scholarly journals Selection for a CEACAM Receptor-Specific Binding Phenotype during Neisseria gonorrhoeae Infection of the Human Genital Tract

2015 ◽  
Vol 83 (4) ◽  
pp. 1372-1383 ◽  
Author(s):  
Anna Sintsova ◽  
Henry Wong ◽  
Kelly S. MacDonald ◽  
Rupert Kaul ◽  
Mumtaz Virji ◽  
...  
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Genital Tract ◽  
Specific Binding ◽  
Natural Infection ◽  
Clinical Specimen ◽  
Health Concern ◽  
Phase Variable ◽  
Content Type ◽  
Selection For

Infections byNeisseria gonorrhoeaeare increasingly common, are often caused by antibiotic-resistant strains, and can result in serious and lasting sequelae, prompting the reemergence of gonococcal disease as a leading global health concern.N. gonorrhoeaeis a human-restricted pathogen that primarily colonizes urogenital mucosal surfaces. Disease progression varies greatly between the sexes: men usually present with symptomatic infection characterized by a painful purulent urethral discharge, while in women, the infection is often asymptomatic, with the most severe pathology occurring when the bacteria ascend from the lower genital tract into the uterus and fallopian tubes. Classical clinical studies demonstrated that clinically infectious strains uniformly express Opa adhesins; however, their specificities were unknown at the time. Whilein vitrostudies have since identified CEACAM proteins as the primary target of Opa proteins, the gonococcal specificity for this human family of receptors has not been addressed in the context of natural infection. In this study, we characterize a collection of low-passage-number clinical-specimen-derivedN. gonorrhoeaeisolates for Opa expression and assess their CEACAM-binding profiles. We report markedin vivoselection for expression of phase-variable Opa proteins that bind CEACAM1 and CEACAM5 but selection against expression of Opa variants that bind to the neutrophil-restricted decoy receptor CEACAM3. This is the first study showing phenotypic selection for distinct CEACAM-binding phenotypesin vivo, and it supports the opposing functions of CEACAMs that facilitate infection versus driving inflammation within the genital tract.

scholarly journals Lipid A’s Structure Mediates Neisseria gonorrhoeae Fitness during Experimental Infection of Mice and Men

mBio ◽  
2013 ◽  
Vol 4 (6) ◽  
Author(s):  
Marcia M. Hobbs ◽  
James E. Anderson ◽  
Jacqueline T. Balthazar ◽  
Justin L. Kandler ◽  
Russell W. Carlson ◽  
...  
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Genital Tract ◽  
Lipid A ◽  
Female Genital Tract ◽  
Treatment Strategies ◽  
Wild Type ◽  
Genital Tract Infection ◽  
Content Type

ABSTRACT Phosphoethanolamine (PEA) on Neisseria gonorrhoeae lipid A influences gonococcal inflammatory signaling and susceptibility to innate host defenses in in vitro models. Here, we evaluated the role of PEA-decorated gonococcal lipid A in competitive infections in female mice and in male volunteers. We inoculated mice and men with mixtures of wild-type N. gonorrhoeae and an isogenic mutant that lacks the PEA transferase, LptA. LptA production conferred a marked survival advantage for wild-type gonococci in the murine female genital tract and in the human male urethra. Our studies translate results from test tube to animal model and into the human host and demonstrate the utility of the mouse model for studies of virulence factors of the human-specific pathogen N. gonorrhoeae that interact with non-host-restricted elements of innate immunity. These results validate the use of gonococcal LptA as a potential target for development of novel immunoprophylactic strategies or antimicrobial treatments. IMPORTANCE Gonorrhea is one of the most common bacterial sexually transmitted infections, and increasing antibiotic resistance threatens the use of currently available antimicrobial therapies. In this work, encompassing in vitro studies and in vivo studies of animal and human models of experimental genital tract infection, we document the importance of lipid A’s structure, mediated by a single bacterial enzyme, LptA, in enhancing the fitness of Neisseria gonorrhoeae. The results of these studies suggest that novel agents targeting LptA may offer urgently needed prevention or treatment strategies for gonorrhea.

