Immunogenicity and efficacy of live-attenuated Salmonella Typhi murium vaccine candidate CVD 1926 in a rhesus macaque model of gastroenteritis

2021 ◽  
Author(s):  
Ellen E. Higginson ◽  
Aruna Panda ◽  
Franklin R. Toapanta ◽  
Matthew C. Terzi ◽  
Jennifer A. Jones ◽  
...  
Keyword(s):  
Rhesus Macaques ◽  
Invasive Disease ◽  
Salmonella Typhi ◽  
T Cell Response ◽  
Wild Type ◽  
Live Attenuated Vaccine ◽  
Post Immunization ◽  
Severe Diarrhea ◽  
Macaque Model ◽  
Food Borne

Salmonella Typhi murium are a common cause of food-borne gastroenteritis, and a less frequent but important cause of invasive disease, especially in developing countries. In our previous work, we showed that a live-attenuated S. Typhi murium vaccine (CVD 1921) was safe and immunogenic in rhesus macaques, although shed for an unacceptably long period (10 days) post-immunization. Consequently, we engineered a new strain, CVD 1926, which was shown to be safe and immunogenic in mice, as well as less reactogenic in mice and human cell-derived organoids than CVD 1921. In this study, we assessed reactogenicity and efficacy of CVD 1926 in rhesus macaques. Animals were given two doses of either CVD 1926 or saline perorally. The vaccine was well-tolerated, with shedding in stool limited to a mean of 5 days. All CVD 1926 immunized animals made both a serological and a T cell response to vaccination. At four weeks post-immunization, animals were challenged with wild-type S. Typhi murium I77. Unvaccinated (saline) animals had severe diarrhea, with two animals succumbing to infection. Animals receiving CVD 1926 were largely protected, with only one animal having moderate diarrhea. Vaccine efficacy in this gastroenteritis model was 80%. S. Typhi murium vaccine strain CVD 1926 was safe and effective in rhesus macaques and shed for a shorter period than other previously tested live-attenuated vaccine strains. This strain could be combined with other live-attenuated Salmonella vaccine strains to create a pan- Salmonella vaccine.

scholarly journals Quintuple Deglycosylation Mutant of Simian Immunodeficiency Virus SIVmac239 in Rhesus Macaques: Robust Primary Replication, Tightly Contained Chronic Infection, and Elicitation of Potent Immunity against the Parental Wild-Type Strain

2001 ◽  
Vol 75 (9) ◽  
pp. 4023-4028 ◽  
Author(s):  
Kazuyasu Mori ◽  
Yasuhiro Yasutomi ◽  
Shinji Ohgimoto ◽  
Tadashi Nakasone ◽  
Shiki Takamura ◽  
...  
Keyword(s):  
Simian Immunodeficiency Virus ◽  
Chronic Infection ◽  
Neutralizing Antibodies ◽  
Rhesus Macaques ◽  
Chronic Phase ◽  
Wild Type ◽  
Live Attenuated Vaccine ◽  
Challenge Virus ◽  
Culture Cells ◽  
Immunodeficiency Virus

ABSTRACT We previously generated a mutant of simian immunodeficiency virus (SIV) lacking 5 of a total of 22 N-glycans in its external envelope protein gp120 with no impairment in viral replication capability and infectivity in tissue culture cells. Here, we infected rhesus macaques with this mutant and found that it also replicated robustly in the acute phase but was tightly, though not completely, contained in the chronic phase. Thus, a critical requirement for the N-glycans for the full extent of chronic infection was demonstrated. No evidence indicating reversion to a wild type was obtained during the observation period of more than 40 weeks. Monkeys infected with the mutant were found to tolerate a challenge infection with wild-type SIV very well. Analyses of host responses following challenge revealed no neutralizing antibodies against the challenge virus but strong secondary responses of cytotoxic T lymphocytes against multiple antigens, including Gag-Pol, Nef, and Env. Thus, the quintuple deglycosylation mutant appeared to represent a novel class of SIV live attenuated vaccine.

