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Current Research and Highlights

Center For Infectious Diseases and Immunology

Current Research

Human and mouse Immunology: PCR, qPCR, RT-PCR, FACS, CyTOF, Elispot, ELISA, Functional assays (bactericidal, anti-adherence), cell culture

Gene cloning, protein purification and characterization for vaccine development 

Bacterial genetics: Whole genome sequencing, virulence determinants, pathogenesis

Mouse Models: Sepsis, pneumonia, otitis media, nasopharyngeal colonization, protection, correlates of protection,

Infectious disease pathogenesis and immune mechanistic investigations

Bacteriology (Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis) and Virology (Respiratory viruses)

Epidemiology, Human clinical trials

Vaccine development (protein purification and characterization, lipoprotein conjugation, fusion proteins), adjuvants

Microbiome (nasopharyngeal and gut)

Systems biology (modeling)

 Advanced biostatistics

 

Research Highlights 


  • Pichichero ME, Kaur R, Casey JR, Sabirov A, Khan MN, Almudevar A. Antibody response to Haemophilus influenzae outer membrane protein D, P6, and OMP26 after nasopharyngeal colonization and acute otitis media in children. Vaccine 2010 Oct 18;28(44):7184-92.
  • Pichichero ME, Kaur R, Casey JR, Xu Q, Almudevar A, Ochs M. Antibody response to Streptococcus pneumoniae proteins PhtD, LytB, PcpA, PhtE and Ply after nasopharyngeal colonization and acute otitis media in children. Hum Vaccin Immunother 2012 Jun;8(6):799-805.

Two studies identify vaccine candidates that elicit immune responses in young children to H flu and Strep pneumo.  P6 of H flu and PhtD, PcpA and Ply emerged as best candidates ( 2 Patents pending).

  • Sabirov A, Casey JR, Murphy TF, Pichichero ME. Breast-feeding is associated with a reduced frequency of acute otitis media and high serum antibody levels against NTHi and outer membrane protein vaccine antigen candidate P6. Pediatr Res 2009 Nov;66(5):565-70

Breast milk effects on immunity in children had been thought to be mediated by coating of the nasopharynx with IgA antibody as a mechanism of protetion.  Here we showed that breast fed infants had stimulation of their systemic immunity by study of antibody responses to a vaccine candidate protein of NTHi.

  • Xu Q, Kaur R, Casey JR, Sabharwal V, Pelton S, Pichichero ME. Nontypeable Streptococcus pneumoniae as an otopathogen. Diagn Microbiol Infect Dis 2011 Feb;69(2):200-4.

First description of a nontypeable Strep pneumo to cause otitis media.  Previously only recognized as a pathogen in conjunctivitis.

  • Xu Q, Kaur R, Casey JR, Adlowitz DG, Pichichero ME, Zeng M. Identification of Streptococcus pneumoniae and Haemophilus influenzae in culture-negative middle ear fluids from children with acute otitis media by combination of multiplex PCR and multi-locus sequencing typing. Int J Pediatr Otorhinolaryngol 2011 Feb;75(2):239-44.

Demonstration of molecular techniques to identify key otitis media pathogens in culture negative samples and even identify the specific organism and predicted capsule for Strep pneumo.

  • Xu Q, Casey JR, Chang A, Pichichero ME. When Co-colonizing the Nasopharynx Haemophilus influenzae Predominates Over Streptococcus pneumoniae Except Serotype 19A Strains to Cause Acute Otitis Media. Pediatr Infect Dis J 2012 Jun;31(6):638-40.
  • Xu Q, Almudervar A, Casey JR, Pichichero ME. Nasopharyngeal bacterial interactions in children. Emerg Infect Dis 2012 Nov;18(11):1738-45.

Two studies of bacterial interactions in the nasopharynx relating to pathogenesis of otitis media predicitng the emergence of H. flu as a major respiratory bacterial pathogen in PCV vaccinated persons.

  • Kaur R, Adlowitz DG, Casey JR, Zeng M, Pichichero ME. Simultaneous assay for four bacterial species including Alloiococcus otitidis using multiplex-PCR in children with culture negative acute otitis media. Pediatr Infect Dis J 2010 Aug;29(8):741-5.

Molecular detection  in middle ear fluids increases detection of bacteria such that >95% of cultures taken in our study population have detectable bacteria at onset of otitis media.

  • Kaur R, Casey JR, Pichichero ME. Serum antibody response to five Streptococcus pneumoniae proteins during acute otitis media in otitis-prone and non-otitis-prone children. Pediatr Infect Dis J 2011 Aug;30(8):645-50.        
  • Kaur R, Casey JR, Pichichero ME. Serum antibody response to three non-typeable Haemophilus influenzae outer membrane proteins during acute otitis media and nasopharyngeal colonization in otitis prone and non-otitis prone children. Vaccine 2011 Jan 29;29(5):1023-8.

Two studies identify vaccine candidates that elicit immune responses in otitis prone children to H flu and Strep pneumo.  P6 of H flu and PhtD, PcpA and Ply emerged as best candidates (2 Patents pending).

  • Kaur R, Chang A, Xu Q, Casey JR, Pichichero ME. Phylogenetic relatedness and diversity of non-typable Haemophilus influenzae in the nasopharynx and middle ear fluid of children with acute otitis media. J Med Microbiol 2011 Dec;60(Pt 12):1841-8.

Demonstated that the H flu causing otitis media are genetically very diverse and that the same strain that occurs in the nose also causes the otitis media.

  • Kaur R, Kim T, Casey JR, Pichichero ME. Antibody in middle ear fluid of children originates predominantly from sera and nasopharyngeal secretions. Clin Vaccine Immunol 2012 Oct;19(10):1593-6.

