Myeloid cell-driven nonregenerative pulmonary scarring is conserved in multiple nonhuman primate species regardless of SARS-CoV-2 infection modality

Abstract

The novel coronavirus SARS-CoV-2 has caused a worldwide pandemic resulting in widespread efforts in development of animal models that recapitulate human disease for evaluation of medical countermeasures, and to dissect COVID-19 immunopathogenesis. We tested whether route of experimental infection substantially changes COVID-19 disease characteristics in two species (Macaca mulatta; rhesus macaques; RM, Chlorocebus atheiops; African green monkeys; AGM) of nonhuman primates. Species-specific cohorts of RM and AGM Rhesus macaques (Macaca mulatta, RMs) and African green monkeys (Chlorocebus aethiops, AGMs) were experimentally infected with homologous SARS-CoV-2 by either direct mucosal instillation or small particle aerosol in route-discrete subcohorts. Both species demonstrated equivalent infection initially by either exposure route although the magnitude and duration of viral loading was greater in AGMs than that of the RM. Clinical onset was nearly immediate (+1dpi) in mucosally-exposed cohorts whereas aerosol-infected animals began to show signs +7dpi. Myeloid cell responses indicative of the development of pulmonary scarring and extended lack of regenerative capacity in the pulmonary compartment was a conserved pathologic response in both species by either exposure modality. This pathological commonality may be useful in future anti-fibrosis therapeutic evaluations and expands our understanding of how SARS-CoV-2 infection leads to ARDS and functional lung damage.

Intra-Host SARS-CoV-2 Evolution in the Gut of Mucosally-Infected Chlorocebus aethiops (African Green Monkeys)

“…Eight RhM and eight AGM were challenged with SARS-CoV-2, WA1/2020 isolate, as described [22]. Briefly, four of each species were challenged via the combined intratracheal/intranasal route (2 × 10 6 TCID50) and four via aerosolized virus from the same stock.…”

“…All animals were euthanized four weeks after infection. Viral dynamics were largely the same regardless of route, and AGM tended, on average, to have detectable viral RNA for a longer period, including multiple animals that maintained replicating virus (as evidenced by qRT PCR detection of subgenomic viral RNA) in rectal swab samples for the entirety of the study [22]. Unfortunately, most samples from that study were exhausted and could not be used for sequencing.…”

“…In this study, a focused set of gastrointestinal samples from a previous study [22] was used to examine viral dynamics in SARS-CoV-2 infected African green monkeys (AGM). Consistent patterns of evolution were identified, suggestive of adaptive evolution.…”