scholarly journals Synthetic DNA Delivery of an Optimized and Engineered Monoclonal Antibody Provides Rapid and Prolonged Protection against Experimental Gonococcal Infection

mBio ◽  
2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Elizabeth M. Parzych ◽  
Sunita Gulati ◽  
Bo Zheng ◽  
Mamadou A. Bah ◽  
Sarah T. C. Elliott ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Neisseria Gonorrhoeae ◽  
Bactericidal Activity ◽  
Complement Activation ◽  
Natural Infection ◽  
Effective Vaccine ◽  
Content Type ◽  
Synthetic Dna ◽  
Human Igg1

ABSTRACT Monoclonal antibody (MAb) 2C7 recognizes a lipooligosaccharide epitope expressed by most clinical Neisseria gonorrhoeae isolates and mediates complement-dependent bactericidal activity. We recently showed that a recombinant human IgG1 chimeric variant of MAb 2C7 containing an E430G Fc modification (2C7_E430G), which enhances complement activation, outperformed the parental MAb 2C7 (2C7_WT) in vivo. Because natural infection with N. gonorrhoeae often does not elicit protective immunity and reinfections are common, approaches that prolong bacterial control in vivo are of great interest. Advances in DNA-based approaches have demonstrated the combined benefit of genetic engineering, formulation optimizations, and facilitated delivery via CELLECTRA-EP technology, which can induce robust in vivo expression of protective DNA-encoded monoclonal antibodies (DMAbs) with durable serum activity relative to traditional recombinant MAb therapies. Here, we created optimized 2C7-derived DMAbs encoding the parental Fc (2C7_WT) or complement-enhancing Fc variants (2C7_E430G and 2C7_E345K). 2C7 DMAbs were rapidly generated and detected throughout the 4-month study. While all complement-engaging 2C7 variants facilitated rapid clearance following primary N. gonorrhoeae challenge (day 8 after DMAb administration), the complement-enhancing 2C7_E430G variant demonstrated significantly higher potency against mice rechallenged 65 days after DMAb administration. Passive intravenous transfer of in vivo-produced, purified 2C7 DMAbs confirmed the increased potency of the complement-enhancing variants. This study highlights the ability of the DMAb platform to launch the in vivo production of antibodies engineered to promote and optimize downstream innate effector mechanisms such as complement-mediated killing, leading to hastened bacterial elimination. IMPORTANCE Neisseria gonorrhoeae has become resistant to most antibiotics in clinical use. Currently, there is no safe and effective vaccine against gonorrhea. Measures to prevent the spread of gonorrhea are a global health priority. A monoclonal antibody (MAb) called 2C7, directed against a lipooligosaccharide glycan epitope expressed by most clinical isolates, displays complement-dependent bactericidal activity and hastens clearance of gonococcal vaginal colonization in mice. Fc mutations in a human IgG1 chimeric version of MAb 2C7 further enhance complement activation, and the resulting MAb displays greater activity than wild-type MAb 2C7 in vivo. Here, we utilized a DNA-encoded MAb (DMAb) construct designed to launch production and assembly of “complement-enhanced” chimeric MAb 2C7 in vivo. The ensuing rapid and sustained MAb 2C7 expression attenuated gonococcal colonization in mice at 8 days as well as 65 days postadministration. The DMAb system may provide an effective, economical platform to deliver MAbs for durable protection against gonorrhea.

scholarly journals Opacity Proteins Increase Neisseria gonorrhoeae Fitness in the Female Genital Tract Due to a Factor under Ovarian Control

