scholarly journals Characterization of a novel intratracheal aerosol challenge model of Brucella melitensis in guinea pigs

2018 ◽  
Author(s):  
M.E. Hensel ◽  
D.G. Garcia-Gonzalez ◽  
S.P. Chaki ◽  
J. Samuel ◽  
A.M. Arenas-Gamboa
Keyword(s):  
Animal Model ◽  
Mouse Model ◽  
Guinea Pig ◽  
Lymph Nodes ◽  
Guinea Pigs ◽  
Brucella Melitensis ◽  
Recurrent Fever ◽  
Human Brucellosis ◽  
High Dose ◽  
Post Inoculation

AbstractB. melitensis is considered the most virulent of the Brucella species, and a need exists for an improved laboratory animal model of infection that mimics natural transmission and disease. Guinea pigs are highly susceptible to infection with Brucella spp. and develop a disease syndrome that mimics natural disease after aerosol inoculation. Intratracheal inoculation is a targeted means of generating aerosols that offer advantages over aerosol chamber delivery. To establish this delivery method, female, Hartley guinea pigs were infected via intratracheal inoculation with PBS or 16M B. melitensis at low dose (101 to 103) or high dose (106 to 108) and monitored for 30 days for signs of disease. Guinea pigs in the high dose groups developed fever between 12-17 days post-inoculation. Bacteria were recovered from the spleen, liver, lymph nodes, lung, and uterus at 30-days post-inoculation and demonstrated dose dependent mean increases in colonization and pathologic changes consistent with human brucellosis. To study the kinetics of extrapulmonary dissemination, guinea pigs were inoculated with 107 CFU and euthanized at 2-hours post inoculation and at weekly intervals for 3 weeks. 5.8×105 to 4.2×106 CFU were recovered from the lung 2 hours post-inoculation indicating intratracheal inoculation is an efficient means of infecting guinea pigs. Starting at 1-week post inoculation bacteria were recovered from the aforementioned organs with time dependent mean increases in colonization. This data demonstrates that guinea pigs develop a disease syndrome that models the human manifestation of brucellosis, which makes the guinea pig a valuable model for pathogenesis studies.Author summaryBrucellosis is caused by a gram-negative, intracellular bacterial pathogen with a worldwide distribution and affects up to half a million people per year. It is a neglected zoonosis that impacts not only animal welfare, but also exert economic pressure on afflicted individuals through loss of wages and decreased productivity. In people, recurrent fever, malaise, and anorexia accompanied by enlargement of the spleen and lymph nodes are common clinical symptoms of infection. The mouse model has been used extensively to study the pathogenesis of brucellosis, but there are drawbacks to extrapolating studies in mice to develop vaccines or therapeutics for people. Mice are frequently inoculated via intraperitoneal injection, which is an artificial means of producing disease that does not mimic natural transmission or disease features, such as fever. An animal model is needed that can be infected through natural transmission routes and subsequently develop a syndrome that matches clinical disease seen in people in order to study the pathogenesis of disease and to develop vaccines and therapeutics. The guinea pig offers an improvement on the mouse model because it can be infected via aerosol inoculation and develops fever, a humoral immune response, systemic colonization, and macroscopic and microscopic lesions of disease. As such, guinea pigs could be used a more biologically relevant model for evaluation of host-pathogen interactions.

scholarly journals Pathology and Pathophysiology of Inhalational Anthrax in a Guinea Pig Model

2013 ◽  
Vol 81 (4) ◽  
pp. 1152-1163 ◽  
Author(s):  
Vladimir Savransky ◽  
Daniel C. Sanford ◽  
Emily Syar ◽  
Jamie L. Austin ◽  
Kevin P. Tordoff ◽  
...  
Keyword(s):  
Animal Model ◽  
Guinea Pig ◽  
Lymph Nodes ◽  
Guinea Pigs ◽  
Alternative Model ◽  
Lethal Dose ◽  
Clinical Signs ◽  
Regional Lymph Nodes ◽  
Content Type ◽  
Ames Strain

