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��ࡱ�>��	(+����%&'�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������]�	���!bjbj�1�1	;(�[,\�[,\��l�������""������������8���4��Cf�f<"R"R"R"A#�%��%d:C<C<C<C<C<C<C9E��G�<CQ�9&A#A#9&9&<C��R"R"��C3/3/3/9&��R"�R"F:�3/9&:C3/3/1b1R"�����@/�������-�.12:�C0�C61,uH�-�uHb1b1�uH�"29&9&3/9&9&9&9&9&<C<C3/9&9&9&�C9&9&9&9&��������������������������������������������������������������������uH9&9&9&9&9&9&9&9&9&">`:	Immunization with SseB from Salmonella reduces bacterial burden in a calf challenge when administered with the adjuvant dmLT.

Francisco J. Martinez-Becerraa, Kelly Harrisona, Tamara Gullb, Todd A. Jacksonb, Timothy A. Sniderb, Daniel R. Pickingc, John D. Clementsd, Olivia Arizmendia, William D. Pickinga, Wendy L. Pickinga*.


a Department of Microbiology and Molecular Genetics, Oklahoma State University, Stillwater, OK. (Current address: Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS)
b Department of Veterinary Pathobiology, Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, OK.
c Department of Microbiology and Molecular Genetics, Oklahoma State University, Stillwater, OK. 
d Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA.

*Corresponding author: Wendy L. Picking, PhD; Department of Microbiology and Molecular Genetics, Oklahoma State University, 307 Life Science East, Stillwater, OK 74078; Tel: 405-744-4600; Fax: 405-744-6790 E-mail:  HYPERLINK "mailto:wendy.picking@okstate.edu" wendy.picking@okstate.edu
*Corresponding author current address: Wendy L. Picking, PhD; Department of Pharmaceutical Chemistry, University of Kansas, 2030 Becker Drive, Lawrence, KS 66045; Tel: 785-864-5963; Email: wendy.picking@ku.edu

Abstract. 
Salmonella enterica represents an important burden to human and animal health around the world.  Non-typhoidal salmonellosis (NTS) is usually characterized by a severe gastrointestinal disease and is caused by several Salmonella enterica serovars (in particular S. Typhimurium).  We investigated the potential use of type III secretion system proteins as broadly protective vaccine candidates.  We tested the immunogenicity and protective capacity of the Salmonella pathogenicity island 2 (SPI-2) protein SseB in calves.  When administered subcutaneously with the adjuvant double mutant heat-labile toxin (dmLT), specific IgG and IgA antibodies were generated in vaccinated animals.  We also detected specific cytokine secretion when splenocytes from vaccinated animals were stimulated with SseB.  When vaccinated animals were challenged with the heterologous S. enterica serovar Newport, we observed a marked reduction in fecal shedding duration and number of CFUs shed compared to non-vaccinated controls.  These results indicate that formulations containing SseB from Salmonella have potential applications for vaccine development.
Keywords: Salmonella, type III secretion system, calves, vaccine, SseB, SPI-2.








Introduction
Salmonella enterica infects a wide variety of hosts causing a broad range of diseases from gastroenteritis to bacteremia to enteric fever. In humans, non-typhoidal salmonellosis (NTS) causes gastroenteritis and is responsible for over 90 million cases of disease globally  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_1" \o "Majowicz, 2010 #1" 1]. In the United States, it is the leading cause of hospitalization and death due to foodborne illness  ADDIN EN.CITE <EndNote><Cite><Author>Scallan</Author><Year>2011</Year><RecNum>2</RecNum><DisplayText>[2]</DisplayText><record><rec-number>2</rec-number><foreign-keys><key app="EN" db-id="dxravvafi9tef3epa0gx2weodesa5wasrx0r">2</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Scallan, E.</author><author>Hoekstra, R. M.</author><author>Angulo, F. J.</author><author>Tauxe, R. V.</author><author>Widdowson, M. A.</author><author>Roy, S. L.</author><author>Jones, J. L.</author><author>Griffin, P. M.</author></authors></contributors><auth-address>Centers for Disease Control and Prevention, Atlanta, Georgia, USA. elaine.scallan@ucdenver.edu</auth-address><titles><title>Foodborne illness acquired in the United States--major pathogens</title><secondary-title>Emerg Infect Dis</secondary-title></titles><periodical><full-title>Emerg Infect Dis</full-title></periodical><pages>7-15</pages><volume>17</volume><number>1</number><edition>2011/01/05</edition><dates><year>2011</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1080-6059 (Electronic)&#xD;1080-6040 (Linking)</isbn><accession-num>21192848</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=21192848</url></related-urls></urls><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_2" \o "Scallan, 2011 #2" 2].  Additionally, many animal species are infected with various Salmonella serovars such as calves, which are most commonly affected by serovars Dublin, Newport, and Typhimurium.  Infection by these pathogens impacts both animal and human health and continues to be a major burden to the beef industry  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_3" \o "Brichta-Harhay, 2011 #3" 3,  HYPERLINK \l "_ENREF_4" \o "Gragg, 2013 #4" 4]. 