2010 ◽  
Vol 78 (4) ◽  
pp. 1629-1641 ◽  
Author(s):  
Jessica G. Cole ◽  
Nanette B. Fulcher ◽  
Ann E. Jerse
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Reproductive Cycle ◽  
Genital Tract ◽  
Female Genital Tract ◽  
Phase Variable ◽  
Ovariectomized Mice ◽  
Selection Pattern ◽  
Strain Fa1090 ◽  
Female Genital

ABSTRACT The neisserial opacity (Opa) proteins are a family of antigenically distinct outer membrane proteins that undergo phase-variable expression. Opa+ variants of Neisseria gonorrhoeae strain FA1090 are selected in a cyclical pattern from the lower genital tract of estradiol-treated mice. Here we show that cyclical recovery of Opa+ gonococci does not occur in ovariectomized mice; therefore, the reproductive cycle plays a role in the selection kinetics in vivo. As predicted by the selection pattern shown by wild-type gonococci, we demonstrated that a constitutive Opa-expressing strain was more fit than an Opa-deficient mutant in the early and late phases of infection. We found no evidence that Opa-mediated colonization selects for Opa+ variants during murine infection based on adherence assays with cultured murine epithelial cells. We also tested the hypothesis that complement selects for Opa protein expression during infection. Although some Opa+ variants of a serum-sensitive derivative of strain FA1090 were more resistant to the bactericidal activity of normal human serum, selection for Opa expression was not abrogated in C3-depleted mice. Finally, as previously reported, Opa+ gonococci were more sensitive to serine proteases. Thus, proteases or protease inhibitors may contribute to the observed in vivo selection pattern. We concluded that Opa proteins promote persistence of N. gonorrhoeae in the female genital tract and that opa gene phase variation allows gonococci to evade or capitalize upon unidentified host factors of the mammalian reproductive cycle. This work revealed an intimate interaction between pathogen and host and provides evidence that hormonally related factors shape bacterial adaptation.

scholarly journals Phase-Variable Expression oflptAModulates the Resistance of Neisseria gonorrhoeae to Cationic Antimicrobial Peptides

2014 ◽  
Vol 58 (7) ◽  
pp. 4230-4233 ◽  
Author(s):  
Justin L. Kandler ◽  
Sandeep J. Joseph ◽  
Jacqueline T. Balthazar ◽  
Vijaya Dhulipala ◽  
Timothy D. Read ◽  
...  
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Antimicrobial Peptides ◽  
High Frequency ◽  
Lipid A ◽  
Bacterial Resistance ◽  
Phase Variable ◽  
Cationic Antimicrobial Peptides ◽  
Content Type ◽  
Variable Expression

ABSTRACTPhosphoethanolamine (PEA) decoration of lipid A produced byNeisseria gonorrhoeaehas been linked to bacterial resistance to cationic antimicrobial peptides/proteins (CAMPs) andin vivofitness during experimental infection. We now report that thelptAgene, which encodes the PEA transferase responsible for this decoration, is in an operon and that high-frequency mutation in a polynucleotide repeat withinlptAcan influence gonococcal resistance to CAMPs.

scholarly journals α-2,3-Sialyltransferase Expression Level Impacts the Kinetics of Lipooligosaccharide Sialylation, Complement Resistance, and the Ability of Neisseria gonorrhoeae to Colonize the Murine Genital Tract

mBio ◽  
2015 ◽  
Vol 6 (1) ◽  
Author(s):  
Lisa A. Lewis ◽  
Sunita Gulati ◽  
Elizabeth Burrowes ◽  
Bo Zheng ◽  
Sanjay Ram ◽  
...  
Keyword(s):  
Sialic Acid ◽  
Neisseria Gonorrhoeae ◽  
Neisseria Meningitidis ◽  
Genital Tract ◽  
Ex Vivo ◽  
Factor H ◽  
Novel Therapies ◽  
Content Type ◽  
Expression Levels

