Nonhuman primate (NHP) models will expedite therapeutics and vaccines for COVID-19 into clinical trials. We compared acute SARS-CoV-2 infection in young and old rhesus macaques and baboons and old marmosets. Macaques had clinical signs of viral infection, mild-to-moderate pneumonitis and extra-pulmonary pathologies; both age groups recovered in two weeks. Baboons had prolonged viral RNA shedding and substantially more lung inflammation compared with macaques. Inflammation in bronchoalveolar lavage (BAL) was increased in old versus young baboons. Using techniques like CT imaging, immunophenotyping, alveolar/peripheral cytokine responses and immunohistochemical analyses, we delineated cellular immune responses to SARS-CoV-2 infection in macaque and baboon lungs, including innate and adaptive immune cells and a prominent Type I-interferon response. Macaques developed T cell memory phenotype/responses and bystander cytokine production. Old macaques had lower titres of SARS-CoV-2-specific IgG antibody levels compared with young. Acute respiratory distress in macaques and baboons recapitulates the progression of COVID-19 in humans, making them suitable as models to test vaccines and therapies.

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Foot stiffness underlies its mechanical function, and is central to the evolution of human bipedal locomotion. [1][2][3][4][5] The stiff and propulsive human foot has two distinct arches, the longitudinal and transverse. [3][4][5] By contrast, the feet of non-human primates are flat and softer. 6-8 Current understanding of foot stiffness is based on studies that focus solely on the longitudinal arch, [9][10][11][12][13][14] and little is known about the mechanical function of the transverse arch. However, common experience suggests that transverse curvature dominates the stiffness; a drooping dollar bill stiffens significantly upon curling it along the transverse direction, not the longitudinal. We derive a normalized curvature parameter that encapsulates the geometric principle 15 underlying the transverse curvature-induced stiffness. We show that the transverse arch accounts for almost all the difference in stiffness between human and monkey feet (vervet monkeys and pig-tailed macaques) by comparing transverse curvature-based predictions against published data on foot stiffness. 6,7 Using this functional interpretation of the transverse arch, we trace the evolution of hominin feet [16][17][18][19][20] and show that a human-like stiff foot likely predates Homo by ∼ 1.5 million years, and appears in the ∼ 3.4 million year old fossil from Burtele. 19 A distinctly human-like transverse arch is also present in early members of Homo, including Homo naledi, 20 Homo habilis, 16 and Homo erectus. 17 However, the ∼ 3.2 million year old Australopithecus afarensis 18 is estimated to have possessed a transitional foot, softer than humans and stiffer than other extant primates. A foot with human-like stiffness probably evolved around the same time as other lower limb adaptations for regular bipedality, 3,18,21,22 and well before the emergence of Homo, the longitudinal arch, and other adaptations for endurance running. 2 *

SARS-CoV-2 virus has infected more than 92 million people worldwide resulting in the Coronavirus disease 2019 (COVID-19). Using a rhesus macaque model of SARS-CoV-2 infection, we have characterized the transcriptional signatures induced in the lungs of juvenile and old macaques following infection. Genes associated with Interferon (IFN) signaling, neutrophil degranulation and innate immune pathways are significantly induced in macaque infected lungs, while pathways associated with collagen formation are downregulated, as also seen in lungs of macaques with tuberculosis. In COVID-19, increasing age is a significant risk factor for poor prognosis and increased mortality. Type I IFN and Notch signaling pathways are significantly upregulated in lungs of juvenile infected macaques when compared with old infected macaques. These results are corroborated with increased peripheral neutrophil counts and neutrophil lymphocyte ratio in older individuals with COVID-19 disease. Together, our transcriptomic studies have delineated disease pathways that improve our understanding of the immunopathogenesis of COVID-19.