scholarly journals Palmitoylation State Impacts Induction of Innate and Acquired Immunity by the Salmonella enterica Serovar TyphimuriummsbBMutant

2011 ◽  
Vol 79 (12) ◽  
pp. 5027-5038 ◽  
Author(s):  
Qingke Kong ◽  
David A. Six ◽  
Qing Liu ◽  
Lillian Gu ◽  
Kenneth L. Roland ◽  
...  
Keyword(s):  
Salmonella Enterica ◽  
Lipid A ◽  
Inflammatory Responses ◽  
Outer Membrane Proteins ◽  
Acyl Chain ◽  
Wild Type ◽  
Proinflammatory Response ◽  
Content Type ◽  
Serovar Typhimurium

ABSTRACTLipopolysaccharide (LPS), composed of lipid A, core, and O-antigen, is a major virulence factor ofSalmonella entericaserovar Typhimurium, with lipid A being a major stimulator to induce the proinflammatory response via the Toll-like receptor 4 (TLR4)-MD2-CD14 pathway. WhileSalmonella msbBmutants lacking the myristate chain in lipid A were investigated widely as an anticancer vaccine, inclusion of themsbBmutation in aSalmonellavaccine to deliver heterologous antigens has not yet been investigated. We introduced themsbBmutation alone or in combination with mutations in other lipid A acyl chain modification genes encoding PagL, PagP, and LpxR into wild-typeS. entericaserovar Typhimurium. ThemsbBmutation reduced virulence, while thepagL,pagP, andlpxRmutations did not affect virulence in themsbBmutant background when administered orally to BALB/c mice. Also, all mutants exhibited sensitivity to polymyxin B but did not display sensitivity to deoxycholate. LPS derived frommsbBmutants induced less inflammatory responses in human Mono Mac 6 and murine macrophage RAW264.7 cellsin vitro. However, anmsbBmutant did not decrease the induction of inflammatory responses in mice compared to the levels induced by the wild-type strain, whereas anmsbB pagPmutant induced less inflammatory responsesin vivo. The mutations were moved to an attenuatedSalmonellavaccine strain to evaluate their effects on immunogenicity. Lipid A modification caused by themsbBmutation alone and in combination withpagL,pagP, andlpxRmutations led to higher IgA production in the vaginal tract but still retained the same IgG titer level in serum to PspA, a test antigen fromStreptococcus pneumoniae, and to outer membrane proteins (OMPs) fromSalmonella.

scholarly journals Phosphate Groups of Lipid A Are Essential for Salmonella enterica Serovar Typhimurium Virulence and Affect Innate and Adaptive Immunity

2012 ◽  
Vol 80 (9) ◽  
pp. 3215-3224 ◽  
Author(s):  
Qingke Kong ◽  
David A. Six ◽  
Qing Liu ◽  
Lillian Gu ◽  
Shifeng Wang ◽  
...  
Keyword(s):  
Outer Membrane ◽  
Adaptive Immunity ◽  
Salmonella Enterica ◽  
Lipid A ◽  
Outer Membrane Proteins ◽  
Polymyxin B ◽  
Content Type ◽  
Serovar Typhimurium ◽  
Phosphate Groups

ABSTRACTLipid A is a key component of the outer membrane of Gram-negative bacteria and stimulates proinflammatory responses via the Toll-like receptor 4 (TLR4)-MD2-CD14 pathway. Its endotoxic activity depends on the number and length of acyl chains and its phosphorylation state. InSalmonella entericaserovar Typhimurium, removal of the secondary laurate or myristate chain in lipid A results in bacterial attenuation and growth defectsin vitro. However, the roles of the two lipid A phosphate groups in bacterial virulence and immunogenicity remain unknown. Here, we used anS. TyphimuriummsbB pagL pagP lpxRmutant, carrying penta-acylated lipid A, as the parent strain to construct a series of mutants synthesizing 1-dephosphorylated, 4′-dephosphorylated, or nonphosphorylated penta-acylated lipid A. Dephosphorylated mutants exhibited increased sensitivity to deoxycholate and showed increased resistance to polymyxin B. Removal of both phosphate groups severely attenuated the mutants when administered orally to BALB/c mice, but the mutants colonized the lymphatic tissues and were sufficiently immunogenic to protect the host from challenge with wild-typeS. Typhimurium. Mice receivingS. Typhimurium with 1-dephosphorylated or nonphosphorylated penta-acylated lipid A exhibited reduced levels of cytokines. Attenuated and dephosphorylatedSalmonellavaccines were able to induce adaptive immunity against heterologous (PspA ofStreptococcus pneumoniae) and homologous antigens (lipopolysaccharide [LPS] and outer membrane proteins [OMPs]).