ABSTRACT Neisseria meningitidisandNeisseria gonorrhoeaemodify the terminal lacto-N-neotetraose moiety of their lipooligosaccharide (LOS) with sialic acid. N. gonorrhoeae LOS sialylation blocks killing by complement, which is mediated at least in part by enhanced binding of the complement inhibitor factor H (FH). The role of LOS sialylation in resistance of N. meningitidis to serum killing is less well defined. Sialylation in each species is catalyzed by the enzyme LOS α-2,3-sialyltransferase (Lst). Previous studies have shown increased Lst activity in N. gonorrhoeae compared to N. meningitidis due to an ~5-fold increase inlsttranscription. Using isogenic N. gonorrhoeae strains engineered to express gonococcallstfrom either the N. gonorrhoeae or N. meningitidislstpromoter, we show that decreased expression oflst(driven by the N. meningitidis promoter) reduced LOS sialylation as determined by less incorporation of tritium-labeled cytidine monophospho-N-acetylneuraminic acid (CMP-NANA; the donor molecule for sialic acid). Diminished LOS sialylation resulted in reduced rates of FH binding and increased pathway activation compared to N. gonorrhoeae promoter-drivenlstexpression. The N. meningitidislstpromoter generated sufficient Lst to sialylate N. gonorrhoeae LOSin vivo, and the level of sialylation after 24 h in the mouse genital tract was sufficient to mediate resistance to human serumex vivo. Despite demonstrable LOS sialylationin vivo, gonococci harboring the N. meningitidislstpromoter were outcompeted by those with the N. gonorrhoeaelstpromoter during coinfection of the vaginal tract of estradiol-treated mice. These data highlight the importance of highlstexpression levels for gonococcal pathogenesis.IMPORTANCE Neisseria gonorrhoeaehas become resistant to nearly every therapeutic antibiotic used and is listed as an “urgent threat” by the Centers for Disease Control and Prevention. Novel therapies are needed to combat drug-resistant N. gonorrhoeae. Gonococci express an α-2,3-sialyltransferase (Lst) that can scavenge sialic acid from the host and use it to modify lipooligosaccharide (LOS). Sialylation of gonococcal LOS converts serum-sensitive strains to serum resistance, decreases antibody binding, and combats killing by neutrophils and antimicrobial peptides. Mutant N. gonorrhoeae that lack Lst (cannot sialylate LOS) are attenuated in a mouse model. Lst expression levels differ among N. gonorrhoeae strains, and N. gonorrhoeae typically expresses more Lst thanNeisseria meningitidis. Here we examined the significance of differentiallstexpression levels and determined that the level of LOS sialylation is critical to the ability of N. gonorrhoeae to combat the immune system and survive in an animal model. LOS sialylation may be an ideal target for novel therapies.

scholarly journals Could Dampening Expression of theNeisseria gonorrhoeaemtrCDE-Encoded Efflux Pump Be a Strategy To Preserve Currently or Resurrect Formerly Used Antibiotics To Treat Gonorrhea?

mBio ◽  
2019 ◽  
Vol 10 (4) ◽  
Author(s):  
Shaochun Chen ◽  
Kristie L. Connolly ◽  
Corinne Rouquette-Loughlin ◽  
Alexander D’Andrea ◽  
Ann E. Jerse ◽  
...  
Keyword(s):  
Genital Tract ◽  
Efflux Pump ◽  
Health Concern ◽  
Third Generation ◽  
Global Public Health ◽  
Beta Lactam ◽  
Beta Lactams ◽  
Genital Tract Infection ◽  
Infected Female ◽  
Content Type