Refuted the long held notion that antibody in middle ear fluid originated from cells residing in the middle ear and showed instead the antibody comes by reflux from the nose and by transudation from the serum.      

  • Michel LV, Kalmeta B, McCreary M, Snyder J, Craig P, Pichichero ME. Vaccine candidate P6 of nontypable Haemophilus influenzae is not a transmembrane protein based on protein structural analysis. Vaccine 2011 Feb 11;29(8):1624-7.

Chang A, Adlowitz DG, Yellamatty E, Pichichero M. Haemophilus influenzae outer membrane protein P6 molecular characterization may not differentiate all strains of H. Influenzae from H. haemolyticus. J Clin Microbiol 2010 Oct;48(10):3756-7.

  • Chang A, Kaur R, Michel LV, Casey JR, Pichichero M. Haemophilus influenzae vaccine candidate outer membrane protein P6 is not conserved in all strains. Hum Vaccin 2011 Jan 1;7(1):102-5.
  • Michel LV,  Snyder J, Schmidt R,  Milillo J, Grimaldi K, Kalmeta B,  Khan MN, Sharma S,  Wright LK,    Pichichero ME.  Dual Orientation of the Outer Membrane Lipoprotein P6 in Nontypable Haemophilus influenza. J Bacteriol 2013, revision submitted.

Detailed studies of H flu candidate P6 show its similarities to a related Haemophilus bacteria, its lack of conservation in all strains (a multivalent vaccine will be required), its structural properties and configuration in the outer membrane of H flu.

  • Liu K, Pichichero ME. Clinical significance of serum S100A12 in acute otitis media in young children. Pediatr Infect Dis J 2012 Mar;31(3):e56-e58.
  • Liu K, Casey J, Pichichero M. Serum intercellular adhesion molecule 1 variations in young children with acute otitis media. Clin Vaccine Immunol 2010 Dec;17(12):1909-16.
  • Liu K, Almudevar A, Pichichero M Higher serum levels of interleukin 10 occur at onset of acute otitis media caused by Streptococcus pneumoniae compared to Haemophilus influenzae and Moraxella catarrhalis  Laryngoscope 2013 Feb 12; [Epub ahead of print]

Identification of 3 potential biomarkers of infection and resolution of infection caused by S pneumo and H flu and ability to differentiate infection caused by these bacteria and versus viral infections (1 Patent Pending).

  • Liu K, Chen L, Kaur R, Pichichero M. Transcriptome signature in young children with acute otitis media due to Streptococcus pneumoniae. Microbes Infect 2012 Jul;14(7-8):600-9.
  • Liu K, Chen L, Kaur R, Pichichero M. Transcriptome signature in young children with acute otitis media due to Nontypeable Haemophilus influenzae. International Immunology 2013; Feb 14[Epub ahead of print]

Two papers provide first description of blood immune response transcriptome signature of infection in children involving S pneumo and H flu.

  • Sharma SK, Casey JR, Pichichero ME. Reduced memory CD4+ T-cell generation in the circulation of young children may contribute to the otitis-prone condition. J Infect Dis 2011 Aug 15;204(4):645-53.
  • Sharma SK, Casey JR, Pichichero ME. Reduced serum IgG responses to pneumococcal antigens in otitis-prone children may be due to poor memory B-cell generation. J Infect Dis 2012 Apr 15;205(8):1225-9.

Two papers provide the first descriptions of a specific cellular immune defect that contributes to the otitis prone condition in children.

  • Sharma SK, Pichichero ME. Functional deficits of pertussis-specific CD4+ T cells in infants compared to adults following DTaP vaccination. Clin Exp Immunol 2012 Sep;169(3):281-91.
  • Sharma SK, Roumanes D, Almudevar A, Mosmann T, Pichichero ME. Divergence in CD4+ T-cell Responses Among Young Children And Adults in Response to Streptococcus pneumoniae and Haemophilus influenzae Vaccine Candidate Protein Antigens. Vaccine 2013, in press.

First papers to identify specific cellular immune defect accounting for poor responses of children to a commonly used vaccine (DTaP) and 2 vaccines in development from our lab (2 Patents pending).

  • Khan MN, Kaur R, Pichichero ME. Bactericidal antibody response against P6, protein D, and OMP26 of nontypeable Haemophilus influenzae after acute otitis media in otitis-prone children. FEMS Immunol Med Microbiol 2012 Aug;65(3):439-47.

This paper provides evidence that P6 is an effective vaccine candidate for otitis prone children whereas other candidates protein D and OMP26 are not (Patent Pending).

  • Khan MN, Sharma SK, Filkins LM, Pichichero ME. PcpA of Streptococcus pneumoniae mediates adherence to nasopharyngeal and lung epithelial cells and elicits functional antibodies in humans. Microbes Infect 2012 Oct;14(12):1102-10.
  • Khan MN, Pichichero ME. Vaccine candidates PhtD and PhtE of Streptococcus pneumoniae are adhesins that elicit functional antibodies in humans. Vaccine 2012 Apr 16;30(18):2900-7.

Two papers that show vaccine candidates PcpA and PhtD elicit functional antibody that could protect humans against colonization of the nose and lung cells.

  • Friedel V, Chang A, Wills J, Vargas R, Xu Q, Pichichero ME. Impact of Respiratory Viral Infections on alpha-Hemolytic Streptococci and Otopathogens in the Nasopharynx of Young Children. Pediatr Infect Dis J 2013 Jan;32(1):27-31.

Our first paper on Microbiome interactions in the nasopharynx involving viruses, normal flora (alpha strep) and potential otitis media pathogens.  Viruses increased pathogenicity and alpha strep was protective.