The best prevention against infectious diseases is vaccination.  While much effort has been expended on potential Salmonella vaccines, a broad coverage vaccine is still unavailable.  Current licensed human vaccines only protect against S. Typhi and Paratyphi A and B  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_5" \o "Ohtake, 2011 #5" 5].  An S. Newport vaccine is marketed for bovine use but has not been shown to have any effect on animal health or fecal shedding  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_6" \o "Dodd, 2011 #6" 6].  Recently, we have demonstrated that the tip (IpaD) and first translocator (IpaB) proteins of the type III secretion system (T3SS) provide broad protection against infection by Shigella spp.  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_7" \o "Martinez-Becerra, 2012 #7" 7,  HYPERLINK \l "_ENREF_8" \o "Martinez-Becerra, 2013 #8" 8].  The T3SS is a virulence system that Shigella spp., Salmonella spp. and other Gram-negative bacteria use to modify eukaryotic host functions for the benefit of the bacteria  ADDIN EN.CITE <EndNote><Cite><Author>Hayes</Author><Year>2010</Year><RecNum>9</RecNum><DisplayText>[9]</DisplayText><record><rec-number>9</rec-number><foreign-keys><key app="EN" db-id="dxravvafi9tef3epa0gx2weodesa5wasrx0r">9</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hayes, C. S.</author><author>Aoki, S. K.</author><author>Low, D. A.</author></authors></contributors><auth-address>Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, California 93106, USA.</auth-address><titles><title>Bacterial contact-dependent delivery systems</title><secondary-title>Annu Rev Genet</secondary-title><alt-title>Annual review of genetics</alt-title></titles><periodical><full-title>Annu Rev Genet</full-title><abbr-1>Annual review of genetics</abbr-1></periodical><alt-periodical><full-title>Annu Rev Genet</full-title><abbr-1>Annual review of genetics</abbr-1></alt-periodical><pages>71-90</pages><volume>44</volume><keywords><keyword>Bacteria/*metabolism</keyword><keyword>*Bacterial Secretion Systems</keyword><keyword>Eukaryotic Cells/microbiology</keyword><keyword>Signal Transduction</keyword></keywords><dates><year>2010</year></dates><isbn>1545-2948 (Electronic)&#xD;0066-4197 (Linking)</isbn><accession-num>21047256</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/21047256</url></related-urls></urls><electronic-resource-num>10.1146/annurev.genet.42.110807.091449</electronic-resource-num></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_9" \o "Hayes, 2010 #9" 9].  Strains that lack the tip and translocator proteins cannot invade intestinal epithelial cells.  Salmonella spp. have two unique T3SSs with one each encoded on Salmonella pathogenicity islands 1 and 2 (SPI-1 and SPI-2).  SipD and SipB are the homologs of IpaD and IpaB that are encoded on SPI-1, respectively,  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_10" \o "Kaniga, 1995 #10" 10,  HYPERLINK \l "_ENREF_11" \o "Kaniga, 1995 #11" 11] while SseB and SseC are the SipD and SipB homologs, respectively, encoded on SPI-2  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_12" \o "Hensel, 1998 #12" 12].  Since recombinant SipD and SipB were marginally protective against S. Typhimurium using the mouse typhoid model (Harrison and Martinez-Becerra, manuscript in preparation), SseB and SseC were identified as potential antigens.  While SseC has not yet been purified, SseB provided protection to mice challenged with S. Typhimurium (Harrison and Martinez-Becerra, manuscript in preparation).  Herein we describe the immune response in calves after immunization with SseB admixed with the mucosal adjuvant double mutant heat-labile toxin (dmLT) from enterotoxigenic E. coli  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_13" \o "Norton, 2012 #13" 13] as well as the reduced bacterial shedding after a challenge with S. Newport, selected due to its high virulence in humans and animals, as well as common zoonotic transmission  ADDIN EN.CITE <EndNote><Cite><Author>Richardson</Author><Year>1975</Year><RecNum>14</RecNum><DisplayText>[14]</DisplayText><record><rec-number>14</rec-number><foreign-keys><key app="EN" db-id="dxravvafi9tef3epa0gx2weodesa5wasrx0r">14</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Richardson, A.</author></authors></contributors><titles><title>Outbreaks of bovine salmonellosis caused by serotypes other than S. dublin and S. typhimurium</title><secondary-title>J Hyg (Lond)</secondary-title><alt-title>The Journal of hygiene</alt-title></titles><periodical><full-title>J Hyg (Lond)</full-title><abbr-1>The Journal of hygiene</abbr-1></periodical><alt-periodical><full-title>J Hyg (Lond)</full-title><abbr-1>The Journal of hygiene</abbr-1></alt-periodical><pages>195-203</pages><volume>74</volume><number>2</number><keywords><keyword>Animals</keyword><keyword>Cattle</keyword><keyword>Cattle Diseases/epidemiology/*microbiology/transmission</keyword><keyword>Disease Outbreaks/*veterinary</keyword><keyword>England</keyword><keyword>Feces/microbiology</keyword><keyword>Humans</keyword><keyword>Salmonella/immunology/isolation &amp; purification</keyword><keyword>Salmonella Infections/transmission</keyword><keyword>Salmonella Infections, Animal/*epidemiology/microbiology/transmission</keyword><keyword>Serotyping</keyword><keyword>Zoonoses</keyword></keywords><dates><year>1975</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0022-1724 (Print)&#xD;0022-1724 (Linking)</isbn><accession-num>1054726</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/1054726</url></related-urls></urls><custom2>2130382</custom2></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_14" \o "Richardson, 1975 #14" 14]. 