scholarly journals Development of a Rotavirus-Shedding Model in Rhesus Macaques, Using a Homologous Wild-Type Rotavirus of a New P Genotype

2005 ◽  
Vol 79 (2) ◽  
pp. 944-954 ◽  
Author(s):  
Monica M. McNeal ◽  
Karol Sestak ◽  
Anthony H.-C. Choi ◽  
Mitali Basu ◽  
Michael J. Cole ◽  
...  
Keyword(s):  
Rhesus Macaques ◽  
Nucleotide Sequence Analysis ◽  
Primate Research ◽  
Wild Type ◽  
Primate Model ◽  
Challenge Virus ◽  
Model Studies ◽  
Macaque Model ◽  
Clinically Normal ◽  
New Genotype

ABSTRACT Although there are several reports on rotavirus inoculation of nonhuman primates, no reliable model exists. Therefore, this study was designed to develop a rhesus macaque model for rotavirus studies. The goals were to obtain a wild-type macaque rotavirus and evaluate it as a challenge virus for model studies. Once rotavirus was shown to be endemic within the macaque colony at the Tulane National Primate Research Center, stool specimens were collected from juvenile animals (2.6 to 5.9 months of age) without evidence of previous rotavirus infection and examined for rotavirus antigen. Six of 10 animals shed rotavirus during the 10-week collection period, and the electropherotypes of all isolates were identical to each other but distinct from those of prototype simian rotaviruses. These viruses were characterized as serotype G3 and subgroup 1, properties typical of many animal rotaviruses, including simian strains. Nucleotide sequence analysis of the VP4 gene was performed with a culture-grown isolate from the stool of one animal, designated the TUCH strain. Based on both genotypic and phylogenetic comparisons between TUCH VP4 and cognate proteins of representatives of the reported 22 P genotypes, the TUCH virus belongs to a new genotype, P[23]. A pool of wild-type TUCH was prepared and intragastrically administered to eight cesarean section-derived, specific-pathogen-free macaques 14 to 42 days of age. All animals were kept in a biocontainment level 2 facility. Although no diarrhea was observed and the animals remained clinically normal, all animals shed large quantities of rotavirus antigen in their feces after inoculation, which resolved by the end of the 14-day observation period. Therefore, TUCH infection of macaques provides a useful nonhuman primate model for studies on rotavirus protection.

scholarly journals Comparable Genital Tract Infection, Pathology, and Immunity in Rhesus Macaques Inoculated with Wild-Type or Plasmid-Deficient Chlamydia trachomatis Serovar D

2015 ◽  
Vol 83 (10) ◽  
pp. 4056-4067 ◽  
Author(s):  
Yanyan Qu ◽  
Lauren C. Frazer ◽  
Catherine M. O'Connell ◽  
Alice F. Tarantal ◽  
Charles W. Andrews ◽  
...  
Keyword(s):  
Chlamydia Trachomatis ◽  
Genital Tract ◽  
Rhesus Macaques ◽  
Wild Type ◽  
Genital Tract Infection ◽  
Live Attenuated Vaccine ◽  
Content Type ◽  
Cell Responses ◽  
Histocompatibility Complex ◽  
Mhc Alleles

Rhesus macaques were studied to directly address the potential for plasmid-deficientChlamydia trachomatisto serve as a live attenuated vaccine in the genital tract. Five repeated cervical inoculations of rhesus macaques with wild-type serovar D strain D/UW-3/Cx or a plasmid-deficient derivative of this strain, CTD153, resulted in infections with similar kinetics and induced comparable levels of protective immunity. After all animals received five challenges with D/UW-3/Cx, levels of inflammation observed grossly and histologically were similar between the groups. Animals in both groups developed evidence of oviduct dilatation; however, reduced oviduct dilatation was observed for “controllers,” i.e., animals without detectable chlamydial DNA in the fimbriae at weeks 5 and 12. Grouping animals into “ascenders” and “controllers” revealed that elevated early T cell responses were associated with protection, whereas higher antibody responses were associated with ascension. Protected animals shared common major histocompatibility complex (MHC) alleles. Overall, genetic differences of individual animals, rather than the presence or absence of the chlamydial plasmid in the primary infecting strain, appeared to play a role in determining the outcome of infection.

