scholarly journals Aerosol Exposure of Cynomolgus Macaques to SARS-CoV-2 Results in More Severe Pathology than Existing Models

2021 ◽  
Author(s):  
Sandra L. Bixler ◽  
Christopher P. Stefan ◽  
Alexandra Jay ◽  
Franco Rossi ◽  
Keersten M. Ricks ◽  
...  
Keyword(s):  
Respiratory Disease ◽  
Severe Disease ◽  
Clinical Signs ◽  
Primate Species ◽  
Clinical Endpoints ◽  
Aerosol Exposure ◽  
Cynomolgus Macaques ◽  
Severe Pathology ◽  
Selection Testing ◽  
Medical Countermeasures

AbstractThe emergence of SARS-CoV-2 pandemic has highlighted the need for animal models that faithfully recapitulate the salient features of COVID-19 disease in humans; these models are necessary for the rapid down-selection, testing, and evaluation of medical countermeasures. Here we performed a direct comparison of two distinct routes of SARS-CoV-2 exposure, combined intratracheal/intranasal and small particle aerosol, in two nonhuman primate species: rhesus and cynomolgus macaques. While all four experimental groups displayed very few outward clinical signs, evidence of mild to moderate respiratory disease was present on radiographs and at the time of necropsy. Cynomolgus macaques exposed via the aerosol route also developed the most consistent fever responses and had the most severe respiratory disease and pathology. This study demonstrates that while all four models were suitable representations of mild COVID-like illness, aerosol exposure of cynomolgus macaques to SARS-CoV-2 produced the most severe disease, which may provide additional clinical endpoints for evaluating therapeutics and vaccines.

scholarly journals Pathogenesis of Influenza D Virus in Cattle

2016 ◽  
Vol 90 (12) ◽  
pp. 5636-5642 ◽  
Author(s):  
Lucas Ferguson ◽  
Alicia K. Olivier ◽  
Suzanne Genova ◽  
William B. Epperson ◽  
David R. Smith ◽  
...  
Keyword(s):  
Respiratory Disease ◽  
Clinical Signs ◽  
Dairy Calves ◽  
Nasal Discharge ◽  
Virus Family ◽  
Koch’S Postulates ◽  
Content Type ◽  
Natural Reservoir ◽  
Clinical Endpoints ◽  
Koch's Postulates

ABSTRACTCattle have been proposed as the natural reservoir of a novel member of the virus familyOrthomyxoviridae, which has been tentatively classified as influenza D virus (IDV). Although isolated from sick animals, it is unclear whether IDV causes any clinical disease in cattle. To address this aspect of Koch's postulates, three dairy calves (treatment animals) held in individual pens were inoculated intranasally with IDV strain D/bovine/Mississippi/C00046N/2014. At 1 day postinoculation, a seronegative calf (contact animal) was added to each of the treatment animal pens. The cattle in both treatment and contact groups seroconverted, and virus was detected in their respiratory tracts. Histologically, there was a significant increase in neutrophil tracking in tracheal epithelia of the treatment calves compared to control animals. While infected and contact animals demonstrated various symptoms of respiratory tract infection, they were mild, and the calves in the treatment group did not differ from the controls in terms of heart rate, respiratory rate, or rectal temperature. To mimic zoonotic transmission, two ferrets were exposed to a plastic toy fomite soaked with infected nasal discharge from the treatment calves. These ferrets did not shed the virus or seroconvert. In summary, this study demonstrates that IDV causes a mild respiratory disease upon experimental infection of cattle and can be transmitted effectively among cattle by in-pen contact, but not from cattle to ferrets through fomite exposure. These findings support the hypothesis that cattle are a natural reservoir for the virus.IMPORTANCEA novel influenza virus, tentatively classified as influenza D virus (IDV), was identified in swine, cattle, sheep, and goats. Among these hosts, cattle have been proposed as the natural reservoir. In this study, we show that cattle experimentally infected with IDV can shed virus and transmit it to other cattle through direct contact, but not to ferrets through fomite routes. IDV caused minor clinical signs in the infected cattle, fulfilling another of Koch's postulates for this novel agent, although other objective clinical endpoints were not different from those of control animals. Although the disease observed was mild, IDV induced neutrophil tracking and epithelial attenuation in cattle trachea, which could facilitate coinfection with other pathogens, and in doing so, predispose animals to bovine respiratory disease.