2. Materials and Methods
2.1. Animals  
All animal use was approved by the Oklahoma State University Institutional Animal Care and Use Committee.  Eleven male Holstein or Holstein-Jersey calves were obtained at approximately 21 days of age from a commercial source.  Calves were treated on arrival with 900 mg (20 mg/kg) tilmicosin (Elanco, Indianapolis IN) subcutaneously as metaphylaxis for bovine respiratory disease.  Calves were housed in indoor pens in groups of 3-4 animals and were bottle-fed two quarts of commercial calf milk replacer twice daily.  After day 56 bottle-feeding was reduced to once per day to facilitate oral inoculation of the infective Salmonella bolus.  Calves had ad libitum access to an antibiotic-free commercial calf starter grain mix, Bermuda hay and fresh water.  Fecal cultures were obtained prior to the experiment to assess Salmonella prevalence.  Serum samples were obtained to assay for antibodies against S. Newport extracts.  In a separate experiment, an additional four calves were obtained from Oklahoma State University to assess the immune response to vaccination.  These four calves were not challenged and did not receive milk replacer feeding but were otherwise managed identically to the challenged calves.
2.2. SseB purification
S. Typhimurium SL1344 genomic DNA  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_10" \o "Kaniga, 1995 #10" 10] was used to amplify sseB by PCR (primer sequence: SseBF 5'-GAG AGA GAG cat atg TCT TCA GGA AAC ATC TT and  SseBR 5'-GAG GAG gga tcc TTA TGA GTA CGT TTT CTG CG) which was cloned into the expression vector pET15b (Novagen, Madison, WI).  Correct insertion was confirmed by DNA sequencing.  SseB was expressed in E. coli Tuner(DE3) (Novagen, Madison, WI) and purified from the cytoplasmic fraction by IMAC chromatography as previously described for SipD  ADDIN EN.CITE <EndNote><Cite><Author>Espina</Author><Year>2007</Year><RecNum>15</RecNum><DisplayText>[15]</DisplayText><record><rec-number>15</rec-number><foreign-keys><key app="EN" db-id="dxravvafi9tef3epa0gx2weodesa5wasrx0r">15</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Espina, M.</author><author>Ausar, S. F.</author><author>Middaugh, C. R.</author><author>Baxter, M. A.</author><author>Picking, W. D.</author><author>Picking, W. L.</author></authors></contributors><titles><title>Conformational stability and differential structural analysis of LcrV, PcrV, BipD, and SipD from type III secretion systems</title><secondary-title>Protein Sci</secondary-title></titles><periodical><full-title>Protein Sci</full-title></periodical><pages>704-714</pages><volume>16</volume><number>4</number><dates><year>2007</year><pub-dates><date>Feb 27</date></pub-dates></dates><accession-num>17327391</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=17327391 </url></related-urls></urls></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_15" \o "Espina, 2007 #15" 15].  Purified SseB was stored at -80 �C until use.
2.3. Immunization of calves 
Calves were evenly divided into experimental and control groups.  Experimental group animals were vaccinated subcutaneously in the neck with 2 mg SseB admixed with 50 �g dmLT in a total volume of 1ml using a 20 gauge needle.  Control group animals were vaccinated with 1 ml PBS.  Calves were vaccinated on days of age 28, 42, 56 and 70.  Serum, saliva and fecal samples were collected on each vaccination day and on day 84.