scholarly journals Prevention and treatment of SHIVAD8 infection in rhesus macaques by a potent d-peptide HIV entry inhibitor

2020 ◽  
Vol 117 (36) ◽  
pp. 22436-22442
Author(s):  
Yoshiaki Nishimura ◽  
J. Nicholas Francis ◽  
Olivia K. Donau ◽  
Eric Jesteadt ◽  
Reza Sadjadpour ◽  
...  
Keyword(s):  
Rhesus Macaques ◽  
Entry Inhibitor ◽  
High Dose ◽  
Combination Antiretroviral Therapy ◽  
Promising Candidate ◽  
Macaque Model ◽  
Prevention And Treatment ◽  
Hiv Entry ◽  
Virus Isolates ◽  
Primary Virus

Cholesterol-PIE12-trimer (CPT31) is a potentd-peptide HIV entry inhibitor that targets the highly conserved gp41 N-peptide pocket region. CPT31 exhibited strong inhibitory breadth against diverse panels of primary virus isolates. In a simian-HIV chimeric virus AD8 (SHIVAD8) macaque model, CPT31 prevented infection from a single high-dose rectal challenge. In chronically infected animals, CPT31 monotherapy rapidly reduced viral load by ∼2 logs before rebound occurred due to the emergence of drug resistance. In chronically infected animals with viremia initially controlled by combination antiretroviral therapy (cART), CPT31 monotherapy prevented viral rebound after discontinuation of cART. These data establish CPT31 as a promising candidate for HIV prevention and treatment.

scholarly journals Meningitis Caused by Salmonella Newport in a Five-Year-Old Child

2016 ◽  
Vol 2016 ◽  
pp. 1-4
Author(s):  
Ana De Malet ◽  
Sheila Ingerto ◽  
Israel Gañán
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Neurological Disorders ◽  
Invasive Disease ◽  
Salmonella Typhi ◽  
Gram Negative ◽  
Negative Bacillus ◽  
Salmonella Newport ◽  
Gram Negative Bacillus ◽  
The Central Nervous System

Salmonella Newport is a Gram-negative bacillus belonging to the Enterobacteria family and the nontyphi Salmonella (NTS), usually related to gastroenteritis. Main difference between NTS and Salmonella typhi is that the last one evolves to an invasive disease easier than NTS. These can progress to bacteremias in around 5% of cases and secondary focuses can appear occasionally, as in meningitis. An infection of the central nervous system is uncommon, considering its incidence in 0.6–8% of the cases; most of them are described in developing countries and mainly in childhood, especially neonates. Bacterial meningitis by NTS mostly affects immunosuppressed people in Europe. Prognosis is adverse, with a 50% mortality rate, mainly due to complications of infection: hydrocephalus, ventriculitis, abscesses, subdural empyema, or stroke. Choice antibiotic treatments are cefotaxime, ceftriaxone, or ceftazidime. The aim of this paper is to present a case of meningitis caused by Salmonella Newport diagnosed in a five-year-old girl living in a rural area of the province of Ourense (Spain), with favorable evolution and without neurological disorders.

scholarly journals A Truncated Form of Nef Selected during Pathogenic Reversion of Simian Immunodeficiency Virus SIVmac239Δnef Increases Viral Replication

2003 ◽  
Vol 77 (2) ◽  
pp. 1245-1256 ◽  
Author(s):  
Lisa A. Chakrabarti ◽  
Karin J. Metzner ◽  
Tijana Ivanovic ◽  
Hua Cheng ◽  
Jean Louis-Virelizier ◽  
...  
Keyword(s):  
T Cell ◽  
Viral Replication ◽  
Simian Immunodeficiency Virus ◽  
Rhesus Macaques ◽  
Premature Stop Codon ◽  
Cell Depletion ◽  
Partial Recovery ◽  
Wild Type ◽  
T Cell Depletion ◽  
Immunodeficiency Virus

