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Computational Challenges for Infectious Diseases Michael Shaw, PhD OID/Office of the Director. Office of Infectious Diseases. CDC’s Scientific Agenda for AMD:
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Computational Challenges for Infectious Diseases Michael Shaw, PhD OID/Office of the Director Office of Infectious Diseases
CDC’s Scientific Agenda for AMD: To use modern laboratory and computing technologies to enhance public health surveillance, response to outbreaks, and the control and prevention of infectious diseases
Pathogen Detection and Characterization Applications. Molecular detection as a replacement for traditional methods such as culture/isolation or visualization of antigens/antibodies: Allows more laboratories to detect pathogens and thus increases the amount of surveillance data. Allows surveillance of more pathogens. Makes true Molecular Epidemiology possible.
Challenge: Hepatitis C virus (HCV) exists in infected host as a large population of genetically related intra-host variants • A single sequence cannot adequately represent the intra-host viral population • It is important to sample numerous intra-host viral variants for many molecular epidemiological applications: • - detection of transmission networks • drug resistance • vaccine escape • disease severity
Detection of HCV transmissions using NGS Clinical Institution HCV cases ? ? Computational tools Detection of epidemiological links Next-Generation Sequencing Surveillance ? ? Not linked ? Most probable source Network of transmissions Transmission cluster Ganova-Raeva, L. et al. Detection of hepatitis C virus transmission using mass spectrometry. Journal of Infectious Diseases. 207(6):999-1006.
Challenge: NGS error correction • Blue dot represents the only • real variant • - Yellow dots are NGS errors Skums, P. Et al. Efficient Error Correction of High-throughput Viral Sequencing. 2011. BMC bioinformatics. 2012, 13(Suppl 10):S6.
Challenge: Risk Assessment of an Emerging Pathogen, Influenza A (H7N9) RBS AS-B Hemagglutinin Structure AS-A AS-D AS-E AS-C Antigenic Site A Red Antigenic Site B Gold Antigenic Site C Magenta Antigenic Site D Cyan Antigenic Site E Green Receptor Binding Site Gray Equivalent sites to H3N2 viruses: Wiley et al. 1981, Nature 289:373 Popovaet al. 2012, PLoS One 7:e421895 Daniels et al. 1983, J Gen Virol 64:1657 Stray et al. 2012, Virol J 9:91
H7N9: Genetic Markers Characteristic of Host Adaptation or Virulence • NA stalk deletion aa 69-73 characteristic of poultry adaptation • M1 protein: N30D and T215A – increased virulence in mice • PB2: • 89V – enhanced polymerase activity and increased virulence in mice • 627K - enhanced polymerase activity and increased virulence in mice (most human isolates; absent in avian or environmental virus sequences) • PB1: • H99Y and I368V – H5 transmissibility in ferrets; not present in all • NS1 • P42S – increased virulence in mice
H7 Receptor binding site Netherlands/219/2003 vs 2013 H7N9 180: A/T / A/ A Minimal impact, if any on the RBS. Assuming receptor binding is similar to published structural data, this should not directly interact with receptor 177: V/G /G /V Point towards the RBS pocket. More hydrophobic in Anhui/1/2013 May reduce α2-3 interactions? 212: T P, conserved in other H7 HAs 125: A/T /A / A Glycosylation site at position 123 in NL219 is not present in 2013 H7N9 217: L/Q /Q /I Equivalent to residue 226 in H3 numbering. Crucial for switching between α2-3 and α2-6 receptor specificity in H2/H3 HAs. 128: S A, conserved in other H7 HAs
Glycans and influenza virus specificity A/New Caledonia/20/1999 (pre2009 H1N1) Seasonal Human Pattern A/Netherlands/219/2003 (H7N7) Avian Receptor-binding Pattern A/Anhui/1/2013 (H7N9) a2-3 Avian-type receptors, found in human lower respiratory tract a2-6 Human-type receptors, found in human upper respiratory tract
Outbreak Response • Detection of etiologic agent • Identification of previously unknown pathogens • SARS and MERS CoV • Distinguish from background of commensals • Increasing reliance on PCR and sequencing • Characterization of etiologic agent • Tissue tropism and host range • Clinical recognition and management • Non human reservoir identification (important for control efforts) • Diagnostics development • Susceptibility to antimicrobial therapeutics • Vaccine development and use
Questions? • Michael Shaw, Office of Infectious Diseases • MShaw1@cdc.gov • Yuri Khudyakov, Division of Viral Hepatitis • YKhudyakov@cdc.gov