2.4. Assessment of calf immune response 
Blood samples from all vaccinated animals were allowed to clot and then centrifuged 15 min at 2000rpm to obtain serum.  Saliva was collected on cotton swabs and centrifuged 15 min at 2000rpm in 15 ml tubes to separate saliva.  Fresh fecal samples were collected and ~0.1g was suspended in PBS-0.2% NaN3 according to their weight to a final concentration of 10% (w/v). The samples were cleared with two centrifugation steps and 1mM PMSF was added. An ELISA was used to detect SseB-specific antibodies in serum, saliva and feces as previously described  ADDIN EN.CITE <EndNote><Cite><Author>Martinez-Becerra</Author><Year>2013</Year><RecNum>8</RecNum><DisplayText>[8]</DisplayText><record><rec-number>8</rec-number><foreign-keys><key app="EN" db-id="dxravvafi9tef3epa0gx2weodesa5wasrx0r">8</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Martinez-Becerra, F. J.</author><author>Scobey, M.</author><author>Harrison, K.</author><author>Choudhari, S. P.</author><author>Quick, A. M.</author><author>Joshi, S. B.</author><author>Middaugh, C. R.</author><author>Picking, W. L.</author></authors></contributors><auth-address>Department of Microbiology and Molecular Genetics, Oklahoma State University, Stillwater, OK, United States.</auth-address><titles><title>Parenteral immunization with IpaB/IpaD protects mice against lethal pulmonary infection by Shigella</title><secondary-title>Vaccine</secondary-title><alt-title>Vaccine</alt-title></titles><periodical><full-title>Vaccine</full-title><abbr-1>Vaccine</abbr-1></periodical><alt-periodical><full-title>Vaccine</full-title><abbr-1>Vaccine</abbr-1></alt-periodical><pages>2667-72</pages><volume>31</volume><number>24</number><edition>2013/04/23</edition><dates><year>2013</year><pub-dates><date>May 31</date></pub-dates></dates><isbn>0264-410x</isbn><accession-num>23602665</accession-num><urls></urls><electronic-resource-num>10.1016/j.vaccine.2013.04.012</electronic-resource-num><remote-database-provider>Nlm</remote-database-provider><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_8" \o "Martinez-Becerra, 2013 #8" 8].  Spleen and bone marrow samples were collected at approximately 84 days of age from four animals that had been vaccinated but not challenged (two SseB and two PBS-vaccinated). Cells extracted from both organs were incubated with 5 �g/ml SseB for 24h, and then overlaid with agarose/peroxidase susbstrate. The frequency of specific antibody secreting cells in single cell suspensions was measured by ELISpot  ADDIN EN.CITE <EndNote><Cite><Author>Martinez-Becerra</Author><Year>2013</Year><RecNum>8</RecNum><DisplayText>[8]</DisplayText><record><rec-number>8</rec-number><foreign-keys><key app="EN" db-id="dxravvafi9tef3epa0gx2weodesa5wasrx0r">8</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Martinez-Becerra, F. J.</author><author>Scobey, M.</author><author>Harrison, K.</author><author>Choudhari, S. P.</author><author>Quick, A. M.</author><author>Joshi, S. B.</author><author>Middaugh, C. R.</author><author>Picking, W. L.</author></authors></contributors><auth-address>Department of Microbiology and Molecular Genetics, Oklahoma State University, Stillwater, OK, United States.</auth-address><titles><title>Parenteral immunization with IpaB/IpaD protects mice against lethal pulmonary infection by Shigella</title><secondary-title>Vaccine</secondary-title><alt-title>Vaccine</alt-title></titles><periodical><full-title>Vaccine</full-title><abbr-1>Vaccine</abbr-1></periodical><alt-periodical><full-title>Vaccine</full-title><abbr-1>Vaccine</abbr-1></alt-periodical><pages>2667-72</pages><volume>31</volume><number>24</number><edition>2013/04/23</edition><dates><year>2013</year><pub-dates><date>May 31</date></pub-dates></dates><isbn>0264-410x</isbn><accession-num>23602665</accession-num><urls></urls><electronic-resource-num>10.1016/j.vaccine.2013.04.012</electronic-resource-num><remote-database-provider>Nlm</remote-database-provider><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_8" \o "Martinez-Becerra, 2013 #8" 8].  IFN-( and IL-17 levels in splenocyte culture supernatants were measured by ELISA after stimulating 106 cells/well with 10 �g/ml SseB according to manufacturer�s instructions (Bethyl Laboratories Inc., Montgomery, TX).  
