SARS-CoV-2 infection of African green monkeys results in mild respiratory disease discernible by PET/CT imaging and prolonged shedding of infectious virus from both respiratory and gastrointestinal tracts

Hartman, Amy L.; Nambulli, Shamkumar; McMillen, Cynthia M.; White, Alexander G.; Tilston-Lunel, Natasha L.; Albe, Joseph R.; Cottle, Emily L.; Dunn, Matthew D.; Frye, L. James; Gilliland, Theron; Olsen, Emily L; O’Malley, Katherine J.; Schwarz, Madeline M.; Tomko, Jaime; Walker, Reagan C.; Xia, Mengying; Hartman, Matthew; Klein, Edwin; Scanga, Charles A.; Flynn, JoAnne L.; Klimstra, William B.; McElroy, Anita K.; Reed, Douglas S.; Duprex, W. Paul

doi:10.1101/2020.06.20.137687

Cited by 43 publications

(43 citation statements)

References 39 publications

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“…Major differences in study design may account for the discrepancy between our results and those of prior studies utilizing AGMs including the age of the animals and the strain of virus that was used. Apart from the severe phenotype observed in two of the animals, our findings are otherwise consistent with prior studies with the surviving AGMs showing mild clinical disease, pathology, and prolonged viral shedding (15,18). The RMs in our study also exhibited mild clinical disease and pathology with shorter viral shedding from mucosal sites compared to the AGMs.…”

Section: Discussionsupporting

confidence: 91%

“…NHPs are ideal candidates for the modeling of human respiratory viral infections. Several recent studies have been published utilizing AGMs (15,18) and RMs (16,17) to model SARS-CoV-2 infection and have shown both species are capable of modeling mild to moderate disease and are useful for testing prospective vaccines and therapeutics. However, none of these prior studies have been able to recapitulate the spontaneous, severe disease phenotype seen in a subset of people with COVID-19.…”

Section: Discussionmentioning

confidence: 99%

“…Nonhuman primates (NHPs) are ideally suited to model respiratory human viral infections primarily because of the similarities to human respiratory anatomy and immunologic responses when compared to other animal species. Several NHP species have already been successfully employed to model pathogenesis (15)(16)(17)(18)(19) and test vaccine candidates (20)(21)(22)(23) for SARS-CoV-2. These prior studies have shown NHPs are susceptible to infection and develop mild to moderate disease, but none has been able to recapitulate the rapid clinical deterioration seen in people with severe disease and ARDS.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Blair

Vaccari

Doyle-Meyers

et al. 2020

Preprint

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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 ...

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Blair

Vaccari

Doyle-Meyers

et al. 2020

Preprint

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“…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 .…”

Section: Discussionmentioning

confidence: 99%

Comparative ACE2 variation and primate COVID-19 risk

Melin

Janiak

Marrone

et al. 2020

Preprint

116

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The emergence of the novel coronavirus SARS-CoV-2, which in humans is highly infectious and leads to the potentially fatal disease COVID-19, has caused tens of thousands of deaths and huge global disruption. The viral infection may also represent an existential threat to our closest living relatives, the nonhuman primates, many of which have already been reduced to small and endangered populations. The virus engages the host cell receptor, angiotensin-converting enzyme-2 (ACE2), through the receptor binding domain (RBD) on the spike protein. The contact surface of ACE2 displays amino acid residues that are critical for virus recognition, and variations at these critical residues are likely to modulate infection susceptibility across species. While infection studies have shown that rhesus macaques exposed to the virus develop COVID-19-like symptoms, the susceptibility of other nonhuman primates is unknown. Here, we show that all apes, including chimpanzees, bonobos, gorillas, and orangutans, and all African and Asian monkeys (catarrhines), exhibit the same set of twelve key amino acid residues as human ACE2.Monkeys in the Americas, and some tarsiers, lemurs and lorisoids, differ at significant contact residues, and protein modeling predicts that these differences should greatly reduce the binding affinity of the ACE2 for the virus, hence moderating their susceptibility for infection. Other lemurs are predicted to be closer to catarrhines in their susceptibility. Our study suggests that apes and African and Asian monkeys, as well as some lemurs are all likely to be highly susceptible to SARS-CoV-2, representing a critical threat to their survival. Urgent actions may be necessary to limit their exposure to humans.

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“…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].…”

Section: Introductionmentioning

confidence: 99%

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

Cross

Agans

Prasad

et al. 2020

Preprint

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We recently reported the development of the first African green monkey (AGM) model for COVID-19 based on a combined liquid intranasal (i.n.) and intratracheal (i.t.) exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we followed up on this work by assessing an i.n. particle only route of exposure using the LMA mucosal atomization device (MAD). Six AGMs were infected with SARS-CoV-2; three animals were euthanized near the peak stage of virus replication (day 5) and three animals were euthanized during the early convalescence period (day 34). All six AGMs supported robust SARS-CoV-2 replication and developed respiratory disease. Evidence of coagulation dysfunction as noted by a transient increases in aPTT and circulating levels of fibrinogen was observed in all AGMs. The level of SARS-CoV-2 replication and lung pathology was not quite as pronounced as previously reported with AGMs exposed by the combined i.n. and i.t. routes; however, SARS-CoV-2 RNA was detected in nasal swabs of some animals as late as day 15 and rectal swabs as late as day 28 after virus challenge. Of particular importance to this study, all three AGMs that were followed until the early convalescence stage of COVID-19 showed substantial lung pathology at necropsy as evidenced by multifocal chronic interstitial pneumonia and increased collagen deposition in alveolar walls despite the absence of detectable SARS-CoV-2 in any of the lungs of these animals. These findings are consistent with human COVID-19 further demonstrating that the AGM faithfully reproduces the human condition.

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SARS-CoV-2 infection of African green monkeys results in mild respiratory disease discernible by PET/CT imaging and prolonged shedding of infectious virus from both respiratory and gastrointestinal tracts

Cited by 43 publications

References 39 publications

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

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

Comparative ACE2 variation and primate COVID-19 risk

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

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