scholarly journals Small Particle Aerosol Exposure of African Green Monkeys to MERS-CoV as a Model for Highly Pathogenic Coronavirus Infection

2020 ◽  
Author(s):  
Allison Totura ◽  
Virginia Livingston ◽  
Ondraya Frick ◽  
David Dyer ◽  
Donald Nichols ◽  
...  
Keyword(s):  
Respiratory Disease ◽  
Small Particle ◽  
Severe Disease ◽  
Global Public Health ◽  
Highly Pathogenic ◽  
Initial Development ◽  
Aerosol Exposure ◽  
Coronavirus Infection ◽  
Dose Dependent ◽  
Green Monkeys

Abstract Emerging highly pathogenic coronaviruses (CoV) are a global public health threat due to the potential for person-to-person transmission and higher mortality rates than common seasonal respiratory pathogens. Middle East respiratory syndrome coronavirus (MERS-CoV) emerged in 2012, causing lethal respiratory disease in approximately 35% of human cases.Primate models of highly pathogenic coronavirus infection are needed to support development of therapeutics or vaccines, but few models exist that recapitulate severe disease signs. For initial development of a MERS-CoV primate model, twelve African green monkeys (AGMs) were exposed to 103, 104, or 105 PFU target doses of aerosolized MERS-CoV. We observed a dose- dependent increase of respiratory disease signs and viral titers in serum and throat swabs between the 103 PFU and the 105 PFU dose groups, although all AGMs survived for the 28 day duration of the study. This study is the first to describe dose-dependent effects of highly pathogenic coronavirus infection of primates and uses a route of infection (small particle aerosol) with potential relevance to MERS-CoV transmission in humans. Aerosol exposure of AGMs may provide a platform for the development of primate models of novel coronavirus disease, with potential utility in therapeutic development and viral pathogenesis studies.

scholarly journals Small Particle Aerosol Exposure of African Green Monkeys to MERS-CoV as a Model for Highly Pathogenic Coronavirus Infection

2020 ◽  
Author(s):  
Allison Totura ◽  
Virginia Livingston ◽  
Ondraya Frick ◽  
David Dyer ◽  
Donald Nichols ◽  
...  
Keyword(s):  
Respiratory Disease ◽  
Small Particle ◽  
Severe Disease ◽  
Global Public Health ◽  
Highly Pathogenic ◽  
Initial Development ◽  
Aerosol Exposure ◽  
Coronavirus Infection ◽  
Dose Dependent ◽  
Green Monkeys

Abstract Emerging highly pathogenic coronaviruses (CoV) are a global public health threat due to the potential for person-to-person transmission and higher mortality rates than common seasonal respiratory pathogens. Middle East respiratory syndrome coronavirus (MERS-CoV) emerged in 2012, causing lethal respiratory disease in approximately 35% of human cases. Primate models of highly pathogenic coronavirus infection are needed to support development of therapeutics or vaccines, but few models exist that recapitulate severe disease signs. For initial development of a MERS-CoV primate model, twelve African green monkeys (AGMs) were exposed to 103, 104, or 105 PFU target doses of aerosolized MERS-CoV. We observed a dose-dependent increase of respiratory disease signs and viral titers in serum and throat swabs between the 103 PFU and the 105 PFU dose groups, although all AGMs survived for the 28 day duration of the study. This study is the first to describe dose-dependent effects of highly pathogenic coronavirus infection of primates and uses a route of infection (small particle aerosol) with potential relevance to MERS-CoV transmission in humans. Aerosol exposure of AGMs may provide a platform for the development of primate models of novel coronavirus disease, with potential utility in therapeutic development and viral pathogenesis studies.