scholarly journals Effect of Deletion of Genes Involved in Lipopolysaccharide Core and O-Antigen Synthesis on Virulence and Immunogenicity of Salmonella enterica Serovar Typhimurium

2011 ◽  
Vol 79 (10) ◽  
pp. 4227-4239 ◽  
Author(s):  
Qingke Kong ◽  
Jiseon Yang ◽  
Qing Liu ◽  
Praveen Alamuri ◽  
Kenneth L. Roland ◽  
...  
Keyword(s):  
Salmonella Enterica ◽  
Lipid A ◽  
Outer Core ◽  
Wild Type ◽  
Core Oligosaccharide ◽  
Content Type ◽  
O Antigen ◽  
Serovar Typhimurium

ABSTRACTLipopolysaccharide (LPS) is a major virulence factor ofSalmonella entericaserovar Typhimurium and is composed of lipid A, core oligosaccharide (C-OS), and O-antigen polysaccharide (O-PS). While the functions of the gene products involved in synthesis of core and O-antigen have been elucidated, the effect of removing O-antigen and core sugars on the virulence and immunogenicity ofSalmonella entericaserovar Typhimurium has not been systematically studied. We introduced nonpolar, defined deletion mutations inwaaG(rfaG),waaI(rfaI),rfaH,waaJ(rfaJ),wbaP(rfbP),waaL(rfaL), orwzy(rfc) into wild-typeS.Typhimurium. The LPS structure was confirmed, and a number ofin vitroandin vivoproperties of each mutant were analyzed. All mutants were significantly attenuated compared to the wild-type parent when administered orally to BALB/c mice and were less invasive in host tissues. Strains with ΔwaaGand ΔwaaImutations, in particular, were deficient in colonization of Peyer's patches and liver. This deficiency could be partially overcome in the ΔwaaImutant when it was administered intranasally. In the context of an attenuated vaccine strain delivering the pneumococcal antigen PspA, all of the mutations tested resulted in reduced immune responses against PspA andSalmonellaantigens. Our results indicate that nonreversible truncation of the outer core is not a viable option for developing a live oralSalmonellavaccine, while awzymutant that retains one O-antigen unit is adequate for stimulating the optimal protective immunity to homologous or heterologous antigens by oral, intranasal, or intraperitoneal routes of administration.

scholarly journals Salmonella enterica Serovar Typhimurium Uses PbgA/YejM To Regulate Lipopolysaccharide Assembly during Bacteremia

2019 ◽  
Vol 88 (1) ◽  
Author(s):  
Melina B. Cian ◽  
Nicole P. Giordano ◽  
Revathi Masilamani ◽  
Keaton E. Minor ◽  
Zachary D. Dalebroux
Keyword(s):  
Salmonella Enterica ◽  
Lipid A ◽  
Salmonella Enterica Serovar Typhimurium ◽  
Transmembrane Domain ◽  
Wild Type ◽  
Content Type ◽  
Serovar Typhimurium ◽  
Periplasmic Domain ◽  
Inner Membrane Protein ◽  
Substitution Mutations

ABSTRACT Salmonella enterica serovar Typhimurium (S. Typhimurium) relies upon the inner membrane protein PbgA to enhance outer membrane (OM) integrity and promote virulence in mice. The PbgA transmembrane domain (residues 1 to 190) is essential for viability, while the periplasmic domain (residues 191 to 586) is dispensable. Residues within the basic region (residues 191 to 245) bind acidic phosphates on polar phospholipids, like for cardiolipins, and are necessary for salmonella OM integrity. S. Typhimurium bacteria increase their OM cardiolipin concentrations during activation of the PhoPQ regulators. The mechanism involves PbgA’s periplasmic globular region (residues 245 to 586), but the biological role of increasing cardiolipins on the surface is not understood. Nonsynonymous polymorphisms in three essential lipopolysaccharide (LPS) synthesis regulators, lapB (also known as yciM), ftsH, and lpxC, variably suppressed the defects in OM integrity, rifampin resistance, survival in macrophages, and systemic colonization of mice in the pbgAΔ191–586 mutant (in which the PbgA periplasmic domain from residues 191 to 586 is deleted). Compared to the OMs of the wild-type salmonellae, the OMs of the pbgA mutants had increased levels of lipid A-core molecules, cardiolipins, and phosphatidylethanolamines and decreased levels of specific phospholipids with cyclopropanated fatty acids. Complementation and substitution mutations in LapB and LpxC generally restored the phospholipid and LPS assembly defects for the pbgA mutants. During bacteremia, mice infected with the pbgA mutants survived and cleared the bacteria, while animals infected with wild-type salmonellae succumbed within 1 week. Remarkably, wild-type mice survived asymptomatically with pbgA-lpxC salmonellae in their livers and spleens for months, but Toll-like receptor 4-deficient animals succumbed to these infections within roughly 1 week. In summary, S. Typhimurium uses PbgA to influence LPS assembly during stress in order to survive, adapt, and proliferate within the host environment.

