scholarly journals Yersinia pestis caf1 Variants and the Limits of Plague Vaccine Protection

2008 ◽  
Vol 76 (5) ◽  
pp. 2025-2036 ◽  
Author(s):  
Lauriane E. Quenee ◽  
Claire A. Cornelius ◽  
Nancy A. Ciletti ◽  
Derek Elli ◽  
Olaf Schneewind
Keyword(s):  
Immune Responses ◽  
Yersinia Pestis ◽  
Protective Immunity ◽  
Wild Type ◽  
Vaccine Protection ◽  
Subunit Vaccines ◽  
Humoral Immune ◽  
Humoral Immune Responses ◽  
Plague Vaccine ◽  
Highly Virulent

ABSTRACT Yersinia pestis, the highly virulent agent of plague, is a biological weapon. Strategies that prevent plague have been sought for centuries, and immunization with live, attenuated (nonpigmented) strains or subunit vaccines with F1 (Caf1) antigen is considered effective. We show here that immunization with live, attenuated strains generates plague-protective immunity and humoral immune responses against F1 pilus antigen and LcrV. Y. pestis variants lacking caf1 (F1 pili) are not only fully virulent in animal models of bubonic and pneumonic plague but also break through immune responses generated with live, attenuated strains or F1 subunit vaccines. In contrast, immunization with purified LcrV, a protein at the tip of type III needles, generates protective immunity against the wild-type and the fully virulent caf1 mutant strain, in agreement with the notion that LcrV can elicit vaccine protection against both types of virulent plague strains.

scholarly journals Yersinia pestis IS1541 Transposition Provides for Escape from Plague Immunity

2009 ◽  
Vol 77 (5) ◽  
pp. 1807-1816 ◽  
Author(s):  
Claire A. Cornelius ◽  
Lauriane E. Quenee ◽  
Derek Elli ◽  
Nancy A. Ciletti ◽  
Olaf Schneewind
Keyword(s):  
Immune Responses ◽  
Yersinia Pestis ◽  
Protective Immunity ◽  
Infectious Agent ◽  
Inhibitory Effect ◽  
Effector Proteins ◽  
Host Cells ◽  
Specific Antibodies ◽  
Humoral Immune ◽  
Humoral Immune Responses

ABSTRACTYersinia pestisis perhaps the most feared infectious agent due to its ability to cause epidemic outbreaks of plague disease in animals and humans with high mortality. Plague infections elicit strong humoral immune responses against the capsular antigen (fraction 1 [F1]) ofY. pestis, and F1-specific antibodies provide protective immunity. Here we asked whetherY. pestisgenerates mutations that enable bacterial escape from protective immunity and isolated a variant with an IS1541insertion incaf1Aencoding the F1 outer membrane usher. Thecaf1A::IS1541insertion prevented assembly of F1 pili and provided escape from plague immunity via F1-specific antibodies without a reduction in virulence in mouse models of bubonic or pneumonic plague. F1-specific antibodies interfere withY. pestistype III transport of effector proteins into host cells, an inhibitory effect that was overcome by thecaf1A::IS1541insertion. These findings suggest a model in which IS1541insertion intocaf1Aprovides for reversible changes in envelope structure, enablingY. pestisto escape from adaptive immune responses and plague immunity.

scholarly journals Correlates of Immune Protection following Cutaneous Immunization with an Attenuated Burkholderia pseudomallei Vaccine

2013 ◽  
Vol 81 (12) ◽  
pp. 4626-4634 ◽  
Author(s):  
Ediane B. Silva ◽  
Andrew Goodyear ◽  
Marjorie D. Sutherland ◽  
Nicole L. Podnecky ◽  
Mercedes Gonzalez-Juarrero ◽  
...  
Keyword(s):  
Immune Responses ◽  
Vaccine Strain ◽  
Protective Immunity ◽  
Burkholderia Pseudomallei ◽  
Partial Protection ◽  
Content Type ◽  
Humoral Immune ◽  
Humoral Immune Responses ◽  
Immune Correlates ◽  
Draining Lymph Nodes

