T Cell Responses Are Required for Protection from Clinical Disease and for Virus Clearance in Severe Acute Respiratory Syndrome Coronavirus-Infected Mice

Abstract

A dysregulated innate immune response and exuberant cytokine/chemokine expression are believed to be critical factors in the pathogenesis of severe acute respiratory syndrome (SARS), caused by a coronavirus (SARS-CoV). However, we recently showed that inefficient immune activation and a poor virus-specific T cell response underlie severe disease in SARS-CoV-infected mice. Here, we extend these results to show that virus-specific T cells, in the absence of activation of the innate immune response, were sufficient to significantly enhance survival and diminish clinical disease. We demonstrated that T cells are responsible for virus clearance, as intravenous adoptive transfer of SARS-CoV-immune splenocytes or in vitro-generated T cells to SCID or BALB/c mice enhanced survival and reduced virus titers in the lung. Enhancement of the number of virus-specific CD8 T cells by immunization with SARS-CoV peptide-pulsed dendritic cells also resulted in a robust T cell response, earlier virus clearance, and increased survival. These studies are the first to show that T cells play a crucial role in SARS-CoV clearance and that a suboptimal T cell response contributes to the pathological changes observed in SARS. They also provide a new approach to SARS vaccine design.

T-cell immunity of SARS-CoV: Implications for vaccine development against MERS-CoV

“…HLA-A*1101-, HLA-A*2402-, HLA-B*15-, and HLA-B*4001-restricted T-cell epitopes have also been defined, which can be used to detect T-cell immune responses among populations other than HLA-A2 Oh et al, 2011). Also, several H-2 d -, H-2 k -, and H-2 b -restricted CD4 þ T-cell and CD8 þ T-cell epitopes have been identified using different mouse strains, which are helpful for SARS-CoV-specific T-cell studies among these animal models and the development of vaccines (Zhao et al, , 2010aZhi et al, 2005). Given that all the CD4 þ T cell epitopes identified thus far are derived from the SARS-CoV S protein, further epitope discovery is still needed, especially in other structural proteins.…”

“…Mammalian CHO cells-expressing segments of the SARS-CoV S protein also induce potent T-cell immune responses and protection against the virus (Du et al, 2009b(Du et al, , 2010. Zhao and colleagues observed that enhanced virus-specific CD8 þ T-cells in mice by immunization with SARS-CoV peptide-pulsed dendritic cells also result in earlier virus clearance and increased survival (Zhao et al, 2010a). In a Phase I clinical trial, a single-plasmid DNA vaccine encoding the S protein was well tolerated and induced SARS-CoV-specific CD4 þ T-cell responses in all vaccinees, as well as CD8 þ T-cell responses in~20% of individuals (Martin et al, 2008).…”

“…Different adjuvants have been investigated to increase the efficacy of peptide vaccines. Surface-linked liposomal peptide ), muramyl dipeptide derivative adjuvant (Chen et al, 2010b), and CpG oligodeoxynucleotide (CpG ODN) (Zhao et al, 2010b can augment peptidespecific T-cell responses, some of the which are protective (Du et al, 2010(Du et al, , 2009b(Du et al, , 2008Zhao et al, 2010a) and durable (Du et al, 2008;Kohyama et al, 2009;Yang et al, 2009). Virus-like particle (VLP) vaccines containing S protein as the dominant immunogen and adjuvanted with aluminum provided protection against mice challenged with SARS-CoV (Liu et al, 2011c;Lokugamage et al, 2008).…”

“…A pivotal role for virus-specific memory T-cells in broad and longterm protection against SARS-CoV infection has been elucidated Zhao et al, 2010a). Indeed, the crucial protective role of T-cell immune responses in coronavirus infections has been clearly documented in several animal models, e.g., feline infectious peritonitis virus (FIPV), mouse hepatitis virus (MHV), and avian infectious bronchitis virus (IBV) Takano et al, 2014;Trujillo et al, 2014).…”

How Prepared Are We to Control Severe Acute Respiratory Syndrome in Future

“…All these reports point to that it will be important to establishan appropriatecombination of vaccination route, vaccine vector andchoice of epitopes for each vaccine type.SARS vaccines thatgeneratea predominantly cellular or a predominantly humoral response, as well as therapeutic monoclonal antibodies, have been shown protectiveeffects in animal models. Therefore, what kind of responses are important for protection has not been clear (Subbarao et al, 2004;Zakhartchouk et al, 2005;Lin et al, 2007;See et al, 2008;Zhao and Perlman, 2010). Cameron et al (2012) have recently reported an analysis of transcripts expressed during SARS-CoV infection in vaccination and reinfectiontrials in ferrets (Cameron et al, 2012).…”