Eliminating Potential Effects of Other Infections During Selection of Nonhuman Primates for COVID-19 Research

Abstract

The study of nonhuman primates (NHP) can provide significant insights into our understanding numerous infectious agents. The etiological agent of COVID-19, SARS-CoV-2 virus, first emerged in 2019 and has so far been responsible for the deaths of over 4 million people globally. In the frenzied search to understand its pathogenesis and immunology and to find measures for prevention and control of this pandemic disease, NHP, particularly macaques, are the preferred model because they manifest similar clinical signs and immunologic features as humans. However, possible latent, subclinical, and opportunistic infections not previously detected in animals participating in a study may obscure experimental results and confound data interpretations in testing treatments and vaccine studies for COVID-19. Certain pathophysiologic changes that occur with SARS-CoV-2 virus infection are similar to those of simian pathogens. The current review discusses numerous coinfections of COVID-19 with other diseases and describes possible outcomes and mechanisms in COVID-19 studies of NHP that have coinfections. Due to the urgency triggered by the pandemic, screening that is more rigorous than usual is necessary to limit background noise and maximize the reliability of data from NHP COVID-19 studies. Screening for influenza virus, selected respiratory bacteria, and regional endemic pathogens such as vector-borne agents, together with the animal's individual exposure history, should be the main considerations in selecting a NHP for a COVID-19 study. In addition, because NHP are susceptible to the SARS-CoV-2 virus, management and surveillance measures should be established to prevent transmission to healthy animals from infected colony animals and husbandry staff. This review presents compiled data on the use of NHP in COVID-19 studies, emphasizing the need to create the most reliable NHP model for those studies by extensive screening for other pathogens.

Figure 1.

Immunopathogenesis of SARS-CoV-2 virus in an experimentally infected rhesus monkey (Macaca mulatta). Adapted from Chatterjee and colleagues (2020). Scheme created by BioRender - http://BioRender.com.

Figure 2.

Mechanism of action and life cycle of the SARS-CoV-2 virus, with emphasis on the entry site into the cell membrane through the ACE-2 and TMPRSS2 receptors. Adapted from Machhi and colleagues (2020) and Monteil and colleagues (2020). Scheme created by BioRender - http://BioRender.com.

Figure 3.

Pre-experiment screening recommendations for COVID-19 studies in nonhuman primates. STLV: Simian T-Lymphotropic Virus; SRV/D: Simian Retrovirus type D; SIV: Simian Immunodeficiency Virus; SFV: Simian Foamy Virus; BV: Herpesvirus B; HAV: Hepatitis A virus; HBV: Hepatitis B Virus; FLU: Influenza virus. TB: Tuberculosis. Selection of animals is divided into the clinical and pathogen research phases. Animals with positive (+) and indeterminate (?) results are excluded from the study, while negative are selected. Viral panel includes serology and confirmation with molecular tests. Tuberculosis (TB) history in the animal husbandry requires association of tests. Pathogens were highlighted according to the FELASA recommendations, alerting endemics in the region and pathogens included in the health history of the scientific animal creation. Other clinical tests and pathogens based on each experimental protocol should be considered. Scheme created by BioRender - http://BioRender.com.

Figure 4.

Pathophysiological changes caused by the SARS-CoV-2 virus and coinfections with other simian pathogens, possible mechanisms of coinfections and outcomes in COVID-19 studies with the primate model. ^aRespiratory bacteria: Streptococcus pneumoniae, Bordetella bronchiseptica, Klebsiella pneumoniae and Burkholderia pseudomallei; ^bVector-borne infections: arboviruses, such as dengue, yellow fever, zika virus and chikungunya; ^cGastrointestinal bacteria: Campylobacter, Salmonella, Shigella, Yersinia; ^dIntestinal parasites: Entamoeba histolytica, Balantidium coli, Giardia sp., Strongyloides, Trichuris; ^eOpportunistic agents: herpesviruses (that is cytomegalovirus, epstein-barr virus), rotavirus, SV40, candidiasis, cryptosporidiosis, histoplasmosis, toxoplasmosis, candidiasis, aspergillosis, gastrointestinal agents, respiratory agents.