ABSTRACTNonhuman primates (NHPs) and rabbits are the animal models most commonly used to evaluate the efficacy of medical countermeasures against anthrax in support of licensure under the FDA's “Animal Rule.” However, a need for an alternative animal model may arise in certain cases. The development of such an alternative model requires a thorough understanding of the course and manifestation of experimental anthrax disease induced under controlled conditions in the proposed animal species. The guinea pig, which has been used extensively for anthrax pathogenesis studies and anthrax vaccine potency testing, is a good candidate for such an alternative model. This study was aimed at determining the median lethal dose (LD50) of theBacillus anthracisAmes strain in guinea pigs and investigating the natural history, pathophysiology, and pathology of inhalational anthrax in this animal model following nose-only aerosol exposure. The inhaled LD50of aerosolized Ames strain spores in guinea pigs was determined to be 5.0 × 104spores. Aerosol challenge of guinea pigs resulted in inhalational anthrax with death occurring between 46 and 71 h postchallenge. The first clinical signs appeared as early as 36 h postchallenge. Cardiovascular function declined starting at 20 h postexposure. Hematogenous dissemination of bacteria was observed microscopically in multiple organs and tissues as early as 24 h postchallenge. Other histopathologic findings typical of disseminated anthrax included suppurative (heterophilic) inflammation, edema, fibrin, necrosis, and/or hemorrhage in the spleen, lungs, and regional lymph nodes and lymphocyte depletion and/or lymphocytolysis in the spleen and lymph nodes. This study demonstrated that the course of inhalational anthrax disease and the resulting pathology in guinea pigs are similar to those seen in rabbits and NHPs, as well as in humans.

scholarly journals Intratracheal Inoculation with Brucella melitensis in the Pregnant Guinea Pig Is an Improved Model for Reproductive Pathogenesis and Vaccine Studies

2020 ◽  
Vol 88 (10) ◽  
Author(s):  
Martha E. Hensel ◽  
Sankar P. Chaki ◽  
Lauren Stranahan ◽  
Anthony E. Gregory ◽  
Erin J. van Schaik ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Guinea Pigs ◽  
Pregnancy Loss ◽  
Brucella Melitensis ◽  
Reproductive Failure ◽  
Content Type ◽  
Spontaneous Pregnancy ◽  
Important Complication ◽  
Reproductive Disease ◽  
Improved Model

ABSTRACT Reproductive failure is the hallmark of brucellosis in animals. An uncommon but important complication in pregnant women who become acutely infected with Brucella melitensis is spontaneous pregnancy loss or vertical transmission to the fetus. Unfortunately, the mechanism behind reproductive failure is still obscure, partially due to the lack of a proper study model. Recently, it was demonstrated that intratracheal (IT) inoculation of nonpregnant guinea pigs would replicate features of clinical disease in humans. To determine if IT inoculation would induce reproductive disease, guinea pigs were infected at mid-gestation and monitored daily for fever and abortions. Fever developed between day 14 to 18 postinoculation, and by 3 weeks postinoculation, 75% of pregnant guinea pigs experienced stillbirths or spontaneous abortions mimicking natural disease. Next, to investigate the guinea pig as a model for evaluating vaccine efficacy during pregnancy, nonpregnant guinea pigs were vaccinated with S19, 16MΔvjbR + Quil-A, or 100 μl PBS + Quil-A (as control). Guinea pigs were bred and vaccinated guinea pigs were challenged at mid-gestation with B. melitensis IT inoculation and monitored for fever and abortions. Vaccination with both vaccines prevented fever and protected against abortion. Together, this study indicates that pregnant guinea pigs are an appropriate animal model to study reproductive disease and offer an improved model to evaluate the ability of vaccine candidates to protect against a serious manifestation of disease.

scholarly journals Effects of an antiplatelet glycoprotein Ib antibody on hemostatic function in the guinea pig

Blood ◽  
1989 ◽  
Vol 74 (2) ◽  
pp. 690-694 ◽  
Author(s):  
BH Becker ◽  
JL Miller
Keyword(s):  
Animal Model ◽  
Platelet Count ◽  
Guinea Pig ◽  
Guinea Pigs ◽  
Bleeding Time ◽  
Model System ◽  
Platelet Counts ◽  
Equal Dose ◽  
Guinea Pig Model

