scholarly journals RidA Proteins Prevent Metabolic Damage Inflicted by PLP-Dependent Dehydratases in All Domains of Life

mBio ◽  
2013 ◽  
Vol 4 (1) ◽  
Author(s):  
Jennifer A. Lambrecht ◽  
George E. Schmitz ◽  
Diana M. Downs
Keyword(s):  
Cellular Damage ◽  
Cellular Functions ◽  
Metabolic Intermediate ◽  
Content Type ◽  
Cellular Environment ◽  
Serovar Typhimurium ◽  
Domains Of Life ◽  
Branched Chain

ABSTRACTPyridoxal 5′-phosphate (PLP) is a coenzyme synthesized by all forms of life. Relevant to the work reported here is the mechanism of the PLP-dependent threonine/serine dehydratases, which generate reactive enamine/imine intermediates that are converted to keto acids by members of the RidA family of enzymes. The RidA protein ofSalmonella entericaserovar Typhimurium LT2 is the founding member of this broadly conserved family of proteins (formerly known as YjgF/YER057c/UK114). RidA proteins were recently shown to be enamine deaminases. Here we demonstrate the damaging potential of enamines in the absence of RidA proteins. Notably,S. entericastrains lacking RidA have decreased activity of the PLP-dependent transaminase B enzyme IlvE, an enzyme involved in branched-chain amino acid biosynthesis. We reconstituted the threonine/serine dehydratase (IlvA)-dependent inhibition of IlvEin vitro, show that thein vitrosystem reflects the mechanism of RidA functionin vivo, and show that IlvE inhibition is prevented by RidA proteins from all domains of life. We conclude that 2-aminoacrylate (2AA) inhibition represents a new type of metabolic damage, and this finding provides an important physiological context for the role of the ubiquitous RidA family of enamine deaminases in preventing damage by 2AA.IMPORTANCEExternal stresses that disrupt metabolic components can perturb cellular functions and affect growth. A similar consequence is expected if endogenously generated metabolites are reactive and persist in the cellular environment. Here we show that the metabolic intermediate 2-aminoacrylate (2AA) causes significant cellular damage if allowed to accumulate aberrantly. Furthermore, we show that the widely conserved protein RidA prevents this accumulation by facilitating conversion of 2AA to a stable metabolite. This work demonstrates that the reactive metabolite 2AA, previously considered innocuous in the cell due to a short half-life in aqueous solution, can survive in the cellular environment long enough to cause damage. This work provides insights into the roles and persistence of reactive metabolitesin vivoand shows that the RidA family of proteins is able to prevent damage caused by a reactive intermediate that is created as a consequence of PLP-dependent chemistry.

scholarly journals Needle-Free Delivery of Acetalated Dextran-Encapsulated AR-12 Protects Mice from Francisella tularensis Lethal Challenge

2016 ◽  
Vol 60 (4) ◽  
pp. 2052-2062 ◽  
Author(s):  
Ky V. Hoang ◽  
Heather Curry ◽  
Michael A. Collier ◽  
Hassan Borteh ◽  
Eric M. Bachelder ◽  
...  
Keyword(s):  
Francisella Tularensis ◽  
Lethal Challenge ◽  
Content Type ◽  
Human Macrophages ◽  
Gentamicin Treatment ◽  
Significant Toxicity ◽  
Serovar Typhimurium ◽  
Spectrum Activity

