Seasonal influenza virus infections affect 5-15% of the human population, and 250,000-500,000 deaths occur each year due to severe pneumonia, multiple organ failure, or acute respiratory distress-like syndrome. Although the exact mechanism of influenza pathogenicity is unknown, the induction of an overreacting immune response is the primary suspect. In mice, infection with sub-lethal doses of influenza virus type A induces morbidity manifested as extensive weight loss, labored breathing, and loss of appetite. A recent study on the mechanisms of pathogenicity of influenza virus that caused the 1918 pandemic revealed that mice infected with this virus manifested an early activation of pro-inflammatory and cell-death pathways. What induces the cytokine storm in severe influenza disease is however currently unknown.
My research covers three areas related to influenza virus infection:
analysis of the role played by the innate and the adaptive immune responses in the pathogenicity associated with influenza virus immune response
identification of chemical compounds that can attenuate the lung inflammation and the morbidity induced by viral infection
development of a “universal” vaccine against influenza virus that elicits a potent CD8+ T cell immune response against viral epitopes that are conserved across different flu virus strains.
We study the immune response mounted by C57BL/6 mice experimentally infected with influenza virus type A, in order to examine the very early events of the immune response that may trigger the cytokine storm associated with flu pathogenesis (Toll like receptor signaling, production of type I interferon and tumor necrosis factor, activation of dendritic cells, NK and NKT cells, B cells, CD8+ and CD4+ T cells). Short oligonucleotides have been shown to inhibit pro-inflammatory cytokine production by cells infected with influenza virus. Based on this observation, we are currently examining in vivo the mechanism by which oligonucleotides can block the pro-inflammatory cytokines, lung cellular infiltration, and the weight loss in mice infected with influenza virus. Another mechanism to block viral replication is to target cellular proteins used by influenza virus during its life cycle, such as PI3K. Therefore we test inhibitors of PI3K enzymatic activity for reduction of viral replication in vitro and in vivo.
Conferring protection to multiple strains of influenza virus by vaccination is another way to reduce morbidity associated with this viral infection. We are currently testing in mice a biogel-encapsulated live influenza virus vaccine that generates a strong memory CD8+ T cell immune response to an epitope derived from the nucleoprotein of influenza virus which is conserved across multiple strains of this virus. The efficiency of this vaccine will be further tested in ferrets because of the similarity of the flu infection symptoms between humans and ferrets.
Selected publications: (See all Alina Boesteanu's publications in PubMed.)
Biopolymer encapsulated live influenza virus as a universal CD8+ T cell vaccine against influenza virus.
Boesteanu AC, Nadarajan S, Babu MW, Papazoglou ES, and PD Katsikis.
Costimulation signals for memory CD8+ T cells during viral infections.
Duttagupta P, Boesteanu AC, and PD Katsikis.
Critical Reviews in Immunology, 29(6): 469-486, 2009.
Memory T cells need CD28 to remember.
Boesteanu AC and PD Katsikis.
Seminars in Immunology, 21(2): 69-77, 2009
Chronic antigen stimulation alone is sufficient to drive CD8+ T cell exhaustion.
Bucks CM, Norton JA, Boesteanu AC, Mueller YM, and PD Katsikis.
The Journal of Immunology, 182(11): 6697-6708, 2009.
Late signals from CD27 prevent Fas dependent apoptosis of primary CD8+ T cells.
Douglas V, Dolfi D, Boesteanu AC, Petrovas C, Xia D, Butz EA and PD Katsikis.
The Journal of Immunology, 180: 2912–2921, 2008.
Memory CD8+ T cells require CD28 costimulation.
Borowski AB, Boesteanu AC, Mueller YM, Carafides C, Topham DJ, Altman JD, Jennings SR, and PD Katsikis.
The Journal of Immunology, 179 (10): 6494-6503, 2007
Role of TCR specificity in CD4CD25 regulatory T-cell selection.
Cozzo C, Larkin J 3rd, Boesteanu AC, Lerman MA, Rankin AL, and AJ Caton.
Immunological Reviews, 212: 74-85, 2006.
Impact of effector cell differentiation on CD4+ T cells that evade negative selection by a self-peptide.
Boesteanu AC, AL Rankin, and AJ Caton
International Immunology, 18(7): 1017-1027, 2006.
Selection of CD4+CD25+ regulatory T cells by self-peptides.
Cozzo C, Lerman MA, Boesteanu AC, Larkin J 3rd, Jordan, MS, and AJ Caton.
Current Topics in Microbiology and Immunology, 293: 3-23, 2005
CD4(+) CD25(+) regulatory T cell selection.
Caton AJ, Cozzo C, Larkin J 3rd, Lerman MA, Boesteanu AC, and MS Jordan.
The New York Academy of Sciences, 1029: 101-114, 2004.
The H4b minor histocompatibility antigen is caused by a combination of genetically determined and posttranslational modifications.
Yadav R, Yoshimura Y, Boesteanu AC, Christianson GJ, Ajayi WU, Shashidharamurthy R, Stanic AK, Roopenian DC, and S Joyce
Journal of Immunology, 170(10): 5133-5142, 2003.
Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide.
Jordan MS, Boesteanu AC, Reed AJ, Petrone AL, Holenbeck A.E, Lerman MA, Naji A, and Caton AJ
Nature Immunology, 2(4): 301 - 306, 2001.
Quantitation of CD8(+) T-lymphocyte responses to multiple epitopes from simian virus 40 (SV40) large T antigen in C57BL/6 mice immunized with SV40, SV40 T-antigen-transformed cells, or vaccinia virus recombinants expressing full-length T antigen or epitope minigenes.
Mylin LM, Schell TD, Roberts D, Epler M, Boesteanu AC, Collins EJ, Frelinger JA, Joyce S, and SS Tevethia.
Journal of Virology, 74(15): 6922 -6934, 2000.
Thermolabile H-2Kb molecules expressed by transporter associated with antigen processing-deficient RMA-S cells are occupied by low-affinity peptides.
De Silva D, Boesteanu AC, Song R, Nagy N, Harhaj E, Harding CV, and S Joyce.
Journal of Immunology, 163: 4413 - 4420, 1999.
A molecular basis for how a single T cell receptor interfaces multiple ligands.
Boesteanu AC, Brehm M, Mylin LM, Christianson GJ, Tevethia SS, Roopenian DC, and S Joyce.
Journal of Immunology, 161: 4719-4727, 1998.