Abstract Previous studies in the guinea pig model system have established a close structural homology between human and guinea pig glycoproteins Ib (GPIb) and IIb/IIIa (GPIIb/IIIa). Moreover, the murine monoclonal antibody (MoAb) PG-1, which recognizes GPIb in guinea pig platelets and megakaryocytes, exerted full inhibition on von Willebrand factor (vWF)- dependent platelet agglutination without inhibiting aggregation induced by ADP, collagen, or thrombin. The present research extends this animal model system to study of the effects on hemostatic function following the in vivo injection of MoAb PG-1 or its F(ab')2 fragments. A hind limb template bleeding time methodology was developed for use in guinea pigs. Normal bleeding time was determined to be 2.7 +/- 0.5 minutes (mean +/- SD), with an observed range of two to four minutes. Platelet counts in these same animals were 501 +/- 82 x 10(3)/microL. After intraperitoneal (IP) injection of busulfan, guinea pigs became increasingly thrombocytopenic. As long as the platelet count remained above approximately 150 x 10(3)/microL, the bleeding time was not more than five minutes; however, further decrease in the platelet count was accompanied by more marked prolongations of the bleeding time. For 14 to 72 hours after IP injection of 1.3 mg/kg intact PG-1 MoAb, a hemorrhagic state was produced with a bleeding time greater than 20 minutes. The platelet count concurrently decreased to approximately 50% of its baseline value but could not be further decreased either by raising the initial PG-1 dosage tenfold or by administering a second, equal dose 24 hours after the initial injection. This finding may reflect a heterogeneity of circulating platelets with respect to GPIb, to Fc receptors, or to an interaction between them. After IP injection of 0.63 to 2.5 mg/kg PG-1 F(ab')2 fragment, platelet counts did not decrease more than 21% below baseline levels in a 72-hour period, and bleeding times never increased by more than one minute over baseline values. Nevertheless, platelets obtained from animals 24 hours after injection of 2.5 mg/kg PG-1 F(ab')2 showed full inhibition of agglutination induced by ristocetin. The response of these platelets to aggregation by asialo-vWF was also severely inhibited as compared with control platelets. PG-1 F(ab')2 produced no effect on aggregation induced by ADP. These studies show that virtually complete functional block of the vWF receptor by F(ab')2 fragments of the anti-GPIb MoAb PG- 1 is not sufficient to produce a hemorrhagic state in the guinea pig animal model system.

scholarly journals Experimental induction of cervical lymphadenitis in guinea-pigs with group C streptococci

1976 ◽  
Vol 10 (3) ◽  
pp. 223-231 ◽  
Author(s):  
L. D. Olson ◽  
R. L. Schueler ◽  
G. M. Riley ◽  
L. G. Morehouse
Keyword(s):  
Guinea Pig ◽  
Lymph Nodes ◽  
Guinea Pigs ◽  
Cervical Lymphadenitis ◽  
Cervical Lymph Nodes ◽  
Experimental Induction

Streptococcal lymphadenitis with macroscopic abscesses was induced in guinea-pigs when an isolate of Lancefield's group C streptococci of guinea-pig origin was sprayed orally. The disease was also produced in guinea-pigs when another isolate was injected sublingually but not when it was sprayed orally. Treatment with prednisolone did not increase the susceptibility to the latter isolant when sprayed orally. Abscesses could not be induced in the cervical lymph nodes of guineapigs exposed by injecting group E streptococci sublingually, although the organism was isolated from the cervical lymph nodes 2 days after inoculation. Neither could abscesses be induced by injecting these streptococci sublingually in guinea-pigs treated with prednisolone.

scholarly journals Dietary Intervention Accelerates NASH Resolution Depending on Inflammatory Status with Minor Additive Effects on Hepatic Injury by Vitamin E Supplementation

Antioxidants ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 808
Author(s):  
Julie Hviid Klaebel ◽  
Günaj Rakipovski ◽  
Birgitte Andersen ◽  
Jens Lykkesfeldt ◽  
Pernille Tveden-Nyborg
Keyword(s):  
Vitamin E ◽  
Guinea Pig ◽  
Lipid Accumulation ◽  
Guinea Pigs ◽  
Dietary Intervention ◽  
Liver Weight ◽  
High Dose ◽  
Chow Diet ◽  
Lifestyle Modifications ◽  
Inflammatory Status