ABSTRACTFrancisella tularensiscauses tularemia and is a potential biothreat. Given the limited antibiotics for treating tularemia and the possible use of antibiotic-resistant strains as a biowarfare agent, new antibacterial agents are needed. AR-12 is an FDA-approved investigational new drug (IND) compound that induces autophagy and has shown host-directed, broad-spectrum activityin vitroagainstSalmonella entericaserovar Typhimurium andF. tularensis. We have shown that AR-12 encapsulated within acetalated dextran (Ace-DEX) microparticles (AR-12/MPs) significantly reduces host cell cytotoxicity compared to that with free AR-12, while retaining the ability to controlS.Typhimurium within infected human macrophages. In the present study, the toxicity and efficacy of AR-12/MPs in controlling virulent type AF. tularensisSchuS4 infection were examinedin vitroandin vivo. No significant toxicity of blank MPs or AR-12/MPs was observed in lung histology sections when the formulations were given intranasally to uninfected mice. In histology sections from the lungs of intranasally infected mice treated with the formulations, increased macrophage infiltration was observed for AR-12/MPs, with or without suboptimal gentamicin treatment, but not for blank MPs, soluble AR-12, or suboptimal gentamicin alone. AR-12/MPs dramatically reduced the burden ofF. tularensisin infected human macrophages, in a manner similar to that of free AR-12. However,in vivo, AR-12/MPs significantly enhanced the survival ofF. tularensisSchuS4-infected mice compared to that seen with free AR-12. In combination with suboptimal gentamicin treatment, AR-12/MPs further improved the survival ofF. tularensisSchuS4-infected mice. These studies provide support for Ace-DEX-encapsulated AR-12 as a promising new therapeutic agent for tularemia.

scholarly journals Role of BrnQ1 and BrnQ2 in Branched-Chain Amino Acid Transport and Virulence in Staphylococcus aureus

2014 ◽  
Vol 83 (3) ◽  
pp. 1019-1029 ◽  
Author(s):  
Julienne C. Kaiser ◽  
Sameha Omer ◽  
Jessica R. Sheldon ◽  
Ian Welch ◽  
David E. Heinrichs
Keyword(s):  
Staphylococcus Aureus ◽  
Virulence Gene ◽  
Defined Medium ◽  
Infection Model ◽  
Content Type ◽  
Virulence Gene Expression ◽  
Branched Chain Amino Acid ◽  
Branched Chain

The branched-chain amino acids (BCAAs; Ile, Leu, and Val) not only are important nutrients for the growth ofStaphylococcus aureusbut also are corepressors for CodY, which regulates virulence gene expression, implicating BCAAs as an important link between the metabolic state of the cell and virulence. BCAAs are either synthesized intracellularly or acquired from the environment.S. aureusencodes three putative BCAA transporters, designated BrnQ1, BrnQ2, and BrnQ3; their functions have not yet been formally tested. In this study, we mutated all threebrnQparalogs so as to characterize their substrate specificities and their roles in growthin vitroandin vivo. We demonstrated that in the community-associated, methicillin-resistantS. aureus(CA-MRSA) strain USA300, BrnQ1 is involved in uptake of all three BCAAs, BrnQ2 transports Ile, and BrnQ3 does not have a significant role in BCAA transport under the conditions tested. Of the three, only BrnQ1 is essential for USA300 to grow in a chemically defined medium that is limited for Leu or Val. Interestingly, we observed that abrnQ2mutant grew better than USA300 in media limited for Leu and Val, owing to the fact that this mutation leads to overexpression ofbrnQ1. In a murine infection model, thebrnQ1mutant was attenuated, but in contrast,brnQ2mutants had significantly increased virulence compared to that of USA300, a phenotype we suggest is at least partially linked to enhancedin vivoscavenging of Leu and Val through BrnQ1. These data uncover a hitherto-undiscovered connection between nutrient acquisition and virulence in CA-MRSA.

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.

scholarly journals In Vitro and In Vivo Antibiotic Capacity of Two Host Defense Peptides

2020 ◽  
Vol 64 (7) ◽  
Author(s):  
Iván Arenas ◽  
Marco Antonio Ibarra ◽  
Felix L. Santana ◽  
Elba Villegas ◽  
Robert E. W. Hancock ◽  
...  
Keyword(s):  
Host Defense ◽  
Foot Ulcer ◽  
Diabetic Foot Ulcer ◽  
Immunomodulatory Activity ◽  
Host Defense Peptides ◽  
Content Type ◽  
Serovar Typhimurium ◽  
Infective Activity

