“Acute Respiratory Distress and Cytokine Storm in Aged, SARS-CoV-2 Infected African Green Monkeys, but not in Rhesus Macaques”

Abstract

26SARS-CoV-2 induces a wide range of disease severity ranging from asymptomatic 27 infection, to a life-threating illness, particularly in the elderly and persons with comorbid 28 conditions. Up to now, SARS-CoV-2 has infected more than five million and led to more 29 than 300,000 deaths worldwide. Among those persons with serious COVID-19 disease, 30 acute respiratory distress syndrome (ARDS) is a common and often fatal presentation. 31 SARS-CoV-2-induced ARDS is difficult to treat clinically, and new therapeutic strategies 32 are needed. In order to evaluate such therapeutic strategies, animal models of SARS-CoV-2 33 infection that manifest severe disease are needed. Here we report fatal ARDS in two 34 African green monkeys (AGMs) infected with SARS-CoV-2 that demonstrated pathological 35 lesions and disease similar to severe COVID-19 in humans. Moreover, we report the 36 observation of cytokine release (cytokine storm) in three of four infected AGMs. All four 37 animals showed increased levels of IL-6 in plasma, a predictive marker and presumptive 38 therapeutic target in humans infected with SARS-CoV-2 infection. Our results suggest the 39 AGM is a useful model to study disease pathogenesis of SARS-CoV-2, and for the 40 evaluation of therapeutic interventions designed to combat serious pulmonary disease 41 associated with this infection. 42The coronavirus disease-2019 (COVID-19) pandemic, caused by the novel coronavirus, severe 43 acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has resulted in the deaths of hundreds 44 of thousands of people and has caused massive economic and health disruptions across the globe. 45This unprecedented level of disruption has been driven by two main features of SARS-CoV-2: its 46 high rate of person-to-person transmissibility and the potential to cause severe, life-threatening, 47 pneumonia. Although severe disease is only seen in a small subset of infected people 1 , it is this 48 outcome and minimal understanding of its pathogenesis that has resulted in global unrest. 49Research into the causes and mechanisms of the most severe manifestations of COVID-19 is 50 needed to inform and facilitate the development of prophylactic and therapeutic approaches that 51 can prevent this life-threatening outcome. 53Infection with SARS-CoV-2 and development of COVID-19 results in a mild respiratory disease 54 for most individuals. However, a small subset progress to develop severe respiratory disease 55 which in some cases is fatal 1 . The most severely affected individuals often present with a fever, 56 cough, dyspnea, and bilateral radiographic opacities that in the majority of critically ill patients 57 progresses to acute respiratory distress syndrome (ARDS) 2 . The onset of ARDS is often 58 associated with an increase in circulating pro-inflammatory cytokines resulting in a cytokine 59 release syndrome colloquially referred to as a "cytokine storm" 3,4 . Interleukin-6 (IL-6), in 60 particular has been shown to correlate with radiographic scores in patients with SARS-CoV-2 61 ...

Comparative ACE2 variation and primate COVID-19 risk

“…S2). Consistent with our results, infection studies show that rhesus monkeys (Macaca mulatta), longtailed macaques (M. fascicularis) and vervets (Chlorocebus sabaeus) are permissive to infection by SARS-CoV-2, and go on to develop COVID-19 like symptoms [11][12][13][14]16 . Our results based on protein modeling offer potentially better news for monkeys in the Americas (platyrrhines).…”

“…Nonetheless, the overall pattern of our results is being borne out by infection studies on a few species that are used as biomedical models. So far, all catarrhine species tested by infection studies, including rhesus macaques, longtailed macaques, and vervet monkeys 13,14,64 have exhibited COVID-19-like symptoms in response to infection, including large lung and other organ lesions 13 and cytokine storms 14 . In contrast, marmosets did not exhibit major symptoms in response to infection 13 .…”

“…Infection studies of rhesus monkeys, longtailed macaques, and vervets as biomedical models have made it clear that at least some nonhuman primate species are permissive to SARS-CoV-2 infection and develop symptoms in response to infection that resemble those of humans following the development of COVID-19, including similar age-related effects [11][12][13][14][15][16] . Recognizing the potential danger of COVID-19 to nonhuman primates, the International Union for the Conservation of Nature (IUCN), together with the Great Apes section of the Primate Specialist Group, released a joint statement on precautions that should be taken for researchers and caretakers when interacting with great apes 17 .…”

Intranasal exposure of African green monkeys to SARS-CoV-2 results in acute phase pneumonia with shedding and lung injury still present in the early convalescence phase

“…We previously reported the development of the AGM as a promising animal model of human COVID-19 [10]. Other studies have subsequently reported similar findings [11,12]. The focus of the current study was to assess a more natural route of human exposure, specifically an exposure mimicking an infection resulting from mucosal exposure to infectious droplets expelled from close quarter exposure to a sneeze, cough, or even speech in order to begin characterization of lung pathology in the early convalescence phase of COVID-19.…”

“…Both small animal models and nonhuman primates (NHP) may prove valuable in triaging the most promising medical countermeasures prior to use in humans. Hamsters and ferrets are currently being used as immunocompetent small animal models of COVID-19 [3][4][5] while several NHP models have been quickly developed [6][7][8][9][10][11][12]. Among the nonhuman primate models evaluated the African green monkey (AGM) appears to best recapitulate the most salient features of human COVID-19 [10][11][12].…”