SARS-CoV-2 continues to spread across the globe at an exponential rate with increasing numbers of patients in the hospital. Due to the rapid spread, much remains to be understood about viral pathogenesis and host immune response to infection. Immunological features of COVID-19 progression include a robust pro- inflammatory response driven by innate and adaptive immune cells. Importantly, very recent studies suggest that deficiency in type-I interferon (IFN) signaling is associated with life-threatening COVID-19 outcomes in previously healthy individuals. Establishment of a non-human primate model of severe SARS-CoV-2 infection could prove essential for understanding SARS-CoV-2 pathogenesis and for preclinical testing of candidate antiviral agents and immune modulators able to reduce the extent of viral replication and the excessive inflammation. Herein, we are proposing extensive and state-of-the-art immunologic analyses in SARS-CoV-2 infected rhesus macaques (RMs) to identify markers of inflammation and disease severity that can be used to develop a standardized and robust RM/NHP model of COVID-19 (Aim #1). Furthermore, we will block, specifically and directly in vivo, type- I IFN responses in SARS-CoV-2-infected RMs (Aim #2) via administration of a type-I IFN antagonist (IFN-I ant). This intervention will elucidate the roles of type-I IFN in protecting the host from severe COVID-19 progression and investigate if a short-term IFN-I ant treatment can establish a severe and reproducible NHP COVID-19 model. Additionally, specimens collected longitudinally and at necropsy will be cryo-banked to be shared and used among the COVTEN consortium for validation of established SOPs as well as for addressing additional questions related to COVID-19 inflammation and pathogenesis. The advantage of tracking pathogenesis, immune responses, and viral replication longitudinally, including very early after infection, and across multiple tissues, including lung, heart, and brain, will allow us to address our critical questions with a depth and rigor that is virtually impossible to achieve in humans. These achievements will provide key insights into the mechanisms of SARS-CoV-2 pathogenesis, and will deliver a robust NHP model for prioritizing and accelerating the development of the most promising candidate therapeutics. This study will cross-validate COVTEN SOPs and establish a robust model to be utilized by the ACTIV consortium.

Public Health Relevance

Given the global impetus to develop therapeutics able to reduce COVID-19 morbidity and mortality, we are proposing a series of rigorous and highly controlled studied in SARS-CoV-2 infected rhesus macaques to (i) identify signatures of inflammation and disease severity; (ii) elucidate the role of type-I IFN in protection from severe COVID-19; and (iii) block type-I IFN responses to establish a severe and reproducible NHP COVID-19 model.

Agency
National Institute of Health (NIH)
Institute
Office of The Director, National Institutes of Health (OD)
Type
Primate Research Center Grants (P51)
Project #
3P51OD011132-60S4
Application #
10321484
Study Section
Program Officer
Hild, Sheri Ann
Project Start
2020-12-23
Project End
2021-04-30
Budget Start
2021-03-01
Budget End
2021-04-30
Support Year
60
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Emory University
Department
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Kumar, Nitasha A; McBrien, Julia B; Carnathan, Diane G et al. (2018) Antibody-Mediated CD4 Depletion Induces Homeostatic CD4+ T Cell Proliferation without Detectable Virus Reactivation in Antiretroviral Therapy-Treated Simian Immunodeficiency Virus-Infected Macaques. J Virol 92:
Raper, J; De Biasio, J C; Murphy, K L et al. (2018) Persistent alteration in behavioural reactivity to a mild social stressor in rhesus monkeys repeatedly exposed to sevoflurane in infancy. Br J Anaesth 120:761-767
Hunter, Carissa E; Pongos, Alvince L; Chi, Tim Y et al. (2018) Longitudinal Anthropometric Assessment of Rhesus Macaque (Macaca mulatta) Model of Huntington Disease. Comp Med 68:163-167
Aguilar-Valenzuela, Renan; Netland, Jason; Seo, Young-Jin et al. (2018) Dynamics of Tissue-Specific CD8+ T Cell Responses during West Nile Virus Infection. J Virol 92:
Martin, Allison L; Franklin, Andrea N; Perlman, Jaine E et al. (2018) Systematic assessment of food item preference and reinforcer effectiveness: Enhancements in training laboratory-housed rhesus macaques. Behav Processes 157:445-452
Ulloa, M; Portillo, W; Díaz, N F et al. (2018) Mating and social exposure induces an opioid-dependent conditioned place preference in male but not in female prairie voles (Microtus ochrogaster). Horm Behav 97:47-55
Beck, Goichi; Maehara, Shunsuke; Chang, Phat Ly et al. (2018) A Selective Phosphodiesterase 10A Inhibitor Reduces L-Dopa-Induced Dyskinesias in Parkinsonian Monkeys. Mov Disord 33:805-814
Godfrey, Jodi R; Diaz, Maylen Perez; Pincus, Melanie et al. (2018) Diet matters: Glucocorticoid-related neuroadaptations associated with calorie intake in female rhesus monkeys. Psychoneuroendocrinology 91:169-178
Putnam, Philip T; Young, Larry J; Gothard, Katalin M (2018) Bridging the gap between rodents and humans: The role of non-human primates in oxytocin research. Am J Primatol 80:e22756
Osako, Yoji; Nobuhara, Reiko; Arai, Young-Chang P et al. (2018) Partner Loss in Monogamous Rodents: Modulation of Pain and Emotional Behavior in Male Prairie Voles. Psychosom Med 80:62-68

Showing the most recent 10 out of 810 publications