scholarly journals Absence of Platelet Endothelial Cell Adhesion Molecule 1, PECAM-1/CD31,In VivoIncreases Resistance to Salmonella enterica Serovar Typhimurium in Mice

2013 ◽  
Vol 81 (6) ◽  
pp. 1952-1963 ◽  
Author(s):  
Michael D. Lovelace ◽  
May Lin Yap ◽  
Jana Yip ◽  
William Muller ◽  
Odilia Wijburg ◽  
...  
Keyword(s):  
Salmonella Enterica ◽  
Inflammatory Responses ◽  
Bacterial Load ◽  
Host Cells ◽  
Dependent Manner ◽  
Wild Type ◽  
Mesenteric Lymph Nodes ◽  
Serovar Typhimurium

ABSTRACTPECAM-1/CD31 is known to regulate inflammatory responses and exhibit pro- and anti-inflammatory functions. This study was designed to determine the functional role of PECAM-1 in susceptibility to murine primaryin vivoinfection withSalmonella entericaserovar Typhimurium and inin vitroinflammatory responses of peritoneal macrophages. Lectin profiling showed that cellular PECAM-1 and recombinant human PECAM-1-Ig chimera contain high levels of mannose sugars andN-acetylglucosamine. Consistent with this carbohydrate pattern, both recombinant human and murine PECAM-1-Ig chimeras were shown to bindS. Typhimurium in a dose-dependent mannerin vitro. Using oral and fecal-oral transmission models ofS. Typhimurium SL1344 infection, PECAM-1−/−mice were found to be more resistant toS. Typhimurium infection than wild-type (WT) C57BL/6 mice. While fecal shedding ofS. Typhimurium was comparable in wild-type and PECAM-1−/−mice, the PECAM-1-deficient mice had lower bacterial loads in systemic organs such as liver, spleen, and mesenteric lymph nodes than WT mice, suggesting that extraintestinal dissemination was reduced in the absence of PECAM-1. This reduced bacterial load correlated with reduced tumor necrosis factor (TNF), interleukin-6 (IL-6), and monocyte chemoattractant protein (MCP) levels in sera of PECAM-1−/−mice. Followingin vitrostimulation of macrophages with either wholeS. Typhimurium, lipopolysaccharide (LPS) (Toll-like receptor 4 [TLR4] ligand), or poly(I·C) (TLR3 ligand), production of TNF and IL-6 by PECAM-1−/−macrophages was reduced. Together, these results suggest that PECAM-1 may have multiple functions in resistance to infection withS. Typhimurium, including binding to host cells, extraintestinal spread to deeper tissues, and regulation of inflammatory cytokine production by infected macrophages.

scholarly journals The Homolog of the Gene bstA of the BTP1 Phage from Salmonella enterica Serovar Typhimurium ST313 Is an Antivirulence Gene in Salmonella enterica Serovar Dublin

2017 ◽  
Vol 86 (1) ◽  
Author(s):  
Ana Herrero-Fresno ◽  
Irene Cartas Espinel ◽  
Malene Roed Spiegelhauer ◽  
Priscila Regina Guerra ◽  
Karsten Wiber Andersen ◽  
...  
Keyword(s):  
Salmonella Enterica ◽  
Type Strain ◽  
Wild Type Strain ◽  
Luria Bertani ◽  
Wild Type ◽  
Content Type ◽  
Serovar Typhimurium ◽  
Cattle Blood

