Immune Correlates of Hyperglycemia and Vaccination in a Non-human Primate Model of Long-COVID (preprint)

Hyperglycemia, and exacerbation of pre-existing deficits in glucose metabolism, are major manifestations of the post-acute sequelae of SARS-CoV-2 (PASC). Our understanding of lasting glucometabolic disruptions after acute COVID-19 remains unclear due to the lack of animal models for metabolic PASC. Here, we report a non-human primate model of metabolic PASC using SARS-CoV-2 infected African green monkeys (AGMs). Using this model, we have identified a dysregulated chemokine signature and hypersensitive T cell population during acute COVID-19 that correlates with elevated and persistent hyperglycemia four months post-infection. This persistent hyperglycemia correlates with elevated hepatic glycogen, but there was no evidence of long-term SARS-CoV-2 replication in the liver and pancreas. Finally, we report a favorable glycemic effect of the SARS-CoV-2 mRNA vaccine, administered on day 4 post-infection. Together, these data suggest that the AGM metabolic PASC model exhibits important similarities to human metabolic PASC and can be utilized to assess therapeutic candidates to combat this syndrome.

Neuropathology and Virus in Brain of SARS-CoV-2 Infected Non-Human Primates (preprint)

Neurological manifestations are a significant complication of coronavirus infection disease-19 (COVID-19). Understanding how COVID-19 contributes to neurological disease is needed for appropriate treatment of infected patients, as well as in initiating relevant follow-up care after recovery. Investigation of autopsied brain tissue has been key to advancing our understanding of the neuropathogenesis of a large number of infectious and non-infectious diseases affecting the central nervous system (CNS). Due to the highly infectious nature of the etiologic agent of COVID-19, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), there is a paucity of tissues available for comprehensive investigation. Here, we show for the first time, microhemorrhages and neuropathology that is consistent with hypoxic injury in SARS-CoV-2 infected non-human primates (NHPs). Importantly, this was seen among infected animals that did not develop severe respiratory disease. This finding underscores the importance of vaccinating against SARS-CoV-2, even among populations that have a reduced risk for developing of severe disease, to prevent long-term or permanent neurological sequelae. Sparse virus was detected in brain endothelial cells but did not associate with the severity of CNS injury. We anticipate our findings will advance our current understanding of the neuropathogenesis of SARS-CoV-2 infection and demonstrate SARS-CoV-2 infected NHPs are a highly relevant animal model for investigating COVID-19 neuropathogenesis among human subjects.

Cellular events of acute, resolving or progressive COVID-19 in SARS-CoV-2 infected non-human primates (preprint)

We investigated the immune events following SARS-CoV-2 infection, from the acute inflammatory state up to four weeks post infection, in non-human primates (NHP) with heterogeneous pulmonary pathology. The acute phase was characterized by a robust and rapid migration of monocytes expressing CD16 from the blood and concomitant increase in CD16+ macrophages in the lungs. We identified two subsets of interstitial macrophages (HLA-DR+ CD206-), a transitional CD11c+ CD16+ cell population that was directly associated with IL-6 levels in plasma, and one long lasting CD11b+ CD16+ cell population. Strikingly, levels of monocytes were a correlate of viral replication in bronchial brushes and we discovered TARC (CCL17) as a new potential mediator of myeloid recruitment to the lungs. Worse disease outcomes were associated with high levels of cell infiltration in lungs including CD11b+ CD16hi macrophages and CD11b+ neutrophils. Accumulation of macrophages was long-lasting and detectable even in animals with mild or no signs of disease. Interestingly, animals with anti-inflammatory responses including high IL-10:IL-6 and kynurenine to tryptophan ratios had less signs of disease. Our results unravel cellular mechanisms of COVID-19 and suggest that NHP may be appropriate models to test immune therapies.

ARDS and Cytokine Storm in SARS-CoV-2 Infected Caribbean Vervets (preprint)

SARS-CoV-2 induces a wide range of disease severity ranging from asymptomatic infection, to a life-threating illness, particularly in the elderly and persons with comorbid conditions. Up to now, SARS-CoV-2 has infected more than five million and led to more than 300,000 deaths worldwide. Among those persons with serious COVID-19 disease, acute respiratory distress syndrome (ARDS) is a common and often fatal presentation. SARS-CoV-2-induced ARDS is difficult to treat clinically, and new therapeutic strategies are needed. In order to evaluate such therapeutic strategies, animal models of SARS-CoV-2 infection that manifest severe disease are needed. Here we report fatal ARDS in two African green monkeys (AGMs) infected with SARS-CoV-2 that demonstrated pathological lesions and disease similar to severe COVID-19 in humans. Moreover, we report the observation of cytokine release (cytokine storm) in three of four infected AGMs. All four animals showed increased levels of IL-6 in plasma, a predictive marker and presumptive therapeutic target in humans infected with SARS-CoV-2 infection. Our results suggest the AGM is a useful model to study disease pathogenesis of SARS-CoV-2, and for the evaluation of therapeutic interventions designed to combat serious pulmonary disease associated with this infection.