ABSTRACTInfections with the Gram-negative bacteriumBurkholderia pseudomallei(melioidosis) are associated with high mortality, and there is currently no approved vaccine to prevent the development of melioidosis in humans. Infected patients also do not develop protective immunity to reinfection, and some individuals will develop chronic, subclinical infections withB. pseudomallei. At present, our understanding of what constitutes effective protective immunity againstB. pseudomalleiinfection remains incomplete. Therefore, we conducted a study to elucidate immune correlates of vaccine-induced protective immunity against acuteB. pseudomalleiinfection. BALB/c and C57BL/6 mice were immunized subcutaneously with a highly attenuated, Select Agent-excludedpurMdeletion mutant ofB. pseudomallei(strain Bp82) and then subjected to intranasal challenge with virulentB. pseudomalleistrain 1026b. Immunization with Bp82 generated significant protection from challenge withB. pseudomallei, and protection was associated with a significant reduction in bacterial burden in lungs, liver, and spleen of immunized mice. Humoral immunity was critically important for vaccine-induced protection, as mice lacking B cells were not protected by immunization and serum from Bp82-vaccinated mice could transfer partial protection to nonvaccinated animals. In contrast, vaccine-induced protective immunity was found to be independent of both CD4 and CD8 T cells. Tracking studies demonstrated uptake of the Bp82 vaccine strain predominately by neutrophils in vaccine-draining lymph nodes and by smaller numbers of dendritic cells (DC) and monocytes. We concluded that protection following cutaneous immunization with a live attenuatedBurkholderiavaccine strain was dependent primarily on generation of effective humoral immune responses.

scholarly journals Recombinant Vesicular Stomatitis Virus Vectors Expressing Herpes Simplex Virus Type 2 gD Elicit Robust CD4+ Th1 Immune Responses and Are Protective in Mouse and Guinea Pig Models of Vaginal Challenge

2006 ◽  
Vol 80 (9) ◽  
pp. 4447-4457 ◽  
Author(s):  
Robert J. Natuk ◽  
David Cooper ◽  
Min Guo ◽  
Priscilla Calderon ◽  
Kevin J. Wright ◽  
...  
Keyword(s):  
Herpes Simplex ◽  
Immune Responses ◽  
Vesicular Stomatitis Virus ◽  
Guinea Pigs ◽  
Wild Type ◽  
Humoral Immune ◽  
Humoral Immune Responses ◽  
Vesicular Stomatitis ◽  
Simplex Virus

ABSTRACT Recombinant vesicular stomatitis virus (rVSV) vectors offer an attractive approach for the induction of robust cellular and humoral immune responses directed against human pathogen target antigens. We evaluated rVSV vectors expressing full-length glycoprotein D (gD) from herpes simplex virus type 2 (HSV-2) in mice and guinea pigs for immunogenicity and protective efficacy against genital challenge with wild-type HSV-2. Robust Th1-polarized anti-gD immune responses were demonstrated in the murine model as measured by induction of gD-specific cytotoxic T lymphocytes and increased gamma interferon expression. The isotype makeup of the serum anti-gD immunoglobulin G (IgG) response was consistent with the presence of a Th1-CD4+ anti-gD response, characterized by a high IgG2a/IgG1 IgG subclass ratio. Functional anti-HSV-2 neutralizing serum antibody responses were readily demonstrated in both guinea pigs and mice that had been immunized with rVSV-gD vaccines. Furthermore, guinea pigs and mice were prophylactically protected from genital challenge with high doses of wild-type HSV-2. In addition, guinea pigs were highly protected against the establishment of latent infection as evidenced by low or absent HSV-2 genome copies in dorsal root ganglia after virus challenge. In summary, rVSV-gD vectors were successfully used to elicit potent anti-gD Th1-like cellular and humoral immune responses that were protective against HSV-2 disease in guinea pigs and mice.

scholarly journals Enhanced Susceptibility to Citrobacter rodentium Infection in MicroRNA-155-Deficient Mice

2012 ◽  
Vol 81 (3) ◽  
pp. 723-732 ◽  
Author(s):  
Simon Clare ◽  
Victoria John ◽  
Alan W. Walker ◽  
Jennifer L. Hill ◽  
Cei Abreu-Goodger ◽  
...  
Keyword(s):  
Immune Responses ◽  
Bacterial Pathogen ◽  
Citrobacter Rodentium ◽  
Wild Type ◽  
Content Type ◽  
Humoral Immune ◽  
Humoral Immune Responses ◽  
Control Gene Expression ◽  
Gastrointestinal Tissue ◽  
Deficient Mice

ABSTRACTMicroRNAs (miRNAs) are small noncoding molecules that control gene expression posttranscriptionally, with microRNA-155 (miR-155) one of the first to be implicated in immune regulation. Here, we show that miR-155-deficient mice are less able to eradicate a mucosalCitrobacter rodentiuminfection than wild-type C57BL/6 mice. miR-155-deficient mice exhibited prolonged colonization associated with a higherC. rodentiumburden in gastrointestinal tissue and spread into systemic tissues. Germinal center formation and humoral immune responses againstC. rodentiumwere severely impaired in infected miR-155-deficient mice. A similarly susceptible phenotype was observed in μMT mice reconstituted with miR-155-deficient B cells, indicating that miR-155 is required intrinsically for mediating protection against this predominantly luminal bacterial pathogen.

scholarly journals Intimin-Specific Immune Responses Prevent Bacterial Colonization by the Attaching-Effacing PathogenCitrobacter rodentium

