Identification of a suitable nonhuman primate (NHP) model of COVID-19 remains challenging. Here, we characterized severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in three NHP species: Old World monkeys Macaca mulatta (M. mulatta) and Macaca fascicularis (M. fascicularis) and New World monkey Callithrix jacchus (C. jacchus). Infected M. mulatta and M. fascicularis showed abnormal chest radiographs, an increased body temperature and a decreased body weight. Viral genomes were detected in swab and blood samples from all animals. Viral load was detected in the pulmonary tissues of M. mulatta and M. fascicularis but not C. jacchus. Furthermore, among the three animal species, M. mulatta showed the strongest response to SARS-CoV-2, including increased inflammatory cytokine expression and pathological changes in the pulmonary tissues. Collectively, these data revealed the different susceptibilities of Old World and New World monkeys to SARS-CoV-2 and identified M. mulatta as the most suitable for modeling COVID-19.
COVID-19, caused by SARS-CoV-2 infection, has recently been announced as a pandemic all over the world. Plenty of diagnostic, preventive and therapeutic knowledges have been enriched from clinical studies since December 2019. However, animal models, particularly non-human primate models, are urgently needed for critical questions that could not be answered in clinical patients, evaluations of anti-viral drugs and vaccines. In this study, two families of non-human primates, old world monkeys (12 Macaca mulatta, 6 Macaca fascicularis) and new world monkeys (6 Callithrix jacchus), were experimentally inoculated with SARS-CoV-2. Clinical signs were recorded. Samples were collected for analysis of viral shedding, viremia and histopathological examination. Increased body temperature was observed in 100% (12/12) M. mulatta, 33.3% (2/6) M. fascicularis and none (0/6) of C. jacchus post inoculation of SARS-CoV-2. All of M. mulatta and M. fascicularis showed chest radiographic abnormality. Viral genomes were detected in nasal swabs, throat swabs, anal swabs and blood from all 3 species of monkeys. Viral shedding from upper respiratory reached the peak between day 6 and day 8 post inoculation. From necropsied M. mulatta and M. fascicularis, tissues showing virus positive were mainly lung, weasand, bronchus and spleen. No viral genome was seen in any of tissues from 2 necropsied C.jacchus. Severe gross lesions and histopathological changes were observed in lung, heart and stomach of SARS-CoV-2 infected animals. In summary, we have established a NHP model for COVID-19, which could be used to evaluate drugs and vaccines, and investigate viral pathogenesis. M. mulatta is the most susceptible to SARS-CoV2 infection, followed by M. fascicularis and C. jacchus. One Sentence Summary:M. mulatta is the most susceptible to SARS-CoV-2 infection as compared to M. fascicularis and C. jacchus.
The COVID-19 has emerged as an epidemic, causing severe pneumonia with a high infection rate globally. To better understand the pathogenesis caused by SARS-CoV-2, we developed a rhesus macaque model to mimic natural infection via the nasal route, resulting in the SARS-CoV-2 virus shedding in the nose and stool up to 27 days. Importantly, we observed the pathological progression of marked interstitial pneumonia in the infected animals on 5–7 dpi, with virus dissemination widely occurring in the lower respiratory tract and lymph nodes, and viral RNA was consistently detected from 5 to 21 dpi. During the infection period, the kinetics response of T cells was revealed to contribute to COVID-19 progression. Our findings implied that the antiviral response of T cells was suppressed after 3 days post infection, which might be related to increases in the Treg cell population in PBMCs. Moreover, two waves of the enhanced production of cytokines (TGF-α, IL-4, IL-6, GM-CSF, IL-10, IL-15, IL-1β), chemokines (MCP-1/CCL2, IL-8/CXCL8, and MIP-1β/CCL4) were detected in lung tissue. Our data collected from this model suggested that T cell response and cytokine/chemokine changes in lung should be considered as evaluation parameters for COVID-19 treatment and vaccine development, besides of observation of virus shedding and pathological analysis.
Quantifications of gastro-oesophageal anatomy in cadavers have led some to identify the lower oesophageal sphincter (LOS) with the anatomical gastric sling-clasp fibres at the oesophago-cardiac junction (OCJ). However, in vivo studies have led others to argue for two overlapping components proximally displaced from the OCJ: an extrinsic crural sphincter of skeletal muscle and an intrinsic physiological sphincter of circular smooth-muscle fibres within the abdominal oesophagus. Our aims were to separate and quantify in vivo the skeletal and smooth muscle sphincteric components pharmacologically and clarify the description of the LOS. In two protocols an endoluminal ultrasound-manometry assembly was drawn through the human gastro-oesophageal segment to correlate sphincteric pressure with the anatomic crus. In protocol I, fifteen normal subjects maintained the costal diaphragm at inferior/superior positions by full inspiration/expiration (FI/FE) during pull-throughs. These were repeated after administering atropine to suppress the cholinergic smooth-muscle sphincter. The cholinergic component was reconstructed by subtracting the atropine-resistant pressures from the full pressures, referenced to the anatomic crus. To evaluate the extent to which the cholinergic contribution approximated the full smooth-muscle sphincter, in protocol II seven patients undergoing general anaesthesia for non-oesophageal pathology were administered cisatracurium to paralyse the crus. The smooth-muscle sphincter pressures were measured after lung inflation to approximate FI. The cholinergic smooth-muscle pressure profile in protocol I (FI) matched closely the post-cisatracurium smooth-muscle pressure profile in protocol II, and the atropine-resistant pressure profiles correlated spatially with the crural sling during diaphragmatic displacement. Thus, the atropine-resistant and cholinergic pressure contributions in protocol I approximated the skeletal and smooth muscle sphincteric components. The smooth-muscle pressures had well-defined upper and lower peaks. The upper peak overlapped and displaced rigidly with the crural sling, while the distal peak separated from the crus/upper-peak by 1.1 cm between FI and FE. These results suggest the existence of separate upper and lower intrinsic smooth-muscle components. The 'upper LOS' overlaps and displaces with the crural sling consistent with a physiological LOS. The distal smooth-muscle pressure peak defines a 'lower LOS' that likely reflects the gastric sling/clasp muscle fibres at the OCJ. The distinct physiology of these three components may underlie aspects of normal sphincteric function, and complexity of sphincter dysfunction. Underlying the function of the gastro-oesophageal sphincter is a complex anatomy, physiology and mechanics that is necessary to regulate oesophageal emptying into the stomach and to permit air venting and wanted regurgitation, while protecting against unwanted reflux of gastric content. The relative tonic contributions to the protective function of the gastro-oesop...
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