ABSTRACTIn a previous study, a novel virulence gene,bstA, identified in aSalmonella entericaserovar Typhimurium sequence type 313 (ST313) strain was found to be conserved in all publishedSalmonella entericaserovar Dublin genomes. In order to analyze the role of this gene in the host-pathogen interaction inS. Dublin, a mutant where this gene was deleted (S. Dublin ΔbstA) and a mutant which was further genetically complemented withbstA(S. Dublin 3246-C) were constructed and tested in models ofin vitroandin vivoinfection as well as during growth competition assays in M9 medium, Luria-Bertani broth, and cattle blood. In contrast to the results obtained for a strain ofS. Typhimurium ST313, the lack ofbstAwas found to be associated with increased virulence inS. Dublin. Thus,S. Dublin ΔbstAshowed higher levels of uptake than the wild-type strain during infection of mouse and cattle macrophages and higher net replication within human THP-1 cells. Furthermore, during mouse infections,S. Dublin ΔbstAwas more virulent than the wild type following a single intraperitoneal infection and showed an increased competitive index during competitive infection assays. Deletion ofbstAdid not affect either the amount of cytokines released by THP-1 macrophages or the cytotoxicity toward these cells. The histology of the livers and spleens of mice infected with the wild-type strain and theS. Dublin ΔbstAmutant revealed similar levels of inflammation between the two groups. The gene was not important for adherence to or invasion of human epithelial cells and did not influence bacterial growth in rich medium, minimal medium, or cattle blood. In conclusion, a lack ofbstAaffects the pathogenicity ofS. Dublin by decreasing its virulence. Therefore, it might be regarded as an antivirulence gene in this serovar.

scholarly journals The ABC-Type Efflux Pump MacAB Protects Salmonella enterica serovar Typhimurium from Oxidative Stress

mBio ◽  
2013 ◽  
Vol 4 (6) ◽  
Author(s):  
Lydia M. Bogomolnaya ◽  
Katharine D. Andrews ◽  
Marissa Talamantes ◽  
Aimee Maple ◽  
Yury Ragoza ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Salmonella Enterica ◽  
Efflux Pump ◽  
Wild Type ◽  
Multidrug Efflux ◽  
Multidrug Efflux Pump ◽  
Content Type ◽  
Serovar Typhimurium ◽  
Drug Efflux Pump

ABSTRACTMultidrug efflux pumps are integral membrane proteins known to actively excrete antibiotics. The macrolide-specific pump MacAB, the only ABC-type drug efflux pump inSalmonella, has previously been linked to virulence in mice. The molecular mechanism of this link betweenmacABand infection is unclear. We demonstrate thatmacABplays a role in the detoxification of reactive oxygen species (ROS), compounds that salmonellae are exposed to at various stages of infection.macABis induced upon exposure to H2O2and is critical for survival ofSalmonella entericaserovar Typhimurium in the presence of peroxide. Furthermore, we determined thatmacABis required for intracellular replication inside J774.A1 murine macrophages but is not required for survival in ROS-deficient J774.D9 macrophages.macABmutants also had reduced survival in the intestine in the mouse colitis model, a model characterized by a strong neutrophilic intestinal infiltrate where bacteria may experience the cytotoxic actions of ROS. Using an Amplex red-coupled assay,macABmutants appear to be unable to induce protection against exogenous H2O2in vitro, in contrast to the isogenic wild type. In mixed cultures, the presence of the wild-type organism, or media preconditioned by the growth of the wild-type organism, was sufficient to rescue themacABmutant from peroxide-mediated killing. Our data indicate that the MacAB drug efflux pump has functions beyond resistance to antibiotics and plays a role in the protection ofSalmonellaagainst oxidative stress. Intriguingly, our data also suggest the presence of a soluble anti-H2O2compound secreted bySalmonellacells through a MacAB-dependent mechanism.IMPORTANCEThe ABC-type multidrug efflux pump MacAB is known to be required forSalmonella entericaserovar Typhimurium virulence after oral infection in mice, yet the function of this pump during infection is unknown. We show that this pump is necessary for colonization of niches in infected mice where salmonellae encounter oxidative stress during infection. MacAB is required for growth in cultured macrophages that produce reactive oxygen species (ROS) but is not needed in macrophages that do not generate ROS. In addition, we show that MacAB is required to resist peroxide-mediated killingin vitroand for the inactivation of peroxide in the media. Finally, wild-type organisms, or supernatant from wild-type organisms grown in the presence of peroxide, rescue the growth defect ofmacABmutants in H2O2. MacAB appears to participate in the excretion of a compound that induces protection against ROS-mediated killing, revealing a new role for this multidrug efflux pump.