ABSTRACTNeisseria gonorrhoeaehas developed resistance to every antibiotic introduced for treatment of gonorrhea since 1938, and concern now exists that gonorrheal infections may become refractory to all available antibiotics approved for therapy. The current recommended dual antibiotic treatment regimen of ceftriaxone (CRO) and azithromycin (AZM) is threatened with the emergence of gonococcal strains displaying resistance to one or both of these antibiotics. Non-beta-lactamase resistance to penicillin and third-generation cephalosporins, as well as low-level AZM resistance expressed by gonococci, requires overexpression of themtrCDE-encoded efflux pump, which in wild-type (WT) strains is subject to transcriptional repression by MtrR. Since earlier studies showed that loss of MtrCDE renders gonococci hypersusceptible to beta-lactams and macrolides, we hypothesized that transcriptional dampening ofmtrCDEwould render an otherwise resistant strain susceptible to these antibiotics as assessed by antibiotic susceptibility testing and during experimental infection. In order to test this hypothesis, we ectopically expressed a WT copy of themtrRgene, which encodes the repressor of themtrCDEefflux pump operon, inN. gonorrhoeaestrain H041, the first reported gonococcal strain to cause a third-generation-cephalosporin-resistant infection. We now report that MtrR production can repress the expression ofmtrCDE, increase antimicrobial susceptibilityin vitro, and enhance beta-lactam efficacy in eliminating gonococci as assessed in a female mouse model of lower genital tract infection. We propose that strategies that target the MtrCDE efflux pump should be considered to counteract the increasing problem of antibiotic-resistant gonococci.IMPORTANCEThe emergence of gonococcal strains resistant to past or currently used antibiotics is a global public health concern, given the estimated 78 million infections that occur annually. The dearth of new antibiotics to treat gonorrhea demands that alternative curative strategies be considered to counteract antibiotic resistance expressed by gonococci. Herein, we show that decreased expression of a drug efflux pump that participates in gonococcal resistance to antibiotics can increase gonococcal susceptibility to beta-lactams and macrolides under laboratory conditions, as well as improve antibiotic-mediated clearance of gonococci from the genital tract of experimentally infected female mice.

scholarly journals The Lst Sialyltransferase of Neisseria gonorrhoeae Can Transfer Keto-Deoxyoctanoate as the Terminal Sugar of Lipooligosaccharide: a Glyco-Achilles Heel That Provides a New Strategy for Vaccines to Prevent Gonorrhea

mBio ◽  
2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Freda E.-C. Jen ◽  
Margaret R. Ketterer ◽  
Evgeny A. Semchenko ◽  
Christopher J. Day ◽  
Kate L. Seib ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Neisseria Gonorrhoeae ◽  
Phase Variation ◽  
Multidrug Resistant ◽  
Content Type ◽  
Acetylneuraminic Acid ◽  
New Strategy ◽  
Opsonophagocytic Killing ◽  
Further Development

ABSTRACT The lipooligosaccharide (LOS) of Neisseria gonorrhoeae plays key roles in pathogenesis and is composed of multiple possible glycoforms. These glycoforms are generated by the process of phase variation and by differences in the glycosyltransferase gene content of particular strains. LOS glycoforms of N. gonorrhoeae can be terminated with an N-acetylneuraminic acid (Neu5Ac), which imparts resistance to the bactericidal activity of serum. However, N. gonorrhoeae cannot synthesize the CMP-Neu5Ac required for LOS biosynthesis and must acquire it from the host. In contrast, Neisseria meningitidis can synthesize endogenous CMP-Neu5Ac, the donor molecule for Neu5Ac, which is a component of some meningococcal capsule structures. Both species have an almost identical LOS sialyltransferase, Lst, that transfers Neu5Ac from CMP-Neu5Ac to the terminus of LOS. Lst is homologous to the LsgB sialyltransferase of nontypeable Haemophilus influenzae (NTHi). Studies in NTHi have demonstrated that LsgB can transfer keto-deoxyoctanoate (KDO) from CMP-KDO to the terminus of LOS in place of Neu5Ac. Here, we show that Lst can also transfer KDO to LOS in place of Neu5Ac in both N. gonorrhoeae and N. meningitidis. Consistent with access to the pool of CMP-KDO in the cytoplasm, we present data indicating that Lst is localized in the cytoplasm. Lst has previously been reported to be localized on the outer membrane. We also demonstrate that KDO is expressed as a terminal LOS structure in vivo in samples from infected women and further show that the anti-KDO monoclonal antibody 6E4 can mediate opsonophagocytic killing of N. gonorrhoeae. Taken together, these studies indicate that KDO expressed on gonococcal LOS represents a new antigen for the development of vaccines against gonorrhea. IMPORTANCE The emergence of multidrug-resistant N. gonorrhoeae strains that are resistant to available antimicrobials is a current health emergency, and no vaccine is available to prevent gonococcal infection. Lipooligosaccharide (LOS) is one of the major virulence factors of N. gonorrhoeae. The sialic acid N-acetylneuraminic acid (Neu5Ac) is present as the terminal glycan on LOS in N. gonorrhoeae. In this study, we made an unexpected discovery that KDO can be incorporated as the terminal glycan on LOS of N. gonorrhoeae by the alpha-2,3-sialyltransferase Lst. We showed that N. gonorrhoeae express KDO on LOS in vivo and that the KDO-specific monoclonal antibody 6E4 can direct opsonophagocytic killing of N. gonorrhoeae. These data support further development of KDO-LOS structures as vaccine antigens for the prevention of infection by N. gonorrhoeae.