ABSTRACT The live, attenuated vaccine simian immunodeficiency virus SIVmac239Δnef efficiently protects rhesus macaques against infection with wild-type SIVmac but occasionally causes CD4+ T-cell depletion and progression to simian AIDS (SAIDS). Virus recovered from a vaccinated macaque (Rh1490) that progressed to SAIDS had acquired an additional deletion in the nef gene, resulting in a frameshift that restored the original nef open reading frame (R. I. Connor, D. C. Montefiori, J. M. Binley, J. P. Moore, S. Bonhoeffer, A. Gettie, E. A. Fenamore, K. E. Sheridan, D. D. Ho, P. J. Dailey, and P. A. Marx, J. Virol. 72:7501-7509, 1998). Intravenous inoculation of the Rh1490 viral isolate into four naive rhesus macaques induced CD4+ T-cell depletion and disease in three out of four animals within 2 years, indicating a restoration of virulence. A DNA fragment encompassing the truncated nef gene amplified from the Rh1490 isolate was inserted into the genetic backbone of SIVmac239. The resulting clone, SIVmac239-Δ2nef, expressed a Nef protein of approximately 23 kDa, while the original SIVmac239Δnef clone expressed a shorter protein of 8 kDa. The revertant form of Nef did not cause downregulation of CD4, CD3, or major histocompatibility complex class I. The infectivity of SIVmac239-Δ2nef was similar to that of SIVmac239Δnef in single-cycle assays using indicator cell lines. In contrast, SIVmac239-Δ2nef replicated more efficiently than SIVmac239Δnef in peripheral blood mononuclear cell (PBMC) cultures infected under unstimulated conditions. The p27 Gag antigen levels in SIVmac239-Δ2nef-infected cultures were still lower than those obtained with wild-type SIVmac239, consistent with a partial recovery of Nef function. The transcriptional activity of long terminal repeat (LTR)-luciferase constructs containing the nef deletions did not differ markedly from that of wild-type LTR. Introduction of a premature stop codon within Nef-Δ2 abolished the replicative advantage in PBMCs, demonstrating that the Nef-Δ2 protein, rather than the structure of the U3 region of the LTR, was responsible for the increase in viral replication. Taken together, these results show that SIV with a deletion in the nef gene can revert to virulence and that expression of a form of nef with multiple deletions may contribute to this process by increasing viral replication.

scholarly journals Role Of Selected Fimbrial Adheins In Pathogenesis Of Acid-Induced Eneterohemorrhagic Escherichia Coli 0157:H7

2021 ◽  
Author(s):  
Shahnaz Haque
Keyword(s):  
Fatty Acid ◽  
Type Strain ◽  
Wild Type Strain ◽  
Short Chain Fatty Acid ◽  
Acid Stress ◽  
Chain Fatty Acid ◽  
Short Chain ◽  
Wild Type ◽  
Food Borne

Enterohemorrhagic Escherichia coli (EHEC) 0157:H7 is a food-borne pathogen that causes hemolytic uremic syndrome and hemorrhagic colitis. The mechanisms underlying the adhesion of EHEC 0157:H7 to intestinal epithelial cells are not well understood. Like other food-borne pathogens, ECEC 0157:H7 must survive the acid stress of the gastric juice in the stomach and short chain fatty acid in the intestine in order to colonize the large intestine. We have found that acid stress and short chain fatty acid stress significantly enhance host-adhesion of EHEC 0157:H7 and also upregulates expression of EHEC fimbrial genes, lpfA1, lpfA2 and yagZ, as demonstrated by our DNA microarray. We now report that disruption of the yagZ (also known as the E. coli common pilus A) gene results in loss of the acid-induced and short chain fatty acid-induced adhesion increase seen for the wild type strain. When the yagZ mutant is complemented with yagZ, the sress-induced and short chain fatty acid-induced adhesion increase seen for the wild type strain. When the yagZ mutant is complemented with yagZ, the stress-induced adhesion pehnotype is restored, confirming the role of yagZ in the acid as well as short chain fatty acid induced adhesion to HEp-2 cells. On the other hand, neither disruption in the long polar fimbria genes lpfA1 or lpfA2 in the wild type showed any effect in adherence to HEp-2 cells; rather displaying a hyperadherant phenotype to HEp-2 cells after acid-induced or short chain fatty acid-induced stress. The results also indicate that acid or short chain fatty acid stress, which is a part of the host's natural defense mechanism against pathogens, may regulate virulence factors resulting in enhanced bacteria-host attachment during colonization in the human or bovine host.

