Regulation of the CD8 T Cell Response during Lethal Influenza Infection

Seasonal influenza A viruses (IAV) typically infect 10-20% of the population in the U.S. each year resulting in approximately 200,000 hospitalizations and 36,000 deaths. Importantly influenza virus can undergo dramatic antigenic shifts (i.e. reassortment) that result in new highly virulent strains. One such shift resulted in the highly pathogenic H5N1 virus. Infections with this virus in humans are associated with a severe lymphopenia and poor outcomes (i.e. currently a 50-60% mortality rate in the Southeast Asia). Prior work in the laboratory has identified a novel mechanism where dendritic cells in the lung draining lymph nodes target and kill the developing influenza-specific CD8 T cell response during highly virulent IAV infections, leaving the individual in an immunocompromised lymphopenic state. My dissertation work has identified a novel dendritic cell population that may be responsible for the killing of CD8 T cells during lethal dose IAV infections. A better understanding of this novel cell population and it’s mechanism of T cell elimination during lethal infection and it’s contribution to immunity during sublethal infections holds the promise to allow targeted therapies to reverse the lymphopenia during highly pathogenic influenza virus infections.

Zacharias ZR, Legge KL. Chronic Ethanol Consumption Reduces Existing CD8 T Cell Memory and Is Associated with Lesions in Protection against Secondary Influenza A Virus Infections. J Immunol. 2019 Nov 11. pii: ji1900770. doi:10.4049/jimmunol.1900770. [Epub ahead of print] PubMed PMID: 31712384.

Zacharias ZR, Ross KA, Hornick EE, Goodman JT, Narasimhan B, Waldschmidt TJ, Legge KL. Polyanhydride Nanovaccine Induces Robust Pulmonary B and T Cell Immunity and Confers Protection Against Homologous and Heterologous Influenza A Virus Infections. Front Immunol. 2018 Aug 28;9:1953. doi:10.3389/fimmu.2018.01953. eCollection 2018. PubMed PMID: 30233573; PubMed Central PMCID: PMC6127617.

Carlin LE, Hemann EA, Zacharias ZR, Heusel JW, Legge KL. Natural Killer Cell Recruitment to the Lung During Influenza A Virus Infection Is Dependent on CXCR3, CCR5, and Virus Exposure Dose. Front Immunol. 2018 Apr 17;9:781. doi:10.3389/fimmu.2018.00781. eCollection 2018. PubMed PMID: 29719539; PubMed Central PMCID: PMC5913326.

Hornick EE, Banoth B, Miller AM, Zacharias ZR, Jain N, Wilson ME, Gibson-Corley KN, Legge KL, Bishop GA, Sutterwala FS, Cassel SL. Nlrp12 Mediates Adverse Neutrophil Recruitment during Influenza Virus Infection. J Immunol. 2018 Feb 1;200(3):1188-1197. doi: 10.4049/jimmunol.1700999. Epub 2017 Dec 27. PubMed PMID: 29282312; PubMed Central PMCID: PMC5831365.

Strother RK, Danahy DB, Kotov DI, Kucaba TA, Zacharias ZR, Griffith TS, Legge KL, Badovinac VP. Polymicrobial Sepsis Diminishes Dendritic Cell Numbers and Function Directly Contributing to Impaired Primary CD8 T Cell Responses In Vivo. J Immunol. 2016 Dec 1;197(11):4301-4311. Epub 2016 Oct 26. PubMed PMID: 27798171; PubMed Central PMCID: PMC5123856.