scholarly journals Growth of Neisseria gonorrhoeae in the Female Mouse Genital Tract Does Not Require the Gonococcal Transferrin or Hemoglobin Receptors and May Be Enhanced by Commensal Lactobacilli

2002 ◽  
Vol 70 (5) ◽  
pp. 2549-2558 ◽  
Author(s):  
Ann E. Jerse ◽  
Emily T. Crow ◽  
Amy N. Bordner ◽  
Ishrat Rahman ◽  
Cynthia Nau Cornelissen ◽  
...  
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Genital Tract ◽  
Female Genital Tract ◽  
Iron Chelator ◽  
Iron Store ◽  
Human Transferrin ◽  
Mucosal Surfaces ◽  
Phase Variants

ABSTRACT Neisseria gonorrhoeae is capable of utilizing a variety of iron sources in vitro, including human transferrin, human lactoferrin, hemoglobin, hemoglobin-haptoglobin complexes, heme, and heterologous siderophores. Transferrin has been implicated as a critical iron store for N. gonorrhoeae in the human male urethra. The demonstration that gonococci can infect the lower genital tracts of estradiol-treated BALB/c mice in the absence of human transferrin, however, suggests that other usable iron sources are present in the murine genital tract. Here we demonstrate that gonococcal transferrin and hemoglobin receptor mutants are not attenuated in mice, thereby ruling out transferrin and hemoglobin as essential for murine infection. An increased frequency of phase variants with the hemoglobin receptor “on” (Hg+) occurred in ca. 50% of infected mice; this increase was temporally associated with an influx of neutrophils and detectable levels of hemoglobin in the vagina, suggesting that the presence of hemoglobin in inflammatory exudates selects for Hg+ phase variants during infection. We also demonstrate that commensal lactobacilli support the growth of N. gonorrhoeae in vitro unless an iron chelator is added to the medium. We hypothesize that commensal lactobacilli may enhance growth of gonococci in vivo by promoting the solubilization of iron on mucosal surfaces through the production of metabolic intermediates. Finally, transferrin-binding lipoprotein (TbpB) was detected on gonococci in vaginal smears, suggesting that although gonococci replicate within the genital tracts of mice, they may be sufficiently iron-stressed to express iron-repressible proteins. In summary, these studies support the potential role of nontransferrin, nonhemoglobin iron sources during gonococcal infection of the female genital tract.

scholarly journals Novel Genes Related to Ceftriaxone Resistance Found among Ceftriaxone-Resistant Neisseria gonorrhoeae Strains SelectedIn Vitro