2001 ◽  
Vol 69 (9) ◽  
pp. 5597-5605 ◽  
Author(s):  
Marjan Ghaem-Maghami ◽  
Cameron P. Simmons ◽  
Sarah Daniell ◽  
Mariagrazia Pizza ◽  
David Lewis ◽  
...  
Keyword(s):  
Immune Responses ◽  
Bacterial Colonization ◽  
Wild Type ◽  
Epec Strain ◽  
E Coli ◽  
Humoral Immune ◽  
Humoral Immune Responses ◽  
Genes Encoding ◽  
Enterocyte Effacement ◽  
Carboxy Terminal

ABSTRACT The formation of attaching and effacing (A/E) lesions on gut enterocytes is central to the pathogenesis of enterohemorrhagic (EHEC)Escherichia coli, enteropathogenic E. coli (EPEC), and the rodent pathogen Citrobacter rodentium. Genes encoding A/E lesion formation map to a chromosomal pathogenicity island termed the locus of enterocyte effacement (LEE). Here we show that the LEE-encoded proteins EspA, EspB, Tir, and intimin are the targets of long-lived humoral immune responses in C. rodentium-infected mice. Mice infected with C. rodentium developed robust acquired immunity and were resistant to reinfection with wild-type C. rodentium or a C. rodentium derivative, DBS255(pCVD438), which expressed intimin derived from EPEC strain E2348/69. The receptor-binding domain of intimin polypeptides is located within the carboxy-terminal 280 amino acids (Int280). Mucosal and systemic vaccination regimens using enterotoxin-based adjuvants were employed to elicit immune responses to recombinant Int280α from EPEC strain E2348/69. Mice vaccinated subcutaneously with Int280α, in the absence of adjuvant, were significantly more resistant to oral challenge with DBS255(pCVD438) but not with wild-type C. rodentium. This type-specific immunity could not be overcome by employing an exposed, highly conserved domain of intimin (Int388–667) as a vaccine. These results show that anti-intimin immune responses can modulate the outcome of a C. rodentium infection and support the use of intimin as a component of a type-specific EPEC or EHEC vaccine.

scholarly journals 2777. Live-Attenuated Vaccine Against RSV Generates Robust Cellular and Humoral Immune Responses

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S980-S980
Author(s):  
Steffen Mueller ◽  
Cyril Le Nouen ◽  
Ursula J Buchholz ◽  
Raj Kalkeri ◽  
Fusataka Koide ◽  
...  
Keyword(s):  
Immune Responses ◽  
The Elderly ◽  
Wild Type ◽  
Live Attenuated Vaccine ◽  
Virus Shedding ◽  
Humoral Immune ◽  
Humoral Immune Responses ◽  
Tracheal Lavage ◽  
Circulating Antibodies ◽  
Syncytial Virus

Abstract Background In people over 65, there are on average 177,000 hospitalizations and 14,000 deaths because of respiratory syncytial virus (RSV) each year. Elderly patients infected with RSV can suffer serious infections leading to pneumonia and congestive heart failure. RSV vaccines have failed in the elderly in part because they have been unable to mount a robust cellular immune response. Methods RSV-MinL4.0 is a live-attenuated intranasal vaccine candidate that was generated by codon pair deoptimization of the L gene followed by the addition of four stabilizing mutations found via stress passaging. Four African Green Monkeys (AGMs) per group were vaccinated with RSV-MinL4.0 or wild-type (WT) RSV at 2 × 106 PFU, boosted on day 28 and challenged with wild-type (WT) RSV on day 104. Oropharyngeal swabs and tracheal lavage were collected daily and every other day, respectively, to evaluate virus shedding (qPCR) and blood was drawn on days 1, 14, 21, 28, and 49 for antibody titers (PRNT50), and PBMC activation (IFNγ ELISPOT with whole inactivated virus). Results MinL4.0 was 2 to 3 log10 attenuated when compared with WT RSV in AGMs. Despite the presence of antibodies on day 28, there was a “take” of the boost indicating the potential for this vaccine to be immunogenic in the elderly with pre-existing circulating antibodies (Figure 1A). MinL4.0 led to robust activation of PBMCs comparable to WT RSV (> 2,000 spots per 106 total cells, Figure 1B). Shedding of the vaccine and challenge viruses was minimal (data not shown). Conclusion MinL4.0 led to robust activation of cellular and humoral immune responses, which are critical for induction of protective immunity in the elderly. Animals were protected from WT challenge. Preliminary data in AGMs with pre-existing antibodies to RSV indicate that circulating antibodies do not prevent vaccine “take,” critical for a vaccine targeting sero-positive elderly individuals. Disclosures All authors: No reported disclosures.

scholarly journals Helicobacter pylori with a Truncated Lipopolysaccharide O Chain Fails To Induce Gastritis in SCID Mice Injected with Splenocytes from Wild-Type C57BL/6J Mice