2.5. S. Newport Challenge of calves
S. Newport (ATCC 27869) was grown in LB at 37�C 200 rpm agitation until A600 ~1.0.  The bacteria were collected by centrifugation, washed and resuspended in PBS. Calves were challenged on day 85 with S. Newport at 0.9 x 106 CFUs by feeding the bacteria in one liter of milk replacer.  Esophageal groove function prevents reticuloruminal deposition of the milk/bacteria mixture and channels it directly into the abomasum.  Calves were evaluated three times daily post-inoculation.  Fecal samples were obtained per rectum daily post-inoculation to evaluate bacterial shedding which was determined by dilution plating onto Brilliant Green agar plates  ADDIN EN.CITE <EndNote><Cite><Author>Snider</Author><Year>2013</Year><RecNum>16</RecNum><DisplayText>[16]</DisplayText><record><rec-number>16</rec-number><foreign-keys><key app="EN" db-id="dxravvafi9tef3epa0gx2weodesa5wasrx0r">16</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Snider, T.A., Gull, T., Jackson, T.A., Martinez-Becerra, F.J., Picking, D.R., Picking, W.D., Picking, W.L</author></authors></contributors><titles><title>Salmonellosis Challenge Model in Older Calves</title><secondary-title>Veterinary Microbiology</secondary-title></titles><periodical><full-title>Veterinary Microbiology</full-title></periodical><volume>in press</volume><dates><year>2013</year></dates><urls></urls><electronic-resource-num>10.1016/j.vetmic.2013.11.018</electronic-resource-num></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_16" \o "Snider, 2013 #16" 16], and calculating bacterial shedding per gram of fecal material.  Animal health was assessed based on rectal temperature, attitude/appetite, hydration status, and fecal consistency. A score of 1(normal) to 4 (very altered) was employed. Calves with a score of 12 were euthanized, calves with a score of 10-11 were assessed by the attending veterinarian for the need for euthanasia, with all animals being euthanized by eleven days post-challenge. 
2.6. Statistics
Statistical analysis was performed using Graphpad prism software.  Differences among treatments were analyzed using t-test or Mann-Whitney u test. A P value < 0.05 was considered significant for all analysis.
3. Results
3.1. Analysis of immune response elicited following vaccination with SseB+dmLT
Serum anti-SseB IgG was detected after the second immunization of SseB+dmLT (Fig.1, left panel) with titers reaching 1000 EU/ml.  No specific IgG to SseB was detected in the calves immunized with PBS.  To assess the mucosal antibody response, SseB-specific IgA was measured in saliva (Fig. 1, right panel).  Anti-SseB IgA was not detected until day 84 with the final titer reaching 1000 EU/ml.  No anti-SseB IgA was detected in fecal samples. 
To characterize antibody secretion due to plasma and memory cells, spleen and bone marrow were obtained at 84 days of age from the unchallenged calves.  The cells from one of the PBS-vaccinated animals became contaminated and were removed from the study.  In the spleens of the SseB-vaccinated calves, the frequency of ASCs specific for SseB was 100-125 cells/106 cells (Fig. 2, top left panel).  No SseB specific cells were detected in the calf vaccinated with PBS. In the bone marrow the frequency was 70-75 cells/106 cells in the SseB vaccinates with none detected in the control calf (Fig. 2, top right panel).  To begin to characterize the cellular immune response, splenocytes from these same animals were analyzed for cytokine secretion.  For cells obtained from SseB-vaccinated calf #1, IFN-( levels reached values of 8 ng/ml and cells from SseB calf #2 reached levels of 25 ng/ml.  IFN-( secretion in the PBS-vaccinated calf was below the detection level (Fig. 2, bottom left panel).  A similar pattern was seen when the supernatants were assessed for secretion of IL-17A (Fig. 2, bottom right panel).  Calf #1 had IL-17A levels of 3.5 ng/ml while calf #2 IL-17A levels reached 8.5 ng/ml.  Again, cells from the calf immunized with PBS exhibited IL-17A secretion at the lower limit of detection. 
