Vaccination with a Single CD4 T Cell Peptide Epitope from a Salmonella Type III-Secreted Effector Protein Provides Protection against Lethal Infection

Kurtz, Jonathan R.; Petersen, Hailey; Frederick, Daniel R.; Morici, Lisa A.; McLachlan, James B.

doi:10.1128/iai.00052-14

Cited by 32 publications

(32 citation statements)

References 60 publications

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“…The importance of CD4 T cells in controlling chronic virus infection has made them a focus in the context of vaccine development (43,44). To assess whether these cells have the capacity to provide protection against CMV in a vaccine setting, immunocompetent mice received a single vaccination with m53 and m78 peptides in CFA, followed by MCMV challenge and assessment of viral replication 4 days later.…”

Section: Fig 2 Phenotypic Analysis Of M78-specific Cd4 T Cells After mentioning

confidence: 99%

Cytomegalovirus-Specific CD4 T Cells Are Cytolytic and Mediate Vaccine Protection

Verma

Weiskopf

Gupta

et al. 2016

J Virol

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CD4 T cells provide protection against cytomegalovirus (CMV) and other persistent viruses, and the ability to quantify and characterize epitope-specific responses is essential to gain a more precise understanding of their effector roles in this regard. Here, we report the first two I-A d -restricted CD4 T cell responses specific for mouse CMV (MCMV) epitopes and use a major histocompatibility complex class II (MHC-II) tetramer to characterize their phenotypes and functions. We demonstrate that MCMV-specific CD4 T cells can express high levels of granzyme B and kill target cells in an epitope-and organ-specific manner. In addition, CD4 T cell epitope vaccination of immunocompetent mice reduced MCMV replication in the same organs where CD4 cytotoxic T lymphocyte (CTL) activity was observed. Together, our studies show that MCMV epitope-specific CD4 T cells have the potential to mediate antiviral defense by multiple effector mechanisms in vivo. C ytomegalovirus (CMV)/human herpesvirus 5 (HHV-5) (the prototypic betaherpesvirus) infection is endemic in humans and wild mice and establishes a lifelong infection in the absence of acute disease in healthy hosts. Adaptive immunity is a critical component of CMV defenses, restricting primary infection and dampening reactivation, helping to maintain the largely benign host-virus equilibrium. However, if immunity is naive or compromised (e.g., in transplant recipients or congenital infection), CMV can cause serious disease (1, 2). In immunocompetent mice, CD8 T cells help to control acute CMV infection and establish latency (3, 4), and their adoptive transfer prevents disease in mice and humans with weakened immunity (5-8). Although much less well studied, CD4 T cells also contribute to defense against CMV. Their rapid expansion and numbers correlate with reduced disease in transplant and HIV patients (9-11), and correspondingly, delayed induction of CMV-specific CD4 T cells is associated with increased congenital infection (12) and prolonged viral shedding in infants (13). Notably, no protective correlates were seen with CMV-specific CD8 T cell responses in several of these studies. In mice, CD4 T cells are absolutely required to control mouse cytomegalovirus (MCMV) replication in the salivary glands-the key site of viral dissemination, where CD8 T cells can exert no control (14, 15)-and also contribute to immune control in several other organs. Adoptive transfer of MCMV-specific transgenic CD4 T cells provides some protection in immunocompromised mice (16), and cotransferring CMV-specific CD4 T cells reduces viral load and promotes "help" for CMV-specific CD8 T cell responses in patients receiving cellular immunotherapy (17).In addition to traditional helper functions, CD4 T cells can also mediate direct antiviral activity in some cases. In chronic human CMV (HCMV), Epstein-Barr virus (EBV), and HIV infections, CD4 T cells displaying a terminally differentiated effector phenotype and/or expressing canonical cytolytic molecules (e.g., granzymes and perforin) are pres...

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Section: Fig 2 Phenotypic Analysis Of M78-specific Cd4 T Cells After mentioning

confidence: 99%

Cytomegalovirus-Specific CD4 T Cells Are Cytolytic and Mediate Vaccine Protection

Verma

Weiskopf

Gupta

et al. 2016

J Virol

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“…However, due to a rise in antibiotic resistance of NTS (Feasey et al, 2012;Lunguya et al, 2013), the emergence of the highly antibiotic resistant and virulent ST313 strain in sub-Saharan Africa (Kingsley et al, 2009;Okoro et al, 2012), and the increasing severity of NTS-mediated disease in developed countries, a pressing need exists for the development of an effective vaccine to prevent NTS infection. Vaccine strategies for NTS have included: 1) liveattenuation of housekeeping genes or genes that are important for essential biosynthetic processes such as aro (Hormaeche et al, 1990(Hormaeche et al, , 1991, dam (Heithoff et al, 2001), crp/ cdt (Zhang et al, 1997b(Zhang et al, , 1999, relA/ spoT (Na et al, 2006), or guaA/ clpP/ fliD (Tennant et al, 2011); 2) conjugate vaccines consisting of conjugation of the lipopolysaccharide (LPS)-derived serovar-specific O-polysaccharide to protein (Jazani et al, 2005;Simon et al, 2011bSimon et al, , 2013Svenson et al, 1979;Watson et al, 1992); and 3) subunit vaccines utilizing peptides from the type 3 secretion system (T3SS) (Kurtz et al, 2014), fimbriae (Pang et al, 2013), and flagellin (Bobat et al, 2011). Nevertheless, despite years of research no licensed human NTS vaccines currently exist.…”