scholarly journals Association between clinical respiratory signs, lung lesions detected by thoracic ultrasonography and growth performance in pre‐weaned dairy calves

2021 ◽  
Vol 74 (1) ◽  
Author(s):  
Inmaculada Cuevas-Gómez ◽  
Mark McGee ◽  
José María Sánchez ◽  
Edward O’Riordan ◽  
Nicky Byrne ◽  
...  
Keyword(s):  
Respiratory Disease ◽  
Rectal Temperature ◽  
Clinical Signs ◽  
Live Weight ◽  
Dairy Calves ◽  
Post Mortem ◽  
Lung Lesions ◽  
Lung Lobe ◽  
Lung Consolidation ◽  
Severe Lung

Abstract Background Bovine respiratory disease (BRD) is the main cause of mortality among 1-to-5 month old calves in Ireland, accounting for approximately one-third of deaths. Despite widespread use of clinical respiratory signs for diagnosing BRD, lung lesions are detected, using thoracic ultrasonography (TUS) or following post-mortem, in calves showing no clinical signs. This highlights the limitation of clinical respiratory signs as a method of detecting sub-clinical BRD. Using 53 purchased artificially-reared male dairy calves, the objectives of this study were to: (i) characterise the BRD incidence detected by clinical respiratory signs and/or TUS, (ii) investigate the association between clinical respiratory signs and lung lesions detected by TUS, and (iii) assess the effect of BRD on pre-weaning growth. Results Clinical BRD (based on Wisconsin clinical respiratory score and/or rectal temperature > 39.6 ºC) was detected in 43 % and sonographic changes (lung lesions) were detected in 64 % of calves from purchase (23 (SD; 6.2) days of age) until weaning, 53 days post-arrival. Calves with clinical BRD were treated. Sixty-one per cent calves affected with clinical BRD had lung lesions 10.5 days (median) before detection of clinical signs. Moderate correlations (rsp 0.70; P < 0.05) were found between cough and severe lung lesions on arrival day, and between rectal temperature > 39.6 ºC and lung lesions ≥ 2 cm2 on day 7 (rsp 0.40; P < 0.05) post-arrival. Mean average daily live weight gain (ADG) of calves from purchase to weaning was 0.75 (SD; 0.10) kg; calves with or without clinical BRD did not differ in ADG (P > 0.05), whereas ADG of those with severe lung lesions (lung lobe completely consolidated or pulmonary emphysema) was 0.12 kg/d less (P < 0.05) than calves without lung lesions. Conclusions Thoracic ultrasonography detected lung consolidation in calves that did not show signs of respiratory disease. The presence of severe lung lesions was associated with reduced pre-weaning growth. These findings emphasise the importance of using TUS in addition to clinical respiratory scoring of calves for an early and accurate detection of clinical and sub-clinical BRD.

scholarly journals Experimental infection of indigenous North African goats with goatpox virus

2021 ◽  
Vol 63 (1) ◽  
Author(s):  
Jihane Hamdi ◽  
Zahra Bamouh ◽  
Mohammed Jazouli ◽  
Meryem Alhyane ◽  
Najet Safini ◽  
...  
Keyword(s):  
Antibody Response ◽  
Experimental Infection ◽  
Subcutaneous Tissue ◽  
Severe Disease ◽  
Clinical Signs ◽  
Economic Losses ◽  
North African ◽  
Cutaneous Lesions ◽  
Viral Dna ◽  
Goatpox Virus