scholarly journals Genotypic and demographic characterization of invasive isolates of Salmonella Typhimurium in HIV co-infected patients in South Africa

2009 ◽  
Vol 3 (08) ◽  
pp. 585-592 ◽  
Author(s):  
Karen H. Keddy ◽  
Sarika Dwarika ◽  
Penny Crowther ◽  
Olga Perovic ◽  
Jeanette Wadula ◽  
...  
Keyword(s):  
South Africa ◽  
Salmonella Typhimurium ◽  
Antimicrobial Agents ◽  
Invasive Disease ◽  
Hospital Environment ◽  
Hiv Positive ◽  
Food Borne ◽  
Microbiological Techniques ◽  
Age Range ◽  
Multiple Antibiotics

BACKGROUND: Non-typhoidal Salmonella are frequently food-borne zoonotic pathogens that may cause invasive disease in HIV-positive individuals. METHODOLOGY: Invasive isolates (n = 652) of Salmonella Typhimurium from human patients in Gauteng Province of South Africa were investigated for the years 2006 and 2007. Bacteria were identified using standard microbiological techniques and serotyping was performed using commercially available antisera. Susceptibility testing to antimicrobial agents was determined by the E-test. Genotypic relatedness of isolates was investigated by pulsed-field gel electrophoresis analysis of digested genomic DNA. RESULTS: Forty-five clusters of isolates were identified, of which four (clusters 3, 5, 6 and 11) were major clusters. Most isolates originated from hospital H2 and most were isolated from patients in the age range of 15 to 64 years. Ninety-three percent (213/230) of patients with a known HIV status were HIV-positive. Most isolates showed resistance to multiple antibiotics. The most commonly expressed antibiotic resistance profiles were ACSSuNa (14%; 75/555) and ACSSuTNa (13%; 72/555). Some evidence was found for nosocomial acquisition of isolates. Of the isolates from the major clusters 3, 5, 6, and 11, 33% (8/24), 6% (7/117), 4% (1/26) and 6% (3/52) were of nosocomial origin, respectively. CONCLUSIONS: In South Africa, Salmonella Typhimurium remains a major opportunistic infection of predominantly HIV-positive patients. Clonally diverse strains that are resistant to multiple antibiotics may circulate in patients aged between 15 and 64 years over prolonged periods within the hospital environment, adding to the health care burden.

scholarly journals Role of Campylobacter jejuni Respiratory Oxidases and Reductases in Host Colonization

2008 ◽  
Vol 74 (5) ◽  
pp. 1367-1375 ◽  
Author(s):  
Rebecca A. Weingarten ◽  
Jesse L. Grimes ◽  
Jonathan W. Olson
Keyword(s):  
Campylobacter Jejuni ◽  
Anaerobic Respiration ◽  
Wild Type ◽  
Respiratory Enzymes ◽  
Host Colonization ◽  
Enzymatic Function ◽  
Food Borne ◽  
Transport Chain ◽  
Respiratory Oxidases