Despite the lack of effective pharmacotherapy against nonalcoholic steatohepatitis (NASH) and liver fibrosis, vitamin E (vitE) supplementation and lifestyle modifications are recommended for the management of NASH due to promising clinical results. We recently reported a positive effect of supplementation with 800 IU vitE and atorvastatin on NASH resolution in guinea pigs. In the present study, we investigated the effect of high-dose vitE therapy combined with dietary intervention against progressive NASH and advanced fibrosis in the guinea pig model. Sixty-six guinea pigs received either high-fat (HF) or standard guinea pig chow diet (Control) for 25 weeks. Prior to eight weeks of intervention, HF animals were allocated into groups; dietary intervention (Chow) or dietary intervention with 2000 IU/d vitE supplementation (CvitE). Both Chow and CvitE reduced dyslipidemia, hepatic lipid accumulation and liver weight (p < 0.05), while CvitE further decreased hepatocellular ballooning (p < 0.05). Subanalyses of individual responses within intervention groups showed significant correlation between the hepatic hallmarks of NASH and lipid accumulation vs. inflammatory state (p < 0.05). Collectively, our results indicate that individual differences in sensitivity towards intervention and inflammatory status determine the potential beneficial effect of dietary intervention and high-dose vitE supplementation. Moreover, the study suggests that inflammation is a primary target in NASH treatment.

Quantitative studies on tissue transplantation immunity - VI. Hypersensitivity reactions associated with the rejection of homografts

1962 ◽  
Vol 156 (963) ◽  
pp. 187-209 ◽  
Keyword(s):  
Guinea Pig ◽  
Lymph Nodes ◽  
Guinea Pigs ◽  
Transfer Reaction ◽  
Living Cells ◽  
Lymphoid Cells ◽  
Transfer Reactions ◽  
Repeated Injection ◽  
Direct Reaction ◽  
Inflammatory Reactions

If a guinea-pig R is sensitized by the transplantation of a skin homograft from a guinea-pig D , the intradermal injection into R of antigenic matter from D provokes an inflammatory response of delayed onset ( direct reaction ) that is outwardly and histologically similar to a tuberculin reaction. A reaction of the same kind is provoked when living cells expressed from the regional lymph nodes of R are injected intradermally into D ( transfer reaction ). The transfer reaction is interpreted as a local passive transfer of the state of reactivity dis­closed by the direct reaction. When due allowance is made for the sharing of antigens by members of outbred populations of guinea-pigs, both direct and transfer reactions are immunologically specific (§§ 2.3, 2.4, 3.1). The direct reaction can be provoked by cellular extracts (§ 2.3) as well as by living cells (§ 2-4). Its intensity is strongly correlated with the strength of the homograft reaction (§ 8). After sensitization by a single set of skin homografts, direct reactivity persists for a period of the order of hundreds of days (§ 4). ‘Hyperimmunization’ by the repeated injection of D cells into R is accompanied by a decline of direct reactivity (§ 6). The transfer reaction can be mediated through blood leucocytes (§ 3.2) and peritoneal exudate cells (§ 3.3) as well as by cells from lymph nodes. Although the regional node is the first node to be activated by a regional homograft, activity spreads thereafter to other nodes (§ 3.4). After the intravenous injection into R of 40 million lymphoid cells from D , transfer reactivity can be demonstrated in the leucocytes of R within 3 days (§ 3.2). Sensitized cells killed by heating, freezing or drying do not mediate the transfer reaction (§ 7.1). Extracts of leucocytes disrupted in the presence of deoxyribonuclease (Lawrence’s ‘transfer factor’) cannot deputize for living cells in the transfer reaction (§ 7.3), and evidence that such extracts can transfer direct reactivity to normal guinea-pigs is equivocal (§ 7.4). Disrupted leucocytes and especially blood platelets of syngeneic (‘isologous’) origin can give rise to violent non-specific delayed inflammatory reactions which resemble tuberculin reactions superficially but differ from them histologically (§ 7.3). Direct and transfer reactions were combined in an experiment in which cells or antigenic extracts from D were mixed with sensitized cells from R and then injected into a normal guinea-pig syngeneic with R (§ 3.5). Thus both direct and transfer reactions seem to depend essentially upon the local engagement of antigen with sensitized cells. Neither direct nor transfer reactions were affected by the administration of high doses of hydrocortisone (§ 5). It has not been possible to demonstrate direct or transfer reactions in mice, but the transfer reaction in rabbits is violent and prolonged (§ 3.0). (Other workers have demon­ strated direct reactivity in man.) The evidence, taken in the round, suggests that the delayed cutaneous inflammatory reactions revealed by the direct and transfer tests are manifestations of the homograft reaction, and not of an immunological reaction associated with some different iso-antigenic system. It thus supports the analogy long since drawn between the homograft and tuberculin reactions, and upholds the contention that the ‘second set’ homograft reaction reveals a pre-existing and not are-awakened (anamnestic) sensitivity (§ 8).

