophage Infiltration in Pregnant mice Not Pregnant Pregnant Mock Mock 220 220 Virus Virus 220 220

  14. Elevated Arginase -1 in Lungs of Pregnant mice Pregnant Not Pregnant Mock Mock Virus Virus 220 220 220 220

  15. Mechanism of Action? • Macrophages and neutrophils can contribute to severe infections through the secretion of nitric oxide (NO) • NO has several functions: • Anti-viral signaling molecule • Vasodilator vascular permeability • Impair tissue restoration Oda et al. 1989 Science; Kubes et al. 1992 Am J Physiol

  16. Lung Repair is Impaired in Pregnant Mice Pregnant Not Pregnant NO responses in the Lung Virus Virus Naive Naive 400 400 400 400 Arrows: attenuated epithelia *p<0.05 Griess method *p<0.05

  17. Pregnant Mice Develop Increased Numbers of T Regulatory Cells in the Lung Gated on CD4+ CD25+ 9 dpi MLN: mediastinal lymph nodes

  18. Summary Elevated Virus replication NO Lung Injury MACS Cytokines Th2>>Th1 DCs MACS MACS Tregs Neuts Neuts Neuts

  19. Therapies which modulate inflammation and lung repair processes may aid in reducing severity in pregnant women for future pandemics http://www.searo.who.int/entity/emerging_diseases/topics/h1n1/en/index.html

  20. BEI Resources Collection and Reagents Mission: NIAID funded bio-repositoryto provide reagents, tools and information for studying Category A, B, and C priority pathogens and emerging infectious disease agents, vectors of disease, non-pathogenic microbes relevant to human health and other microbiological materials of relevance to the research community. All materials are free of cost. Organism/Reagents: http://www.beiresources.org/ • Viruses • Antigens • Assays/Panels • Nucleic Acids • Antibodies • Antisera • Peptide Arrays • Bacteria • Cell Banks • Primers/Probes • Parasitic Worms • Rickettsiales • Clones • Fungi • Protists • Arthropod Vectors • Toxins • Libraries

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