In a recent study posted to the bioRxiv* preprint server, researchers studied the kinetics of host response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in a golden Syrian hamster model. They tracked disease pathology, viral loads, antibody responses, and inflammatory cytokine production in multiple organs.
Immunocompetent and immunocompromised hamsters were used to examine the kinetics of SARS-CoV-2 pathogenesis and the genome-wide lung transcriptome.
Study: Comprehensive analysis of disease pathology in immunocompetent and immunocompromised hamster models of SARS-CoV-2 infection. Image Credit: CKA/Shutterstock
Coronavirus disease 2019 (COVID-19) pathogenesis is linked to immune system changes in the host, which start early in the infection and lead to uncontrolled SARS-CoV-2 proliferation. SARS-CoV-2 pathogenesis in the setting of a unique immune niche is still unknown. To comprehend pathological complications, it is necessary to examine the degree of disease pathology in the extrapulmonary system.
About the study
In this study, hamsters were intranasally infected with a low dose (LD) or high dose (HD) inoculum of the virus to better understand disease pathophysiology after pulmonary SARS-CoV-2 infection. To measure replicating viral load in distinct tissues, the researchers used a plaque-forming unit (PFU) assay on tissue homogenates. The effect of immune suppression on SARS-CoV-2 replication and time to viral clearance in tissues was then investigated. Infectious virus was identified in tissue homogenates after hamsters were given cyclophosphamide and inoculated with LD inoculum.
On hematoxylin and eosin-stained sections, histopathological examinations of SARS-CoV-2 infected lung tissues were performed at 4, 7, and 16 dpi (days post-infection). Since hypertension is linked to arteriolar smooth muscle growth in the lungs and kidneys and hepatocyte steatosis is frequent in COVID-19 patients, the researchers examined if hamsters infected with SARS-CoV-2 showed any of these symptoms.
They also used smRNA FISH to look at the expression of ACE2, CD147, and SARS-CoV-2 in lung cells. RNAseq analysis of immunocompetent and immunosuppressed hamster lungs was performed at 4 dpi (acute) and 16 dpi (chronic) to learn more about the pulmonary response to SARS-CoV-2 infection. Then, in immunocompetent animals, they looked at the gene networks and pathways that were differentially impacted by SARS-CoV-2 infection at 4dpi and 16dpi. The researchers examined the RNAseq data at 4 dpi and 16 dpi between these two groups after normalization to uninfected controls to evaluate the differential regulation of gene networks and pathways in the lungs of immunocompromised versus immunocompetent hamsters infected with SARS-CoV-2.
Results and conclusion
The results showed that the pulmonary system of the hamsters had the largest viral load and that SARS-CoV-2 had spread to other organs by extrapulmonary transmission. Despite a 5 log difference in the initial infectious inoculum between the LD and HD doses, a similar virus load was reported in various LD and HD infected hamster tissues. Neutralizing antibodies were detectable at 7 dpi in the hamster trials, and viral clearance correlated with the emergence of these serum neutralizing antibodies. As in other investigations, the viral neutralizing antibody titer in these hamsters was proportional to the virus’s initial infectious dose.
In the sera of infected immunocompromised hamsters, the researchers found no SARS-CoV-2 neutralizing antibodies, which was also described in a prior investigation. As a result, no viral clearance was detected in immunocompromised animals infected with SARS-CoV-2 up to 16 days after infection. The B cell activation network genes CD19, CD22, CD72, and FcgR were downregulated among the immunocompromised hamsters infected with SARS-CoV-2, according to lung RNA expression analyses on 16 dpi.
Infected immunocompromised animals had lower IL4 expression, which is required for B cell development. In addition, immunocompromised hamsters have substantially atrophied splenic lymphoid follicles as compared to immunocompetent hamsters. In comparison to immunocompetent hamsters, SARS-CoV-2-infected immunocompromised hamsters experienced modest pulmonary lymphocytic infiltration and poor clearance of pneumonia, as well as a protracted weight loss.
Infected immunocompetent and immunocompromised hamsters had higher amounts of inflammatory cytokines. Furthermore, hamsters infected with an HD of the virus lost much more weight. Inflammation and disease pathology were also more pronounced in these animals than in LD-infected animals. Even though HD-infected hamsters had more severe hyperinflammation than LD hamsters, the expression of cytokines in LD and HD was not statistically different, with the exception of IFNG (4 dpi) and IL4 (16 dpi).
Infectious-inoculum dose-dependent thickening of bronchiolar smooth muscles was reported in SARS CoV-2-infected hamsters. In addition, the researchers found substantial smooth muscle hypertrophy/hyperplasia in the SARS-CoV-2 infected hamster pulmonary and renal arterioles, as well as pulmonary artery rupture in some animals, as reported in human clinical investigations. Both LD and HD SARS CoV-2-infected hamsters showed moderate degeneration and steatosis. In immunocompetent and immunocompromised hamsters, acute tubular epithelial necrosis of the kidneys was found following SARS-CoV-2 infection.
In conclusion, the hamster models’ histopathologic findings closely resemble the clinical and pathological signs seen in human COVID-19 cases. The pathogenesis, tissue injury, and viral transmission within and beyond the infected animal may all be studied using the two hamster models described in this study. These models can also be used as a preclinical tool to test possible COVID-19 intervention techniques like medicines and vaccinations.
Bodyweight loss was more prominent and prolonged in infected immunocompromised hamsters.”
*Important notice
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