ABSTRACT Two nonamidated host defense peptides named Pin2[G] and FA1 were evaluated against three types of pathogenic bacteria: two (Staphylococcus aureus UPD13 and Pseudomonas aeruginosa UPD3) isolated from diabetic foot ulcer patients, and another (Salmonella enterica serovar Typhimurium [ATCC 14028]) from a commercial collection. In vitro experiments showed that the antimicrobial performance of the synthetic peptides Pin2[G] and FA1 was modest, although FA1 was more effective than Pin2[G]. In contrast, Pin2[G] had superior in vivo anti-infective activity to FA1 in rabbit wound infections by the diabetic foot ulcer pathogens S. aureus UPD13 and P. aeruginosa UPD3. Indeed, Pin2[G] reduced bacterial colony counts of both S. aureus UPD13 and P. aeruginosa UPD3 by >100,000-fold after 48 to 72 h on skin wounds of infected rabbits, while in similar infected wounds, FA1 had no major effects at 72 to 96 h of treatment. Ceftriaxone was equally effective versus Pseudomonas but less effective versus S. aureus infections. Additionally, the two peptides were evaluated in mice against intragastrically inoculated S. enterica serovar Typhimurium (ATCC 14028). Only Pin2[G] at 0.56 mg/kg was effective in reducing systemic (liver) infection by >67-fold, equivalent to the effect of treatment with levofloxacin. Pin2[G] showed superior immunomodulatory activity in increasing chemokine production by a human bronchial cell line and suppressing polyinosinic-polycytidylic acid (poly[I:C])-induced proinflammatory IL-6 production. These data showed that the in vitro antimicrobial activity of these peptides was not correlated with their in vivo anti-infective activity and suggest that other factors such as immunomodulatory activity were more important.

scholarly journals In Salmonella enterica, the Gcn5-Related Acetyltransferase MddA (Formerly YncA) Acetylates Methionine Sulfoximine and Methionine Sulfone, Blocking Their Toxic Effects

2014 ◽  
Vol 197 (2) ◽  
pp. 314-325 ◽  
Author(s):  
Kristy L. Hentchel ◽  
Jorge C. Escalante-Semerena
Keyword(s):  
Salmonella Enterica ◽  
Physiological Role ◽  
Methionine Sulfoximine ◽  
Amino Acid Transporters ◽  
Content Type ◽  
Methionine Sulfone ◽  
Serovar Typhimurium ◽  
Acylation Reactions

Protein and small-molecule acylation reactions are widespread in nature. Many of the enzymes catalyzing acylation reactions belong to theGcn5-relatedN-acetyltransferase (GNAT; PF00583) family, named after the yeast Gcn5 protein. The genome ofSalmonella entericaserovar Typhimurium LT2 encodes 26 GNATs, 11 of which have no known physiological role. Here, we providein vivoandin vitroevidence for the role of the MddA (methioninederivativedetoxifier; formerly YncA) GNAT in the detoxification of oxidized forms of methionine, including methionine sulfoximine (MSX) and methionine sulfone (MSO). MSX and MSO inhibited the growth of anS. entericaΔmddAstrain unless glutamine or methionine was present in the medium. We used anin vitrospectrophotometric assay and mass spectrometry to show that MddA acetylated MSX and MSO. AnmddA+strain displayed biphasic growth kinetics in the presence of MSX and glutamine. Deletion of two amino acid transporters (GlnHPQ and MetNIQ) in a ΔmddAstrain restored growth in the presence of MSX. Notably, MSO was transported by GlnHPQ but not by MetNIQ. In summary, MddA is the mechanism used byS. entericato respond to oxidized forms of methionine, which MddA detoxifies by acetyl coenzyme A-dependent acetylation.

scholarly journals Abbreviated Pathway for Biosynthesis of 2-Thiouridine in Bacillus subtilis

