The pigtail macaque (Macaca nemestrina) model of COVID-19 reproduces diverse clinical outcomes and reveals new and complex signatures of disease

Abstract

The novel coronavirus SARS-CoV-2, the causative agent of COVID-19 disease, has killed over four million people worldwide as of July 2021 with infections rising again due to the emergence of highly transmissible variants. Animal models that faithfully recapitulate human disease are critical for assessing SARS-CoV-2 viral and immune dynamics, for understanding mechanisms of disease, and for testing vaccines and therapeutics. Pigtail macaques (PTM, Macaca nemestrina) demonstrate a rapid and severe disease course when infected with simian immunodeficiency virus (SIV), including the development of severe cardiovascular symptoms that are pertinent to COVID-19 manifestations in humans. We thus proposed this species may likewise exhibit severe COVID-19 disease upon infection with SARS-CoV-2. Here, we extensively studied a cohort of SARS-CoV-2-infected PTM euthanized either 6- or 21-days after respiratory viral challenge. We show that PTM demonstrate largely mild-to-moderate COVID-19 disease. Pulmonary infiltrates were dominated by T cells, including CD4+ T cells that upregulate CD8 and express cytotoxic molecules, as well as virus-targeting T cells that were predominantly CD4+. We also noted increases in inflammatory and coagulation markers in blood, pulmonary pathologic lesions, and the development of neutralizing antibodies. Together, our data demonstrate that SARS-CoV-2 infection of PTM recapitulates important features of COVID-19 and reveals new immune and viral dynamics and thus may serve as a useful animal model for studying pathogenesis and testing vaccines and therapeutics.

A Single Dose SARS-CoV-2 Replicon RNA Vaccine Induces Cellular and Humoral Immune Responses in Simian Immunodeficiency Virus Infected and Uninfected Pigtail Macaques

“…Many nonhuman primate species including rhesus macaques (Macaca mulatta), cynomolgus macaques (Macaca fascicularis), African green monkeys (Chlorocebus aethiops) and pigtail macaques reported here (Macaca nemestrina), have been critical for investigating COVID-19 disease and pre-clinical testing of COVID-19 vaccines (31,32). Recent findings from Melton et al, demonstrate moderate SARS-CoV-2 disease in pigtail macaques (33), as compared to the more mild disease observed in rhesus macaques, but with similar levels of viral load in respiratory mucosa between the two species (34). There are several unique features of the pigtail macaque model of HIV infection that are worth noting.…”

Medical imaging of pulmonary disease in SARS-CoV-2-exposed non-human primates

“…In general, BAL and imaging should be concurrently used with caution, as BAL may produce CXR or CT imaging artifacts when performed on consecutive days [72], interfere with pulmonary pathogenesis (within-lung spread), and potentially confound histopathology. Of the 41 NHP SARS-CoV-2 studies examined, 24 used BAL during the infection phase and included imaging [12][13][14][15][16]20,[22][23][24][27][28][29][30]33,35,50,51,53,54,56,65,73,74]. Eight included single BAL immediately before or at necropsy [12,20,22,33,54,57,65,73].…”

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

“…Accordingly, multiple nonhuman primate (NHP) species have been experimentally infected with SARS-CoV-2, with most studies focusing on Chlorocebus aethiops (African green monkeys, AGMs) or Macaca mulatta (Rhesus macaques, RMs). Other examples of species studied include Macaca nemestrina (Southern pigtail macaque) 7 , Macaca leonina (Northern pigtail macaque) 8 , Macaca fascicularis (Cynomolgus macaque) 9 , Callithrix jacchus (Common marmoset) and Papio hamadryas (Baboon) 10 . Most of these models involve installation of the virus directly to mucosal surfaces 11,12 , though some have included the aerosol modality of exposure 13 .…”