2016 ◽  
Vol 60 (4) ◽  
pp. 2043-2051 ◽  
Author(s):  
Zijian Gong ◽  
Wei Lai ◽  
Min Liu ◽  
Zhengshuang Hua ◽  
Yayin Sun ◽  
...  
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Resistance Mechanisms ◽  
Health Concern ◽  
Cross Resistance ◽  
Growth Time ◽  
Single Mutation ◽  
Global Public Health ◽  
Differential Analysis ◽  
Content Type ◽  
Genes Encoding

ABSTRACTThe emergence of ceftriaxone-resistantNeisseria gonorrhoeaeis currently a global public health concern. However, the mechanism of ceftriaxone resistance is not yet fully understood. To investigate the potential genes related to ceftriaxone resistance inNeisseria gonorrhoeae, we subcultured six gonococcal strains with increasing concentrations of ceftriaxone and isolated the strains that became resistant. After analyzing several frequently reported genes involved in ceftriaxone resistance, we found only a single mutation inpenA(A501V). However, differential analysis of the genomes and transcriptomes between pre- and postselection strains revealed many other mutated genes as well as up- and downregulated genes. Transformation of the mutatedpenAgene into nonresistant strains increased the MIC between 2.0- and 5.3-fold, and transformation of mutatedftsXincreased the MIC between 3.3- and 13.3-fold. Genes encoding the ABC transporters FarB, Tfq, Hfq, and ExbB were overexpressed, whilepilM,pilN, andpilQwere downregulated. Furthermore, the resistant strain developed cross-resistance to penicillin and cefuroxime, had an increased biochemical metabolic rate, and presented fitness defects such as prolonged growth time and downregulated PilMNQ. In conclusion, antimicrobial pressure could result in the emergence of ceftriaxone resistance, and the evolution of resistance ofNeisseria gonorrhoeaeto ceftriaxone is a complicated process at both the pretranscriptional and posttranscriptional levels, involving several resistance mechanisms of increased efflux and decreased entry.

scholarly journals Coxiella burnetii Interaction with Neutrophils and MacrophagesIn Vitroand in SCID Mice following Aerosol Infection

2013 ◽  
Vol 81 (12) ◽  
pp. 4604-4614 ◽  
Author(s):  
Alexandra Elliott ◽  
Ying Peng ◽  
Guoquan Zhang
Keyword(s):  
Immune Response ◽  
Coxiella Burnetii ◽  
Q Fever ◽  
Natural Infection ◽  
Scid Mice ◽  
Innate Immune ◽  
Content Type ◽  
Aerosol Infection

ABSTRACTCoxiella burnetiiis an obligate intracellular bacterium that causes acute and chronic Q fever in humans. Human Q fever is mainly transmitted by aerosol infection. However, there is a fundamental gap in the knowledge regarding the mechanisms of pulmonary immunity againstC. burnetiiinfection. This study focused on understanding the interaction betweenC. burnetiiand innate immune cellsin vitroandin vivo. Both virulentC. burnetiiNine Mile phase I (NMI) and avirulent Nine Mile phase II (NMII) were able to infect neutrophils, while the infection rates were lower than 29%, suggesting thatC. burnetiican infect neutrophils, but infection is limited. Interestingly,C. burnetiiinside neutrophils can infect and replicate within macrophages, suggesting that neutrophils cannot killC. burnetiiandC. burnetiimay be using infection of neutrophils as an evasive strategy to infect macrophages. To elucidate the mechanisms of the innate immune response toC. burnetiinatural infection, SCID mice were exposed to aerosolizedC. burnetii. Surprisingly, neutrophil influx into the lungs was delayed until day 7 postinfection in both NMI- and NMII-infected mice. This result suggests that neutrophils may play a unique role in the early immune response against aerosolizedC. burnetii. Studying the interaction betweenC. burnetiiand the innate immune system can provide a model system for understanding how the bacteria evade early immune responses to cause infection.

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