title: Virus-specific memory CD8 T cells provide substantial protection from lethal severe acute respiratory syndrome coronavirus infection.
abstract: Severe acute respiratory syndrome coronavirus (SARS-CoV) caused an acute human respiratory illness with high morbidity and mortality in 2002-2003. Several studies have demonstrated the role of neutralizing antibodies induced by the spike (S) glycoprotein in protecting susceptible hosts from lethal infection. However, the anti-SARS-CoV antibody response is short-lived in patients who have recovered from SARS, making it critical to develop additional vaccine strategies. SARS-CoV-specific memory CD8 T cells persisted for up to 6 years after SARS-CoV infection, a time at which memory B cells and antivirus antibodies were undetectable in individuals who had recovered from SARS. In this study, we assessed the ability of virus-specific memory CD8 T cells to mediate protection against infection in the absence of SARS-CoV-specific memory CD4 T or B cells. We demonstrate that memory CD8 T cells specific for a single immunodominant epitope (S436 or S525) substantially protected 8- to 10-month-old mice from lethal SARS-CoV infection. Intravenous immunization with peptide-loaded dendritic cells (DCs) followed by intranasal boosting with recombinant vaccinia virus (rVV) encoding S436 or S525 resulted in accumulation of virus-specific memory CD8 T cells in bronchoalveolar lavage fluid (BAL), lungs, and spleen. Upon challenge with a lethal dose of SARS-CoV, virus-specific memory CD8 T cells efficiently produced multiple effector cytokines (gamma interferon [IFN-γ], tumor necrosis factor alpha [TNF-α], and interleukin 2 [IL-2]) and cytolytic molecules (granzyme B) and reduced lung viral loads. Overall, our results show that SARS-CoV-specific memory CD8 T cells protect susceptible hosts from lethal SARS-CoV infection, but they also suggest that SARS-CoV-specific CD4 T cell and antibody responses are necessary for complete protection.
  
  
  OBJECTIVE
  Virus-specific CD8 T cells are required for pathogen clearance following primary SARS-CoV infection. However, the role of SARS-CoV-specific memory CD8 T cells in mediating protection after SARS-CoV challenge has not been previously investigated. In this study, using a prime-boost immunization approach, we showed that virus-specific CD8 T cells protect susceptible 8- to 10-month-old mice from lethal SARS-CoV challenge. Thus, future vaccines against emerging coronaviruses should emphasize the generation of a memory CD8 T cell response for optimal protection.
authors: Department of Microbiology, University of Iowa, Iowa City, Iowa, USA.
authors: Rudragouda
authors: R
authors: Channappanavar
authors: Department of Microbiology, University of Iowa, Iowa City, Iowa, USA.
authors: Craig
authors: C
authors: Fett
authors: Department of Microbiology, University of Iowa, Iowa City, Iowa, USA.
authors: Jincun
authors: J
authors: Zhao
authors: Department of Pathology, University of Iowa, Iowa City, Iowa, USA.
authors: David K
authors: DK
authors: Meyerholz
authors: Department of Microbiology, University of Iowa, Iowa City, Iowa, USA Stanley-perlman@uiowa.edu.
authors: Stanley
authors: S
authors: Perlman
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis*; D000956:Antigens, Viral / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D003713:Dendritic Cells / Q000276:immunology / Q000637:transplantation / Q000821:virology; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D005260:Female; D015870:Gene Expression; D006801:Humans; D007110:Immunity, Active; D007111:Immunity, Cellular / Q000187:drug effects; D056724:Immunity, Humoral / Q000187:drug effects; D007114:Immunization; D007156:Immunologic Memory; D051379:Mice; D010455:Peptides / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D045473:Severe acute respiratory syndrome-related coronavirus / Q000276:immunology* / Q000472:pathogenicity; D045169:Severe Acute Respiratory Syndrome / Q000276:immunology / Q000401:mortality / Q000517:prevention & control* / Q000821:virology; D016019:Survival Analysis
chemical_list: D000914:Antibodies, Viral; D000956:Antigens, Viral; D018984:Epitopes, T-Lymphocyte; D010455:Peptides