ABSTRACT Campylobacter jejuni is the leading cause of human food-borne bacterial gastroenteritis. The C. jejuni genome sequence predicts a branched electron transport chain capable of utilizing multiple electron acceptors. Mutants were constructed by disrupting the coding regions of the respiratory enzymes nitrate reductase (napA::Cm), nitrite reductase (nrfA::Cm), dimethyl sulfoxide, and trimethylamine N-oxide reductase (termed Cj0264::Cm) and the two terminal oxidases, a cyanide-insensitive oxidase (cydA::Cm) and cbb3-type oxidase (ccoN::Cm). Each strain was characterized for the loss of the associated enzymatic function in vitro. The strains were then inoculated into 1-week-old chicks, and the cecal contents were assayed for the presence of C. jejuni 2 weeks postinoculation. cydA::Cm and Cj0264c::Cm strains colonized as well as the wild type; napA::Cm and nrfA::Cm strains colonized at levels significantly lower than the wild type. The ccoN::Cm strain was unable to colonize the chicken; no colonies were recovered at the end of the experiment. While there appears to be a role for anaerobic respiration in host colonization, oxygen is the most important respiratory acceptor for C. jejuni in the chicken cecum.

scholarly journals Identification of Zinc-Dependent Mechanisms Used by Group B Streptococcus To Overcome Calprotectin-Mediated Stress

mBio ◽  
2020 ◽  
Vol 11 (6) ◽  
Author(s):  
Lindsey R. Burcham ◽  
Yoann Le Breton ◽  
Jana N. Radin ◽  
Brady L. Spencer ◽  
Liwen Deng ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Metal Ion ◽  
Invasive Disease ◽  
Female Reproductive Tract ◽  
Zinc Uptake ◽  
Wild Type ◽  
Metal Transporters ◽  
High Concentrations ◽  
Group B

ABSTRACT Nutritional immunity is an elegant host mechanism used to starve invading pathogens of necessary nutrient metals. Calprotectin, a metal-binding protein, is produced abundantly by neutrophils and is found in high concentrations within inflammatory sites during infection. Group B Streptococcus (GBS) colonizes the gastrointestinal and female reproductive tracts and is commonly associated with severe invasive infections in newborns such as pneumonia, sepsis, and meningitis. Although GBS infections induce robust neutrophil recruitment and inflammation, the dynamics of GBS and calprotectin interactions remain unknown. Here, we demonstrate that disease and colonizing isolate strains exhibit susceptibility to metal starvation by calprotectin. We constructed a mariner transposon (Krmit) mutant library in GBS and identified 258 genes that contribute to surviving calprotectin stress. Nearly 20% of all underrepresented mutants following treatment with calprotectin are predicted metal transporters, including known zinc systems. As calprotectin binds zinc with picomolar affinity, we investigated the contribution of GBS zinc uptake to overcoming calprotectin-imposed starvation. Quantitative reverse transcriptase PCR (qRT-PCR) revealed a significant upregulation of genes encoding zinc-binding proteins, adcA, adcAII, and lmb, following calprotectin exposure, while growth in calprotectin revealed a significant defect for a global zinc acquisition mutant (ΔadcAΔadcAIIΔlmb) compared to growth of the GBS wild-type (WT) strain. Furthermore, mice challenged with the ΔadcAΔadcAIIΔlmb mutant exhibited decreased mortality and significantly reduced bacterial burden in the brain compared to mice infected with WT GBS; this difference was abrogated in calprotectin knockout mice. Collectively, these data suggest that GBS zinc transport machinery is important for combatting zinc chelation by calprotectin and establishing invasive disease. IMPORTANCE Group B Streptococcus (GBS) asymptomatically colonizes the female reproductive tract but is a common causative agent of meningitis. GBS meningitis is characterized by extensive infiltration of neutrophils carrying high concentrations of calprotectin, a metal chelator. To persist within inflammatory sites and cause invasive disease, GBS must circumvent host starvation attempts. Here, we identified global requirements for GBS survival during calprotectin challenge, including known and putative systems involved in metal ion transport. We characterized the role of zinc import in tolerating calprotectin stress in vitro and in a mouse model of infection. We observed that a global zinc uptake mutant was less virulent than the parental GBS strain and found calprotectin knockout mice to be equally susceptible to infection by wild-type (WT) and mutant strains. These findings suggest that calprotectin production at the site of infection results in a zinc-limited environment and reveals the importance of GBS metal homeostasis to invasive disease.

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