2015 ◽  
Vol 197 (11) ◽  
pp. 1952-1962 ◽  
Author(s):  
Katherine A. Black ◽  
Patricia C. Dos Santos
Keyword(s):  
Escherichia Coli ◽  
Bacillus Subtilis ◽  
Cysteine Desulfurase ◽  
Content Type ◽  
E Coli ◽  
Wobble Position ◽  
Lysine Trna ◽  
Domains Of Life

ABSTRACTThe 2-thiouridine (s2U) modification of the wobble position in glutamate, glutamine, and lysine tRNA molecules serves to stabilize the anticodon structure, improving ribosomal binding and overall efficiency of the translational process. Biosynthesis of s2U inEscherichia colirequires a cysteine desulfurase (IscS), a thiouridylase (MnmA), and five intermediate sulfur-relay enzymes (TusABCDE). TheE. coliMnmA adenylates and subsequently thiolates tRNA to form the s2U modification.Bacillus subtilislacks IscS and the intermediate sulfur relay proteins, yet its genome contains a cysteine desulfurase gene,yrvO, directly adjacent tomnmA. The genomic synteny ofyrvOandmnmAcombined with the absence of the Tus proteins indicated a potential functionality of these proteins in s2U formation. Here, we provide evidence that theB. subtilisYrvO and MnmA are sufficient for s2U biosynthesis. A conditionalB. subtilisknockout strain showed that s2U abundance correlates with MnmA expression, andin vivocomplementation studies inE. coliIscS- or MnmA-deficient strains revealed the competency of these proteins in s2U biosynthesis.In vitroexperiments demonstrated s2U formation by YrvO and MnmA, and kinetic analysis established a partnership between theB. subtilisproteins that is contingent upon the presence of ATP. Furthermore, we observed that the slow-growth phenotype ofE. coliΔiscSand ΔmnmAstrains associated with s2U depletion is recovered byB. subtilis yrvOandmnmA. These results support the proposal that the involvement of a devoted cysteine desulfurase, YrvO, in s2U synthesis bypasses the need for a complex biosynthetic pathway by direct sulfur transfer to MnmA.IMPORTANCEThe 2-thiouridine (s2U) modification of the wobble position in glutamate, glutamine, and lysine tRNA is conserved in all three domains of life and stabilizes the anticodon structure, thus guaranteeing fidelity in translation. The biosynthesis of s2U inEscherichia colirequires seven proteins: the cysteine desulfurase IscS, the thiouridylase MnmA, and five intermediate sulfur-relay enzymes (TusABCDE).Bacillus subtilisand most Gram-positive bacteria lack a complete set of biosynthetic components. Interestingly, themnmAcoding sequence is located adjacent toyrvO, encoding a cysteine desulfurase. In this work, we provide evidence that theB. subtilisYrvO is able to transfer sulfur directly to MnmA. Both proteins are sufficient for s2U biosynthesis in a pathway independent of the one used inE. coli.

scholarly journals HilE Regulates HilD by Blocking DNA Binding in Salmonella enterica Serovar Typhimurium

2018 ◽  
Vol 200 (8) ◽  
Author(s):  
Jesse R. Grenz ◽  
Jessica E. Cott Chubiz ◽  
Pariyamon Thaprawat ◽  
James M. Slauch
Keyword(s):  
Systemic Disease ◽  
Environmental Parameters ◽  
Negative Regulator ◽  
Reporter System ◽  
Protein Activity ◽  
Content Type ◽  
Protein Protein Interaction ◽  
Serovar Typhimurium