scholarly journals Development and Characterization of a Guinea Pig-Adapted Sudan Virus

2015 ◽  
Vol 90 (1) ◽  
pp. 392-399 ◽  
Author(s):  
Gary Wong ◽  
Shihua He ◽  
Haiyan Wei ◽  
Andrea Kroeker ◽  
Jonathan Audet ◽  
...  
Keyword(s):  
Animal Model ◽  
Guinea Pig ◽  
Guinea Pigs ◽  
Lethal Dose ◽  
Fatal Outcome ◽  
Small Animal ◽  
Disease Outbreak ◽  
Small Animal Model ◽  
Content Type

ABSTRACT Infections with Sudan virus (SUDV), a member of the genus Ebolavirus , result in a severe hemorrhagic fever with a fatal outcome in over 50% of human cases. The paucity of prophylactics and therapeutics against SUDV is attributed to the lack of a small-animal model to screen promising compounds. By repeatedly passaging SUDV within the livers and spleens of guinea pigs in vivo , a guinea pig-adapted SUDV variant (SUDV-GA) uniformly lethal to these animals, with a 50% lethal dose (LD 50 ) of 5.3 × 10 −2 50% tissue culture infective doses (TCID 50 ), was developed. Animals infected with SUDV-GA developed high viremia and died between 9 and 14 days postinfection. Several hallmarks of SUDV infection, including lymphadenopathy, increased liver enzyme activities, and coagulation abnormalities, were observed. Virological analyses and gross pathology, histopathology, and immunohistochemistry findings indicate that SUDV-GA replicates in the livers and spleens of infected animals similarly to SUDV infections in nonhuman primates. These developments will accelerate the development of specific medical countermeasures in preparation for a future disease outbreak due to SUDV. IMPORTANCE A disease outbreak due to Ebola virus (EBOV), suspected to have emerged during December 2013 in Guinea, with over 11,000 dead and 28,000 infected, is finally winding down. Experimental EBOV vaccines and treatments were administered to patients under compassionate circumstances with promising results, and availability of an approved countermeasure appears to be close. However, the same range of experimental candidates against a potential disease outbreak caused by other members of the genus Ebolavirus , such as Sudan virus (SUDV), is not readily available. One bottleneck contributing to this situation is the lack of a small-animal model to screen promising drugs in an efficient and economical manner. To address this, we have generated a SUDV variant (SUDV-GA) that is uniformly lethal to guinea pigs. Animals infected with SUDV-GA develop disease similar to that of SUDV-infected humans and monkeys. We believe that this model will significantly accelerate the development of life-saving measures against SUDV infections.

scholarly journals The ascorbate-deficient guinea pig model of shigellosis allows the study of the entire Shigella life cycle

2020 ◽  
Author(s):  
Antonin C André ◽  
Céline Mulet ◽  
Mark C Anderson ◽  
Louise Injarabian ◽  
Achim Buch ◽  
...  
Keyword(s):  
Animal Model ◽  
Life Cycle ◽  
Guinea Pig ◽  
Guinea Pigs ◽  
Colonic Mucosa ◽  
Extended Period ◽  
Pig Model ◽  
Suitable Animal Model ◽  
Guinea Pig Model

