Pathogenesis of SARS-Cov-2 infection in NHP model: insights for treatment and prevention – AM-Cov-Path

AM-COV-Path aims at the development of a non-human primate model of the SArS-CoV-2 infection and disease. We will use this model to study the mechanisms of transmission and pathogenesis, focusing on dynamics of viral dissemination, the associated tissue damages in the respiratory tract and at sites which also exhibit high expression of ACE2 receptor like the heart and the kidney. Biomarkers of disease progression that may guide future therapeutic strategies will be characterized, including inflammatory response and metabolic changes by combining different omic technologies and in vivo imaging. Key parameters of adaptive immune T and B cell response will be studied to inform future immune therapies and vaccine developments. Of particular interest will be the characterization of B cells producing protective antibodies that can be used to generate future monoclonal therapeutic immunoglobulins.
Based on our previous experience with viral respiratory diseases, the consortium will study the changes in the gut microbiota composition, which might modulate the differentiation of myeloid progenitors and thus distally modulate innate immune defenses in the lung compartment.
The impact of dose of virus exposure, and the age of animals (neonates, young adults, and aged macaques) will be characterized. We surmise based on preliminary data that these factors may significantly modulate the disease development, so providing an opportunity to enrich understanding pathogenic mechanisms, for instance by comparing models with mild and severe disease. We will also work at establishing a model of aerosol exposure, better mimicking natural transmission.
Finally, based on the generated experimental data, we will develop in silico models of viral dynamics in interaction with unraveled biomarkers of disease progression. These models will be highly valuable to test hypothesis on pathogenic mechanisms and to accelerate therapeutic and vaccines developments by reducing the need for multiple preclinical and clinical trials.