ABSTRACT The Salmonella type three secretion system (T3SS), encoded in the Salmonella pathogenicity island 1 (SPI1) locus, mediates the invasion of the host intestinal epithelium. SPI1 expression is dependent upon three AraC-like regulators: HilD, HilC, and RtsA. These regulators act in a complex feed-forward loop to activate each other and hilA , which encodes the activator of the T3SS structural genes. HilD has been shown to be the major integration point of most signals known to activate the expression of the SPI1 T3SS, acting as a switch to control induction of the system. HilE is a negative regulator that acts upon HilD. Here we provide genetic and biochemical data showing that HilE specifically binds to HilD but not to HilC or RtsA. This protein-protein interaction blocks the ability of HilD to bind DNA as shown by both an in vivo reporter system and an in vitro gel shift assay. HilE does not affect HilD dimerization, nor does it control the stability of the HilD protein. We also investigated the role of HilE during the infection of mice using competition assays. Although deletion of hilE does not confer a phenotype, the hilE mutation does suppress the invasion defect conferred by loss of FliZ, which acts as a positive signal controlling HilD protein activity. Together, these data suggest that HilE functions to restrict low-level HilD activity, preventing premature activation of SPI1 until positive inputs reach a threshold required to fully induce the system. IMPORTANCE Salmonella is a leading cause of gastrointestinal and systemic disease throughout the world. The SPI1 T3SS is required for Salmonella to induce inflammatory diarrhea and to gain access to underlying tissue. A complex regulatory network controls expression of SPI1 in response to numerous physiological inputs. Most of these signals impinge primarily on HilD translation or activity. The system is triggered when HilD activity crosses a threshold that allows efficient activation of its own promoter. This threshold is set by HilE, which binds to HilD to prevent the inevitable minor fluctuations in HilD activity from inappropriately activating the system. The circuit also serves as a paradigm for systems that must integrate numerous environmental parameters to control regulatory output.

scholarly journals Role of Mouse Peptidoglycan Recognition Protein PGLYRP2 in the Innate Immune Response to Salmonella enterica Serovar Typhimurium InfectionIn Vivo

2012 ◽  
Vol 80 (8) ◽  
pp. 2645-2654 ◽  
Author(s):  
Jooeun Lee ◽  
Kaoru Geddes ◽  
Catherine Streutker ◽  
Dana J. Philpott ◽  
Stephen E. Girardin
Keyword(s):  
Salmonella Enterica ◽  
Fluorescent Protein ◽  
Intraepithelial Lymphocytes ◽  
Innate Immune ◽  
Th17 Response ◽  
Content Type ◽  
Serovar Typhimurium

ABSTRACTPeptidoglycan recognition proteins (PGRPs) are a family of innate pattern recognition molecules that bind bacterial peptidoglycan. While the role of PGRPs inDrosophilainnate immunity has been extensively studied, how the four mammalian PGRP proteins (PGLYRP1 to PGLYRP4) contribute to host defense against bacterial pathogensin vivoremains poorly understood. PGLYRP1, PGLYRP3, and PGLYRP4 are directly bactericidalin vitro, whereas PGLYRP2 is anN-acetylmuramyl-l-alanine amidase that cleaves peptidoglycan between the sugar backbone and the peptide stem. Because PGLYRP2 cleaves muramyl peptides detected by host peptidoglycan sensors Nod1 and Nod2, we speculated that PGLYRP2 may act as a modifier of Nod1/Nod2-dependent innate immune responses. We investigated the role of PGLYRP2 inSalmonella entericaserovar Typhimurium-induced colitis, which is regulated by Nod1/Nod2 through the induction of an early Th17 response. PGLYRP2 did not contribute to expression of Th17-associated cytokines, interleukin-22 (IL-22)-dependent antimicrobial proteins, or inflammatory cytokines. However, we found thatPglyrp2-deficient mice displayed significantly enhanced inflammation in the cecum at 72 h postinfection, reflected by increased polymorphonuclear leukocyte (PMN) infiltration and goblet cell depletion.Pglyrp2expression was also induced in the cecum ofSalmonella-infected mice, and expression of green fluorescent protein under control of thePglyrp2promoter was increased in discrete populations of intraepithelial lymphocytes. Lastly,Nod2−/−Pglyrp2−/−mice displayed increased susceptibility to infection at 24 h postinfection compared toPglyrp2−/−mice, which correlated with increased PMN infiltration and submucosal edema. Thus, PGLYRP2 plays a protective rolein vivoin the control ofS. Typhimurium infection through a Nod1/Nod2-independent mechanism.

scholarly journals Competition and Resilience between Founder and Introduced Bacteria in the Caenorhabditis elegans Gut