2004 ◽  
Vol 72 (7) ◽  
pp. 3925-3931 ◽  
Author(s):  
K. A. Eaton ◽  
S. M. Logan ◽  
P. E. Baker ◽  
R. A. Peterson ◽  
M. A. Monteiro ◽  
...  
Keyword(s):  
Immune Response ◽  
Helicobacter Pylori ◽  
Immune Responses ◽  
Scid Mice ◽  
Delayed Type Hypersensitivity ◽  
Wild Type ◽  
Humoral Immune ◽  
Humoral Immune Responses ◽  
Ifn Γ ◽  
H Pylori

ABSTRACT The goal of this study was to determine whether Helicobacter pylori lipopolysaccharide (LPS) O-chain polysaccharide contributes to gastritis in a mouse model. C57BL/6J or C57BL/6-Prkdcscid (severe combined immunodeficient [SCID]) mice were inoculated with H. pylori strain SS1 or SS1::0826kan, in which a β-1,4-galactosyltransferase (HP0826), an LPS biosynthetic enzyme, had been disrupted. H. pylori strain SS1::0826kan expresses truncated LPS lacking O chain. Recipient SCID mice were given C57BL/6J splenocytes by intraperitoneal injection. Bacterial colonization, gastric lesions (gastritis, neutrophilic infiltration, and gastric epithelial metaplasia), cellular (delayed-type hypersensitivity) and humoral immune responses to H. pylori sonicate, and gastric gamma interferon (IFN-γ) mRNA expression were quantified. Recipient SCID mice colonized by H. pylori strain SS1 developed extensive gastritis with loss of normal fundic gland morphology. In contrast, gastric mucosa of recipient SCID mice colonized by H. pylori strain SS1::0826kan was not statistically distinguishable from that of uninfected recipient mice. Delayed-type hypersensitivity and humoral immune responses were detected in infected mice inoculated with wild-type SS1, but not with SS1::0826kan. IFN-γ transcription was lower in mice infected with SS1::0826kan than in mice infected with SS1. In this model of rapidly progressive gastritis due to H. pylori, the O chain contributed to the extent of gastritis and to the host immune response. These data support a role for H. pylori LPS O chain in direct induction of the host immune response leading to gastritis and gastric damage and are in contrast to protein antigens, such as urease and cag products which do not contribute to gastritis in mice.

scholarly journals Selected prfA* Mutations in Recombinant Attenuated Listeria monocytogenes Strains Augment Expression of Foreign Immunogens and Enhance Vaccine-Elicited Humoral and Cellular Immune Responses

2008 ◽  
Vol 76 (8) ◽  
pp. 3439-3450 ◽  
Author(s):  
Lin Yan ◽  
Jin Qiu ◽  
Jianbo Chen ◽  
Bridgett Ryan-Payseur ◽  
Dan Huang ◽  
...  
Keyword(s):  
Listeria Monocytogenes ◽  
Immune Responses ◽  
Wild Type ◽  
Vaccine Vectors ◽  
Humoral Immune ◽  
Cellular Immune Responses ◽  
Humoral Immune Responses ◽  
Anticancer Vaccines ◽  
Constitutive Overexpression ◽  
Cellular Immune

ABSTRACT While recombinant Listeria monocytogenes strains can be explored as vaccine candidates, it is important to develop attenuated but highly immunogenic L. monocytogenes vaccine vectors. Here, prfA* mutations selected on the basis of upregulated expression of L. monocytogenes PrfA-dependent genes and proteins were assessed to determine their abilities to augment expression of foreign immunogens in recombinant L. monocytogenes vectors and therefore enhance vaccine-elicited immune responses (a prfA* mutation is a mutation that results in constitutive overexpression of PrfA and PrfA-dependent virulence genes; the asterisk distinguishes the mutation from inactivation or stop mutations). A total of 63 recombinant L. monocytogenes vaccine vectors expressing seven individual viral or bacterial immunogens each in nine different L. monocytogenes strains carrying wild-type prfA or having prfA* mutations were constructed and investigated. Mutations selected on the basis of increased PrfA activation in recombinant L. monocytogenes prfA* vaccine vectors augmented expression of seven individual protein immunogens remarkably. Consistently, prime and boost vaccination studies with mice indicated that the prfA(G155S) mutation in recombinant L. monocytogenes ΔactA prfA* strains enhanced vaccine-elicited cellular immune responses. Surprisingly, the prfA(G155S) mutation was found to enhance vaccine-elicited humoral immune responses as well. The highly immunogenic recombinant L. monocytogenes ΔactA prfA* vaccine strains were as attenuated as the recombinant parent L. monocytogenes ΔactA vaccine vector. Thus, recombinant attenuated L. monocytogenes ΔactA prfA* vaccine vectors potentially are better antimicrobial and anticancer vaccines.

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