3.2. S. Newport challenge of calves immunized with SseB+dmLT
All eleven challenged calves exhibited a significant increase in body temperature by day 2 indicating a successful S. Newport infection (Fig. 3, top panel).  With the exception of days 2 and 3, the trend of the temperatures exhibited by the SseB+dmLT group was lower than those of the PBS group.  In fact, the temperatures of the SseB+dmLT group had returned to normal (39.5 �C) by day 4.  The PBS group did not return to normal until day 6.  Fecal shedding was also used to measure disease state.  Interestingly, while the temperatures of the calves between the two groups were not statistically different, there was a difference in the shedding between the SseB+dmLT and the PBS vaccinate calves (Fig. 3, middle and bottom panels).  On day 1 both groups shed ~105 S. Newport per gram of feces (Fig. 3, middle panel).  As the disease progressed, there was an increase in the shedding of the PBS-vaccinated calves to 108 by day 3 and these calves maintained shedding of 105-107 CFU per gram for the remainder of the study.  Only half of the PBS-vaccinated animals were able to eliminate shedding by day 5. Finally, on day ten, the shedding dropped to below detection levels via dilution plating for all animals.  In stark contrast, the calves vaccinated with SseB+dmLT did not exhibit an increase in fecal shedding of S. Newport. Instead, day 2 and 3 shedding was maintained at 104-105 with a drop to undetectable levels at day 4.  The lack of shedding on day 4 coincides with the return of normal rectal temperatures which also occurred on day 4.  Although a slight increase was seen on day 5 for 2 animals, the remaining days saw no detectable CFUs by dilution plating. When the total shedding over the entire ten day period was calculated, the efficacy of the vaccine in reducing S. Newport shedding was clear (Fig. 3, bottom panel).  The cumulative bacterial shedding per gram of fecal matter over the course of ten days for the group vaccinated with SseB+dmLT was not only lower, but the variation over the course of ten days was less than one log unit which is consistent with no effective increase in shedding over time.  This is in contrast to the group vaccinated with PBS which had a higher average shedding and an average over the course of the study that spanned over 2.5 log units.  Thus, the SseB+dmLT vaccine reduced shedding from the initial time point.
4. Discussion
Salmonella spp. are a serious global public health burden causing morbidity, mortality, and lost productivity in both work hours and agricultural output, however, only a vaccine to prevent typhoid fever has thus far been available.  We have generated proof of concept that Shigella T3SS proteins can serve as protective antigens in mice against homologous and heterologous challenge  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_7" \o "Martinez-Becerra, 2012 #7" 7,  HYPERLINK \l "_ENREF_8" \o "Martinez-Becerra, 2013 #8" 8].  We extended this concept to the T3SS proteins of Salmonella spp. and have performed similar proof of concept experiments in mice (Harrison and Martinez-Becerra, manuscript in preparation).  It has been documented, however, that antigens that protect against the artificial systemic disease caused by S. Typhimurium in mice do not translate to naturally infected hosts  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_17" \o "Boyen, 2009 #17" 17].  Thus, we chose to vaccinate calves with the predicted most effective T3SS protein and a new adjuvant capable of inducing both systemic and mucosal immunity when administered either mucosally or parenterally and to challenge them with the heterologous strain S. Newport.  The SseB+dmLT elicited a specific anti-SseB serum IgG titer and salivary IgA titer.  Although IgA was not detected in feces, it remains unclear as to whether Salmonella clearance is completely antibody-mediated as is the case with antibodies against LPS and the Vi antigen  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_18" \o "Lindow, 2011 #18" 18,  HYPERLINK \l "_ENREF_19" \o "Johanns, 2011 #19" 19].  It is possible that like many intracellular pathogens, cell-mediated immunity is also required or a combination of cell-mediated and humoral immunity.  After vaccination, calves were challenged with S. Newport.  The group that was vaccinated with the SseB+dmLT had a trend of lower temperatures over the course of the challenge study, but more importantly, they had lower bacterial shedding that lasted only four days rather than the nine days that was exhibited by the control group.  SseB-specific IgA-secreting cells were present in spleen and bone marrow of vaccinated, unchallenged calves indicating that memory was associated with the vaccine.  Moreover, the IFN-� and IL-17A cytokine induction indicates that the cytokines often associated with intracellular pathogens are present.  
It is noteworthy that the challenge was performed with S. Newport, which is heterologous to the S. Typhimurium from which the sseB gene was amplified.  This illustrates the broad protection that the SseB+dmLT vaccine can provide against multiple serovars  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_20" \o "Lee, 2012 #20" 20].  While the vaccine formulation used in this study dramatically lowered the fecal shedding in the SseB-vaccinated group, optimization will be necessary to further reduce fecal shedding and reduce disease morbidity and pyrexia.