Abstract Background Goatpox is a viral disease caused by infection with goatpox virus (GTPV) of the genus Capripoxvirus, Poxviridae family. Capripoxviruses cause serious disease to livestock and contribute to huge economic losses. Goatpox and sheeppox are endemic to Africa, particularly north of the Equator, the Middle East and many parts of Asia. GTPV and sheeppox virus are considered host-specific; however, both strains can cause clinical disease in either goats or sheep with more severe disease in the homologous species and mild or sub-clinical infection in the other. Goatpox has never been reported in Morocco, Algeria or Tunisia despite the huge population of goats living in proximity with sheep in those countries. To evaluate the susceptibility and pathogenicity of indigenous North African goats to GTPV infection, we experimentally inoculated eight locally bred goats with a virulent Vietnamese isolate of GTPV. Two uninfected goats were kept as controls. Clinical examination was carried out daily and blood was sampled for virology and for investigating the antibody response. After necropsy, tissues were collected and assessed for viral DNA using real-time PCR. Results Following the experimental infection, all inoculated goats displayed clinical signs characteristic of goatpox including varying degrees of hyperthermia, loss of appetite, inactivity and cutaneous lesions. The infection severely affected three of the infected animals while moderate to mild disease was noticed in the remaining goats. A high antibody response was developed. High viral DNA loads were detected in skin crusts and nodules, and subcutaneous tissue at the injection site with cycle threshold (Ct) values ranging from 14.6 to 22.9, while lower viral loads were found in liver and lung (Ct = 35.7 and 35.1). The results confirmed subcutaneous tropism of the virus. Conclusion Clinical signs of goatpox were reproduced in indigenous North African goats and confirmed a high susceptibility of the North African goat breed to GTPV infection. A clinical scoring system is proposed that can be applied in GTPV vaccine efficacy studies.

scholarly journals Importance and Antimicrobial Resistance of Mycoplasma bovis in Clinical Respiratory Disease in Feedlot Calves

Animals ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 1470
Author(s):  
Ana García-Galán ◽  
Juan Seva ◽  
Ángel Gómez-Martín ◽  
Joaquín Ortega ◽  
Francisco Rodríguez ◽  
...  
Keyword(s):  
Respiratory Disease ◽  
Clinical Signs ◽  
Antimicrobial Treatment ◽  
Mycoplasma Bovis ◽  
Bacterial Disease ◽  
Feedlot Calves ◽  
Fixed Panel

Bovine respiratory disease (BRD) is an important viral and/or bacterial disease that mainly affects feedlot calves. The involvement of Mycoplasma bovis in BRD can lead to chronic pneumonia poorly responsive to antimicrobial treatment. Caseonecrotic bronchopneumonia is a pulmonary lesion typically associated with M. bovis. In Spain, M. bovis is widely distributed in the feedlots and circulating isolates are resistant to most antimicrobials in vitro. However, the role of this species in clinical respiratory disease of feedlot calves remains unknown. Furthermore, available data are relative to a fixed panel of antimicrobials commonly used to treat BRD, but not to the specific set of antimicrobials that have been used for treating each animal. This study examined 23 feedlot calves raised in southeast Spain (2016–2019) with clinical signs of respiratory disease unresponsive to treatment. The presence of M. bovis was investigated through bacteriology (culture and subsequent PCR), histopathology and immunohistochemistry. The pathogen was found in 86.9% (20/23) of the calves, mainly in the lungs (78.26%; 18/23). Immunohistochemistry revealed M. bovis antigens in 73.9% (17/23) of the calves in which caseonecrotic bronchopneumonia was the most frequent lesion (16/17). Minimum inhibitory concentration assays confirmed the resistance of a selection of 12 isolates to most of the antimicrobials specifically used for treating the animals in vivo. These results stress the importance of M. bovis in the BRD affecting feedlot calves in Spain.

scholarly journals Treatment of Experimental Allergic Neuritis With Prednisolone

1987 ◽  
Vol 14 (1) ◽  
pp. 46-49 ◽  
Author(s):  
T.E. Feasby ◽  
J.J. Gilbert ◽  
A.F. Hahn ◽  
D.S. Lovgren
Keyword(s):  
Microscopic Examination ◽  
Severe Disease ◽  
Clinical Signs ◽  
Clinical Disease ◽  
Rapid Recovery ◽  
Experimental Allergic Neuritis ◽  
Nerve Roots ◽  
Lewis Rats ◽  
Experimental Allergic ◽  
Allergic Neuritis

Abstract:Experimental allergic neuritis (EAN) in Lewis rats was treated with prednisolone given prophylactically or therapeutically. Rats treated from the time of immunization with myelin or after the establishment of clinical disease improved more rapidly than controls. Treatment at the onset of clinical signs resulted in less severe disease and more rapid recovery. Rats treated just prior to the onset of clinical signs (day 10) did not develop significant clinical disease and appeared to have less inflammation in their nerves and nerve roots on microscopic examination.