2011 ◽  
Vol 80 (3) ◽  
pp. 1288-1299 ◽  
Author(s):  
Cynthia Portal-Celhay ◽  
Martin J. Blaser
Keyword(s):  
Caenorhabditis Elegans ◽  
Wild Type ◽  
Content Type ◽  
E Coli ◽  
C Elegans ◽  
Serovar Typhimurium ◽  
Colonization Factors

The microbial communities that reside within the intestinal tract in vertebrates are complex and dynamic. In this report, we establish the utility ofCaenorhabditis elegansas a model system for identifying the factors that contribute to bacterial persistence and for host control of gut luminal populations. We found that for N2 worms grown on mixed lawns of bacteria,Salmonella entericaserovar Typhimurium substantially outcompetedEscherichia coli, even whenE. coliwas initially present at 100-fold-higher concentrations. To address whether innate immunity affects the competition, thedaf-2anddaf-16mutants were studied; their total gut bacterial levels reflect overall capacity for colonization, butSalmonellaoutcompetedE. colito an extent similar to wild-type worms. To address the role of virulence properties,SalmonellaΔspi-1Δspi-2was used to compete withE. coli. The net differential was significantly less than that for wild-typeSalmonella; thus,spi-1 spi-2encodesC. eleganscolonization factors. AnE. colistrain with repeatedin vivopassage had an enhanced ability to compete against anin vitro-passedE. colistrain and againstSalmonella. Our data provide evidence of active competition for colonization niches in theC. elegansgut, as determined by bacterial factors and subject toin vivoselection.

scholarly journals Cathelicidin Antimicrobial Peptide Expression Is Not Induced or Required for Bacterial Clearance during Salmonella enterica Infection of Human Monocyte-Derived Macrophages

2012 ◽  
Vol 80 (11) ◽  
pp. 3930-3938 ◽  
Author(s):  
Kristi L. Strandberg ◽  
Susan M. Richards ◽  
John S. Gunn
Keyword(s):  
Antimicrobial Peptide ◽  
Salmonella Enterica ◽  
Active Form ◽  
Human Monocyte ◽  
Content Type ◽  
Mutant Strains ◽  
Serovar Typhimurium ◽  
Proinflammatory Responses

ABSTRACTSalmonella entericaserovar Typhimurium is able to resist antimicrobial peptide killing by induction of the PhoP-PhoQ and PmrA-PmrB two-component systems and the lipopolysaccharide (LPS) modifications they mediate. Murine cathelin-related antimicrobial peptide (CRAMP) has been reported to inhibitS. Typhimurium growthin vitroandin vivo. We hypothesize that infection of human monocyte-derived macrophages (MDMs) withSalmonella entericaserovar Typhi andS. Typhimurium will induce human cathelicidin antimicrobial peptide (CAMP) production, and exposure to LL-37 (processed, active form of CAMP/hCAP18) will lead to upregulation of PmrAB-mediated LPS modifications and increased survivalin vivo. Unlike in mouse macrophages, in which CRAMP is upregulated during infection,campgene expression was not induced in human MDMs infected withS. Typhi orS. Typhimurium. Upon infection, intracellular levels of ΔphoPQ, ΔpmrAB, and PhoPcS. Typhi decreased over time but were not further inhibited by the vitamin D3-induced increase incampexpression. MDMs infected with wild-type (WT)S. Typhi orS. Typhimurium released similar levels of proinflammatory cytokines; however, the LPS modification mutant strains dramatically differed in MDM-elicited cytokine levels. Overall, these findings indicate thatcampis not induced duringSalmonellainfection of MDMs nor is key toSalmonellaintracellular clearance. However, the cytokine responses from MDMs infected with WT or LPS modification mutant strains differ significantly, indicating a role for LPS modifications in altering the host inflammatory response. Our findings also suggest thatS. Typhi andS. Typhimurium elicit different proinflammatory responses from MDMs, despite being capable of adding similar modifications to their LPS structures.

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