A subcutaneous route of vaccination was chosen for ease of administration; however, it is possible that another route, such as intradermal, could produce a better cell-mediated response.  Additionally, the protein:dmLT ratio should be further explored for optimization. Nevertheless, SseB+dmLT provides a promising new vaccine formulation for the reduction of Salmonella fecal shedding in cattle.  Reduction in fecal shedding alone could substantially decrease environmental contamination in feedlots and dairies, which could have beneficial downstream effects on additional animal infections, animal-derived food product contamination and human health.  This vaccine candidate provides an alternative to several vaccines based on attenuated organisms described for S. Typhimurium  ADDIN EN.CITE <EndNote><Cite><Author>Jones</Author><Year>1991</Year><RecNum>21</RecNum><DisplayText>[21]</DisplayText><record><rec-number>21</rec-number><foreign-keys><key app="EN" db-id="dxravvafi9tef3epa0gx2weodesa5wasrx0r">21</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Jones, P. W.</author><author>Dougan, G.</author><author>Hayward, C.</author><author>Mackensie, N.</author><author>Collins, P.</author><author>Chatfield, S. N.</author></authors></contributors><auth-address>Karolinska Institute, Dept. Clinical Bacteriology, Huddinge Hospital, Sweden.</auth-address><titles><title>Oral vaccination of calves against experimental salmonellosis using a double aro mutant of Salmonella typhimurium</title><secondary-title>Vaccine</secondary-title><alt-title>Vaccine</alt-title></titles><periodical><full-title>Vaccine</full-title><abbr-1>Vaccine</abbr-1></periodical><alt-periodical><full-title>Vaccine</full-title><abbr-1>Vaccine</abbr-1></alt-periodical><pages>29-34</pages><volume>9</volume><number>1</number><keywords><keyword>Administration, Oral</keyword><keyword>Animals</keyword><keyword>Animals, Newborn</keyword><keyword>Antibodies, Bacterial/biosynthesis</keyword><keyword>Bacterial Vaccines/*administration &amp; dosage/adverse effects</keyword><keyword>Cattle</keyword><keyword>Cattle Diseases/*prevention &amp; control</keyword><keyword>Mutation</keyword><keyword>Salmonella Infections, Animal/*prevention &amp; control</keyword><keyword>Salmonella typhimurium/genetics/*immunology</keyword><keyword>Vaccines, Attenuated/administration &amp; dosage/adverse effects</keyword></keywords><dates><year>1991</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>0264-410X (Print)&#xD;0264-410X (Linking)</isbn><accession-num>2008797</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/2008797</url></related-urls></urls></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_21" \o "Jones, 1991 #21" 21], S. Choleraesuis  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_22" \o "House, 2001 #22" 22] and S. Dublin  ADDIN EN.CITE <EndNote><Cite><Author>Selim</Author><Year>1995</Year><RecNum>23</RecNum><DisplayText>[23]</DisplayText><record><rec-number>23</rec-number><foreign-keys><key app="EN" db-id="dxravvafi9tef3epa0gx2weodesa5wasrx0r">23</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Selim, S. A.</author><author>Cullor, J. S.</author><author>Smith, B. P.</author><author>Blanchard, P.</author><author>Farver, T. B.</author><author>Hoffman, R.</author><author>Dilling, G.</author><author>Roden, L. D.</author><author>Wilgenburg, B.</author></authors></contributors><auth-address>Department of Pathology, Microbiology and Immunology, School of Veterinary Medicine, University of California (UCD), Davis, USA.</auth-address><titles><title>The effect of Escherichia coli J5 and modified live Salmonella dublin vaccines in artificially reared neonatal calves</title><secondary-title>Vaccine</secondary-title><alt-title>Vaccine</alt-title></titles><periodical><full-title>Vaccine</full-title><abbr-1>Vaccine</abbr-1></periodical><alt-periodical><full-title>Vaccine</full-title><abbr-1>Vaccine</abbr-1></alt-periodical><pages>381-90</pages><volume>13</volume><number>4</number><keywords><keyword>Animals</keyword><keyword>Animals, Newborn/immunology</keyword><keyword>Antibodies, Bacterial/blood</keyword><keyword>Bacterial Vaccines/*immunology</keyword><keyword>Cattle</keyword><keyword>Cause of Death</keyword><keyword>Double-Blind Method</keyword><keyword>Enzyme-Linked Immunosorbent Assay</keyword><keyword>Escherichia coli/*immunology</keyword><keyword>Prospective Studies</keyword><keyword>Salmonella/*immunology</keyword><keyword>Vaccination/*veterinary</keyword></keywords><dates><year>1995</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>0264-410X (Print)&#xD;0264-410X (Linking)</isbn><accession-num>7793136</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/7793136</url></related-urls></urls></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_23" \o "Selim, 1995 #23" 23].
Future studies will include determining the protective efficacy of the SseB+dmLT against other Salmonella serovars including Typhimurium and Dublin as well as in other natural hosts such as pigs and, eventually, humans.
5. Acknowledgements
We thank Atticus Mullon for processing samples used in this study. Funding for this project was provided by the Oklahoma Center for the Advancement of Science and Technology (OCAST) and the Bill and Melinda Gates Foundation through the Grand Challenge Exploration Initiative.