scholarly journals SadA, a Trimeric Autotransporter from Salmonella enterica Serovar Typhimurium, Can Promote Biofilm Formation and Provides Limited Protection against Infection

2011 ◽  
Vol 79 (11) ◽  
pp. 4342-4352 ◽  
Author(s):  
Dhaarini Raghunathan ◽  
Timothy J. Wells ◽  
Faye C. Morris ◽  
Robert K. Shaw ◽  
Saeeda Bobat ◽  
...  
Keyword(s):  
Salmonella Enterica ◽  
Biofilm Formation ◽  
Protective Antigen ◽  
Outer Membrane Proteins ◽  
Cell Aggregation ◽  
Sub Saharan Africa ◽  
Content Type ◽  
Serovar Typhimurium

ABSTRACTSalmonella entericais a major cause of morbidity worldwide and mortality in children and immunocompromised individuals in sub-Saharan Africa. Outer membrane proteins ofSalmonellaare of significance because they are at the interface between the pathogen and the host, they can contribute to adherence, colonization, and virulence, and they are frequently targets of antibody-mediated immunity. In this study, the properties of SadA, a purported trimeric autotransporter adhesin ofSalmonella entericaserovar Typhimurium, were examined. We demonstrated that SadA is exposed on theSalmonellacell surfacein vitroandin vivoduring infection of mice. Expression of SadA resulted in cell aggregation, biofilm formation, and increased adhesion to human intestinal Caco-2 epithelial cells. Immunization of mice with folded, full-length, purified SadA elicited an IgG response which provided limited protection against bacterial challenge. When anti-SadA IgG titers were enhanced by administering alum-precipitated protein, a modest additional protection was afforded. Therefore, despite SadA having pleiotropic functions, it is not a dominant, protective antigen for antibody-mediated protection againstSalmonella.

scholarly journals A Salmonella Virulence Factor Activates the NOD1/NOD2 Signaling Pathway

mBio ◽  
2011 ◽  
Vol 2 (6) ◽  
Author(s):  
A. Marijke Keestra ◽  
Maria G. Winter ◽  
Daisy Klein-Douwel ◽  
Mariana N. Xavier ◽  
Sebastian E. Winter ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Type Iii Secretion ◽  
Salmonella Enterica ◽  
Intestinal Inflammation ◽  
Inflammatory Responses ◽  
Type Iii Secretion System ◽  
Secretion System ◽  
Content Type ◽  
Type Iii

ABSTRACTThe invasion-associated type III secretion system (T3SS-1) ofSalmonella entericaserotype Typhimurium (S. Typhimurium) activates the transcription factor NF-κB in tissue culture cells and induces inflammatory responses in animal models through unknown mechanisms. Here we show that bacterial delivery or ectopic expression of SipA, a T3SS-1-translocated protein, led to the activation of the NOD1/NOD2 signaling pathway and consequent RIP2-mediated induction of NF-κB-dependent inflammatory responses. SipA-mediated activation of NOD1/NOD2 signaling was independent of bacterial invasionin vitrobut required an intact T3SS-1. In the mouse colitis model, SipA triggered mucosal inflammation in wild-type mice but not in NOD1/NOD2-deficient mice. These findings implicate SipA-driven activation of the NOD1/NOD2 signaling pathway as a mechanism by which the T3SS-1 induces inflammatory responsesin vitroandin vivo.IMPORTANCESalmonella entericaserotype Typhimurium (S. Typhimurium) deploys a type III secretion system (T3SS-1) to induce intestinal inflammation and benefits from the ensuing host response, which enhances growth of the pathogen in the intestinal lumen. However, the mechanisms by which the T3SS-1 triggers inflammatory responses have not been resolved. Here we show that the T3SS-1 effector protein SipA induces NF-κB activation and intestinal inflammation by activating the NOD1/NOD2 signaling pathway. These data suggest that the T3SS-1 escalates innate responses through a SipA-mediated activation of pattern recognition receptors in the host cell cytosol.

scholarly journals Caveolin-1-Deficient Mice Show Defects in Innate Immunity and Inflammatory Immune Response during Salmonella enterica Serovar Typhimurium Infection