Lungworms (Metastrongylus Spp.) Demonstrated in Domestic Pigs with Respiratory Disease - What was the True Relevance of that?

2021 ◽  
Author(s):  
Per Wallgren ◽  
Emelie Pettersson
Keyword(s):  
Respiratory Disease ◽  
Pasteurella Multocida ◽  
Ascaris Suum ◽  
Clinical Signs ◽  
Mycoplasma Hyopneumoniae ◽  
Disease Outbreak ◽  
Domestic Pigs ◽  
Faecal Samples ◽  
Routine Inspection ◽  
The Impact

Abstract BackgroundAn outdoor pig herd was affected by severe respiratory disease in one out of three pastures. At necropsy, Mycoplasma hyopneumoniae and Pasteurella multocida were detected in the lungs, as well as the lung worm Metastrongylus apri. The life cycle of Metastrongylus spp. includes earth worms as an intermediate host, and since domesticated pigs mainly are reared indoors lungworms has not been diagnosed in domestic pigs in Sweden for decades, not even in pigs reared outdoors. Therefore, this disease outbreak was scrutinised from the view of validating the impact of Metastrongylus spp..ResultsAt the time of the disease outbreak, neither eggs of Metastrongylus spp. nor Ascaris suum were detected in faeces of pigs aged ten weeks. In contrast, five-months-old pigs at the pasture with respiratory disease shed large amounts of eggs from Ascaris suum, whereas Ascaris suum not was demonstrated in healthy pigs aged six months at another pasture. Low numbers of eggs from Metastrongylus spp. were seen in faecal samples from both these age categories.At slaughter, seven weeks later, ten normal weighted pigs in the preceding healthy batch were compared with ten normal weighted and five small pigs from the affected batch. Healing Mycoplasma-like pneumonic lesions were seen in all groups. Small pigs had more white spot liver lesions, and all small pigs shed eggs of Ascaris suum in faeces, compared to around 50% of the pigs in the normally sized groups. Metastrongylus spp. were demonstrated in 13 of the 25 pigs (52%), %), representing all groups included.ConclusionAs Metastrongylus spp. were demonstrated regardless of health status, and in another healthy outdoor herd, the impact of Metastrongylus spp. on the outbreak of respiratory disease was depreciated. Instead, Metastrongylus spp. was suggested to be common in outdoor production, although rarely diagnosed. The reason for this is because they will escape detection at routine inspection at slaughterhouses, and that they appeared to generally not induce clinical signs of respiratory disease. Instead, a possible association with a high burden of Ascaris suum was suggested to have preceded the severe outbreak with respiratory disease.

scholarly journals Histopathology ofBordetella pertussisin the Baboon Model

2018 ◽  
Vol 86 (11) ◽  
Author(s):  
Lindsey I. Zimmerman ◽  
James F. Papin ◽  
Jason Warfel ◽  
Roman F. Wolf ◽  
Stanley D. Kosanke ◽  
...  
Keyword(s):  
Severe Disease ◽  
Clinical Signs ◽  
Human Infant ◽  
Mucus Production ◽  
Content Type ◽  
Age Related ◽  
Baboon Model ◽  
Relevant Animal Model ◽  
Significant Pathology ◽  
Conducting Airways