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Conflict of Interest statement
No conflicts of interests are identified by the authors of this paper.Figures
Figure 1.  Antibody response elicited by SseB+dmLT vaccination.  The left panel illustrates the kinetics of the serum anti-SseB IgG response.  The white boxes indicate titer in PBS-vaccinated calves while black circles are SseB-vaccinated calves. The right panel illustrates the SseB-specific IgA response detected in the saliva at day 84.  Each time point or bar is the mean �S.D. of six calves/group. *P<0.05 comparing groups that received SseB+dmLT and PBS using T test.

Figure 2.  Antibody secreting cell frequency and cytokine response elicited by SseB+dmLT vaccination.  Top left panel shows the frequency of SseB-specific IgA-secreting cells in the spleen of each calf while the right panel shows the frequency in the bone marrow.  Both were plotted as mean specific ASCs per 106 cells � S.D.  IFN-� (bottom left panel) or IL-17A (bottom right panel) levels were measure in culture supernatants of stimulated splenocytes.  Each bar represents the mean of quadruplicate wells � S.D. *P<0.05 comparing groups that received SseB+dmLT and PBS using T test.
Figure 3.  Rectal temperatures and shedding of S. Newport following bacterial challenge of vaccinated calves.  The top panel illustrates the temperatures of the calves over the course of eight days after challenge.  Black boxes indicate temperature from calves vaccinated with SseB+dmLT while white boxes are PBS-vaccinated calves. The middle panel shows fecal shedding (CFUs/gram of feces) for each of ten days.  &'-./9EJST~����������������������ѳ�����zq��eZOhDohO�OJQJhDoh�a�OJQJhDoh,AQH*OJQJh�&�H*OJQJhDoh�&�H*OJQJhDoh�&�OJQJhDoh�SH*OJQJhDoh1*OJQJhDoh�SOJQJhDohsOJQJh�#�h�#�OJQJhH�OJQJh�#�OJQJhiL�OJQJhDoh�D�6�OJQJhDoh�D�OJQJh�OJQJ~G	H	I	
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Running head: SseB reduces Salmonella burden in calf challenge


 PAGE   \* MERGEFORMAT 6




� � � � � � � � � � � � '!5!;!<!=!?!@!B!C!E!F!H!T!c!n!�!�!�!�!�!�������ⶫ������������uluh`\`h�Ujh3$Uhsv�h�L6�OJQJhp{7h�LOJQJhp{7h�L5�OJQJh0\jh0\Uh$@hs2�OJQJh
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M.</author><author>International Collaboration on Enteric Disease &apos;Burden of Illness, Studies</author></authors></contributors><auth-address>Center for Food-borne, Environmental and Zoonotic Infectious Diseases, Public Health Agency of Canada, Guelph, Ontario, Canada.</auth-address><titles><title>The global burden of nontyphoidal Salmonella gastroenteritis</title><secondary-title>Clin Infect Dis</secondary-title><alt-title>Clinical infectious diseases : an official publication of the Infectious Diseases Society of America</alt-title></titles><periodical><full-title>Clin Infect Dis</full-title><abbr-1>Clinical infectious diseases : an official publication of the Infectious Diseases Society of America</abbr-1></periodical><alt-periodical><full-title>Clin Infect Dis</full-title><abbr-1>Clinical infectious diseases : an official publication of the Infectious Diseases Society of America</abbr-1></alt-periodical><pages>882-9</pages><volume>50</volume><number>6</number><keywords><keyword>Developed Countries</keyword><keyword>Developing Countries</keyword><keyword>Foodborne Diseases/*epidemiology/*microbiology/mortality</keyword><keyword>Gastroenteritis/*epidemiology/*microbiology/mortality</keyword><keyword>Humans</keyword><keyword>Incidence</keyword><keyword>Salmonella/classification/*isolation &amp; purification</keyword><keyword>Salmonella Infections/*epidemiology/*microbiology/mortality</keyword></keywords><dates><year>2010</year><pub-dates><date>Mar 15</date></pub-dates></dates><isbn>1537-6591 (Electronic)&#xD;1058-4838 (Linking)</isbn><accession-num>20158401</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/20158401</url></related-urls></urls><electronic-resource-num>10.1086/650733</electronic-resource-num></record></Cite></EndNote>sD���y������K�	_ENREF_1sD���y������K�	_ENREF_2�D<EndNote><Cite><Author>Brichta-Harhay</Author><Year>2011</Year><RecNum>3</RecNum><DisplayText>[3, 4]</DisplayText><record><rec-number>3</rec-number><foreign-keys><key app="EN" db-id="dxravvafi9tef3epa0gx2weodesa5wasrx0r">3</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Brichta-Harhay, D. 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