Section: Introductionmentioning

confidence: 99%

An enterobacterial common antigen mutant of Salmonella enterica serovar Typhimurium as a vaccine candidate

Bridge

Whitmire

Gilbreath

et al. 2015

International Journal of Medical Microbiology

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Due to increasing rates of invasive Salmonella enterica serovar Typhimurium infection, there is a need for an effective vaccine to prevent this disease. Previous studies showed that a mutation in the first gene of the Enterobacterial common antigen biosynthetic pathway, wecA, resulted in attenuation of S. Typhimurium in a murine model of salmonellosis. Furthermore, immunization with a wecA(-) strain protected against lethal challenge with the parental wild type S. Typhimurium strain. Herein, we examined whether the S. Typhimurium wecA(-) strain could also provide cross-protection against non-parental strains of S. Typhimurium and S. Enteritidis. We found that intraperitoneal immunization (IP) with S. Typhimurium SL1344 wecA(-) resulted in a significant increase in survival compared to control mice for all Salmonella challenge strains tested. Oral immunization with SL1344 wecA(-) also resulted in increased survival; however, protection was less significant than with intraperitoneal immunization. The increase in survival of SL1344 wecA(-) immunized mice was associated with a Salmonella-specific IgG antibody response. Furthermore, analysis of sera from IP and orally immunized animals revealed cross-reactive antibodies to numerous Salmonella isolates. Functional analysis of antibodies found within the sera from IP immunized animals revealed agglutination and opsonophagocytic activity against all tested O:4 Salmonella serovars. Together these results indicate that immunization with a S. Typhimurium wecA(-) strain confers protection against lethal challenge with wild type S. Typhimurium and S. Enteritidis and that immunization correlates with functional antibody production.

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“…It has been reported that IL-17 and its associated cytokines (IL-21 and IL-22) are induced in the gastrointestinal tract during Salmonella infection (Ramarathinam et al, 1993; Lee et al, 2012; Kurtz et al, 2014; McSorley, 2014). While Th1 cells are critical for activation of infected macrophages to kill Salmonella in the tissues, Th17 cells are likely essential for recruiting neutrophils to the site of intestinal infection to engulf bacteria (Ramarathinam et al, 1993; Tükel et al, 2009; Broz et al, 2012; Lee et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Protective Immunity Elicited by Oral Immunization of Mice with Salmonella enterica Serovar Typhimurium Braun Lipoprotein (Lpp) and Acetyltransferase (MsbB) Mutants

Erova

Kirtley

Fitts

et al. 2016

Front. Cell. Infect. Microbiol.

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We evaluated the extent of attenuation and immunogenicity of the ΔlppAB and ΔlppAB ΔmsbB mutants of Salmonella enterica serovar Typhimurium when delivered to mice by the oral route. These mutants were deleted either for the Braun lipoprotein genes (lppA and lppB) or in combination with the msbB gene, which encodes an acetyltransferase required for lipid A modification of lipopolysaccharide. Both the mutants were attenuated (100% animal survival) and triggered robust innate and adaptive immune responses. Comparable levels of IgG and its isotypes were produced in mice infected with wild-type (WT) S. typhimurium or its aforementioned mutant strains. The ΔlppAB ΔmsbB mutant-immunized animals resulted in the production of higher levels of fecal IgA and serum cytokines during later stages of vaccination (adaptive response). A significant production of interleukin-6 from T-cells was also noted in the ΔlppAB ΔmsbB mutant-immunized mice when compared to that of the ΔlppAB mutant. On the other hand, IL-17A production was significantly more in the serum of ΔlppAB mutant-immunized mice (innate response) with a stronger splenic T-cell proliferative and tumor-necrosis factor-α production. Based on 2-dimensional gel analysis, alterations in the levels of several proteins were observed in both the mutant strains when compared to that in WT S. typhimurium and could be associated with the higher immunogenicity of the mutants. Finally, both ΔlppAB and ΔlppAB ΔmsbB mutants provided complete protection to immunized mice against a lethal oral challenge dose of WT S. typhimurium. Thus, these mutants may serve as excellent vaccine candidates and also provide a platform for delivering heterologous antigens.

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Vaccination with a Single CD4 T Cell Peptide Epitope from a Salmonella Type III-Secreted Effector Protein Provides Protection against Lethal Infection

Cited by 32 publications

References 60 publications

Cytomegalovirus-Specific CD4 T Cells Are Cytolytic and Mediate Vaccine Protection

Cytomegalovirus-Specific CD4 T Cells Are Cytolytic and Mediate Vaccine Protection

An enterobacterial common antigen mutant of Salmonella enterica serovar Typhimurium as a vaccine candidate

Protective Immunity Elicited by Oral Immunization of Mice with Salmonella enterica Serovar Typhimurium Braun Lipoprotein (Lpp) and Acetyltransferase (MsbB) Mutants

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