ABSTRACTPertussis is a severe respiratory disease caused byBordetella pertussis. The classic symptoms of pertussis include paroxysmal coughing with an inspiratory whoop, posttussive vomiting, cyanosis, and persistent coryzal symptoms. Infants under 2 months of age experience more severe disease, with most deaths occurring in this age group. Most of what is known about the pathology of pertussis in humans is from the evaluation of fatal human infant cases. The baboon model of pertussis provides the opportunity to evaluate the histopathology of severe but nonfatal pertussis. The baboon model recapitulates the characteristic clinical signs of pertussis observed in humans, including leukocytosis, paroxysmal coughing, mucus production, heavy colonization of the airway, and transmission of the bacteria between hosts. As in humans, baboons demonstrate age-related differences in clinical presentation, with younger animals experiencing more severe disease. We examined the histopathology of 5- to 6-week-old baboons, with the findings being similar to those reported for fatal human infant cases. In juvenile baboons, we found that the disease is highly inflammatory and concentrated to the lungs with signs of disease that would typically be diagnosed as acute respiratory distress syndrome (ARDS) and bronchopneumonia. In contrast, no significant pathology was observed in the trachea. Histopathological changes in the trachea were limited to cellular infiltrates and mucus production. Immunohistostaining revealed that the bacteria were localized to the surface of the ciliated epithelium in the conducting airways. Our observations provide important insights into the pathology of pertussis in typical, severe but nonfatal pertussis cases in a very relevant animal model.

scholarly journals Analysis of Virus Population Profiles within Pigs Infected with Virulent Classical Swine Fever Viruses: Evidence for Bottlenecks in Transmission but Absence of Tissue-Specific Virus Variants

2020 ◽  
Vol 94 (19) ◽  
Author(s):  
Camille Melissa Johnston ◽  
Ulrik Fahnøe ◽  
Louise Lohse ◽  
Jens Bukh ◽  
Graham J. Belsham ◽  
...  
Keyword(s):  
Classical Swine Fever Virus ◽  
Population Change ◽  
Virulent Strain ◽  
Severe Disease ◽  
Clinical Signs ◽  
Classical Swine Fever ◽  
Fever Virus ◽  
Host Cells ◽  
Virus Population ◽  
Highly Virulent

ABSTRACT Classical swine fever virus (CSFV) contains a specific motif within the E2 glycoprotein that differs between strains of different virulence. In the highly virulent CSFV strain Koslov, this motif comprises residues S763/L764 in the polyprotein. However, L763/P764 represent the predominant alleles in published CSFV genomes. In this study, changes were introduced into the CSFV strain Koslov (here called vKos_SL) to generate modified CSFVs with substitutions at residues 763 and/or 764 (vKos_LL, vKos_SP, and vKos_LP). The properties of these mutant viruses, in comparison to those of vKos_SL, were determined in pigs. Each of the viruses was virulent and induced typical clinical signs of CSF, but the vKos_LP strain produced them significantly earlier. Full-length CSFV cDNA amplicons (12.3 kb) derived from sera of infected pigs were deep sequenced and cloned to reveal the individual haplotypes that contributed to the single-nucleotide polymorphism (SNP) profiles observed in the virus population. The SNP profiles for vKos_SL and vKos_LL displayed low-level heterogeneity across the entire genome, whereas vKos_SP and vKos_LP displayed limited diversity with a few high-frequency SNPs. This indicated that vKos_SL and vKos_LL exhibited a higher level of fitness in the host and more stability at the consensus level, whereas several consensus changes were observed in the vKos_SP and vKos_LP sequences, pointing to adaptation. For each virus, only a subset of the variants present within the virus inoculums were maintained in the infected pigs. No clear tissue-dependent quasispecies differentiation occurred within inoculated pigs; however, clear evidence for transmission bottlenecks to contact animals was observed, with subsequent loss of sequence diversity. IMPORTANCE The surface-exposed E2 protein of classical swine fever virus is required for its interaction with host cells. A short motif within this protein varies between strains of different virulence. The importance of two particular amino acid residues in determining the properties of a highly virulent strain of the virus has been analyzed. Each of the different viruses tested proved highly virulent, but one of them produced earlier, but not more severe, disease. By analyzing the virus genomes present within infected pigs, it was found that the viruses which replicated within inoculated animals were only a subset of those within the virus inoculum. Furthermore, following contact transmission, it was shown that a very restricted set of viruses had transferred between animals. There were no significant differences in the virus populations present in various tissues of the infected animals. These results indicate mechanisms of virus population change during transmission between animals.

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