AbstractShigella spp. are the causative agents of bacillary dysentery or shigellosis, mainly in children living in developing countries. The study of Shigella entire life cycle in vivo and the evaluation of vaccine candidates’ protection efficacy have been hampered by the lack of a suitable animal model of infection (1). None of the ones evaluated so far (mouse, rabbit, guinea pig) allows to recapitulate shigellosis symptoms upon Shigella oral challenge. Historical reports suggest that dysentery and scurvy are both metabolic diseases associated with ascorbate-deficiency. Mammals which are susceptible to Shigella infection (humans, non-human primates and guinea pigs) are the lonely ones which are unable to synthesize ascorbate. We optimized a low-ascorbate diet to induce moderate ascorbate-deficiency but not scurvy in guinea pigs (Ascplasma conc.=1.6 μM vs 36 μM with optimal ascorbate supply). We demonstrated that moderate ascorbate-deficiency increases shigellosis severity during extended period of time (up to 48h) with all strains tested (Shigella flexneri 5a and 2a, Shigella sonnei). At late time-points, a massive influx of neutrophils was observed both within the disrupted colonic mucosa and in the luminal compartment, although Shigella remains able to disseminate deep into the organ to reach the sub-mucosal layer and the bloodstream. This new model of shigellosis opens new doors for the study both of Shigella infection strategy and innate and adaptive immune responses to Shigella infection. It may be also of a great interest to study the virulence of other pathogen for which no suitable animal model of infection is available (Vibrio cholerae, Yersinia pestis, Mycobacterium tuberculosis or Campylobacter jejuni, among others).SignificanceThe study of Shigella virulence cycle in vivo has been hampered by the lack of a suitable animal model, which would allow the colonic mucosa infection upon oral challenge. Based on historical reports and physiological aspects, it was suggested that ascorbate-deficiency may stand as a new dysentery risk-factor. To test this hypothesis, we set up a new ascorbate-deficient guinea pig model and demonstrated for the first time that the Shigella infectious process occurred for extended period of time (up to 48h) and demonstrated that shigellosis severity was higher in ascorbate-deficient animal. Ascorbate-deficient guinea pig model of infection may be used to assess the virulence of other pathogens for which no suitable animal model of infection is still lacking.

scholarly journals A new candidate vaccine for human brucellosis based on influenza viral vectors: development of immunization schedule in guinea pig model

2020 ◽  
Author(s):  
Dina Bugybayeva ◽  
Zhailaubay Kydyrbayev ◽  
Nadezhda Zinina ◽  
Nurika Assanzhanova ◽  
Bolat Yespembetov ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Guinea Pigs ◽  
Viral Vectors ◽  
Virulent Strain ◽  
Pig Model ◽  
Effective Vaccine ◽  
Human Brucellosis ◽  
Sublingual Administration ◽  
Vector Vaccine ◽  
Guinea Pig Model

Abstract Background: A new candidate vector vaccine against human brucellosis based on recombinant influenza viral vectors (rIVV) subtypes H5N1 expressing Brucella Omp16, L7/L12, Omp19 or Cu-Zn SOD proteins has been developed. This paper presents the results of the study of protection of the vaccine with various options of administering, dosing and frequency of use on guinea pigs.Methods: General states of guinea pigs was assessed based on , behavior and dynamics of a guinea pig weight-gain test. The effectiveness of the new anti-brucellosis vector vaccine was determined by studying its protective effect after conjunctival, intranasal and sublingual administration in doses 105 EID50, 106 EID50 and 107 EID50 during prime and boost vaccinations of animals, followed by challenge with a virulent strain of B. mellitensis 16M infection. For sake of comparison, the commercial B. melitensis Rev.1 vaccine was used as a control. The protective properties of vaccines were assessed by quantitation of Brucella colonization in organs and tissues of infected animals and compared to the control groups.Results: It was observed a gradual increase in body weight of guinea pigs after prime and booster immunization with the vaccine using conjunctival, intranasal and sublingual routes of administration, as well as after using various doses of vaccine. . The most optimal way of using the vaccine has been established: double intranasal immunization of guinea pigs at a dose of 106 EID50, which provides 80% protection of guinea pigs from B. melitensis 16M infection (P < 0.05), which is comparable to the results of the effectiveness of the commercial B. melitensis Rev.1 vaccine.Conclusions: We developed effective vaccine candidate against brucellosis and developed its immunization protocol in guinea pig model. We believe that this study is a substantial step for using the vaccine for future pre-clinical and clinical trials in human.

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