2006 ◽  
Vol 74 (12) ◽  
pp. 6665-6674 ◽  
Author(s):  
Freddy A. Medina ◽  
Cecilia J. de Almeida ◽  
Elliott Dew ◽  
Jiangwei Li ◽  
Gloria Bonuccelli ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Salmonella Enterica ◽  
Inflammatory Responses ◽  
Systemic Infection ◽  
Bacterial Invasion ◽  
Chemokine Production ◽  
Caveolin 1 ◽  
Serovar Typhimurium ◽  
Deficient Mice

ABSTRACT A number of studies have shown an association of pathogens with caveolae. To this date, however, there are no studies showing a role for caveolin-1 in modulating immune responses against pathogens. Interestingly, expression of caveolin-1 has been shown to occur in a regulated manner in immune cells in response to lipopolysaccharide (LPS). Here, we sought to determine the role of caveolin-1 (Cav-1) expression in Salmonella pathogenesis. Cav-1−/− mice displayed a significant decrease in survival when challenged with Salmonella enterica serovar Typhimurium. Spleen and tissue burdens were significantly higher in Cav-1−/− mice. However, infection of Cav-1−/− macrophages with serovar Typhimurium did not result in differences in bacterial invasion. In addition, Cav-1−/− mice displayed increased production of inflammatory cytokines, chemokines, and nitric oxide. Regardless of this, Cav-1−/− mice were unable to control the systemic infection of Salmonella. The increased chemokine production in Cav-1−/− mice resulted in greater infiltration of neutrophils into granulomas but did not alter the number of granulomas present. This was accompanied by increased necrosis in the liver. However, Cav-1−/− macrophages displayed increased inflammatory responses and increased nitric oxide production in vitro in response to Salmonella LPS. These results show that caveolin-1 plays a key role in regulating anti-inflammatory responses in macrophages. Taken together, these data suggest that the increased production of toxic mediators from macrophages lacking caveolin-1 is likely to be responsible for the marked susceptibility of caveolin-1-deficient mice to S. enterica serovar Typhimurium.

scholarly journals Terminal Deoxynucleotidyl Transferase Is Not Required for Antibody Response to Polysaccharide Vaccines againstStreptococcus pneumoniaeandSalmonella entericaSerovar Typhi

2018 ◽  
Vol 86 (9) ◽  
Author(s):  
Vivek Belde ◽  
Matthew P. Cravens ◽  
Dania Gulandijany ◽  
Justin A. Walker ◽  
Isabel Palomo-Caturla ◽  
...  
Keyword(s):  
Antibody Response ◽  
B Cell ◽  
Salmonella Enterica ◽  
Passive Immunization ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Human Infants ◽  
Content Type ◽  
Serovar Typhimurium

ABSTRACTB cell antigen receptor (BCR) diversity increases by several orders of magnitude due to the action of terminal deoxynucleotidyl transferase (TdT) during V(D)J recombination. Unlike adults, infants have limited BCR diversity, in part due to reduced expression of TdT. Since human infants and young mice respond poorly to polysaccharide vaccines, such as the pneumococcal polysaccharide vaccine Pneumovax23 and Vi polysaccharide (ViPS) ofSalmonella entericaserovar Typhi, we tested the contribution of TdT-mediated BCR diversity in response to these vaccines. We found that TdT+/−and TdT−/−mice generated comparable antibody responses to Pneumovax23 and survivedStreptococcus pneumoniaechallenge. Moreover, passive immunization of B cell-deficient mice with serum from Pneumovax23-immunized TdT+/−or TdT−/−mice conferred protection. TdT+/−and TdT−/−mice generated comparable levels of anti-ViPS antibodies and antibody-dependent, complement-mediated bactericidal activity againstS. Typhiin vitro. To test the protective immunity conferred by ViPS immunizationin vivo, TdT+/−and TdT−/−mice were challenged with a chimericSalmonella entericaserovar Typhimurium strain expressing ViPS, since mice are nonpermissive hosts forS. Typhi infection. Compared to their unimmunized counterparts, immunized TdT+/−and TdT−/−mice challenged with ViPS-expressingS. Typhimurium exhibited a significant reduction in the bacterial burden and liver pathology. These data suggest that the impaired antibody response to the Pneumovax23 and ViPS vaccines in the young is not due to limited TdT-mediated BCR diversification.

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