SARS-CoV-2 infection, neuropathogenesis and transmission among deer mice: Implications for spillback to New World rodents

Abstract

Coronavirus disease-19 (COVID-19) emerged in late 2019 in China and rapidly became pandemic. As with other coronaviruses, a preponderance of evidence suggests the virus originated in horseshoe bats (Rhinolophus spp.) and may have infected an intermediate host prior to spillover into humans. A significant concern is that SARS-CoV-2 could become established in secondary reservoir hosts outside of Asia. To assess this potential, we challenged deer mice (Peromyscus maniculatus) with SARS-CoV-2 and found robust virus replication in the upper respiratory tract, lungs and intestines, with detectable viral RNA for up to 21 days in oral swabs and 6 days in lungs. Virus entry into the brain also occurred, likely via gustatory-olfactory-trigeminal pathway with eventual compromise to the blood-brain barrier. Despite this, no conspicuous signs of disease were observed, and no deer mice succumbed to infection. Expression of several innate immune response genes were elevated in the lungs, including IFNα, IFNβ, Cxcl10, Oas2, Tbk1 and Pycard. Elevated CD4 and CD8β expression in the lungs was concomitant with Tbx21, IFNγ and IL-21 expression, suggesting a type I inflammatory immune response. Contact transmission occurred from infected to naive deer mice through two passages, showing sustained natural transmission and localization into the olfactory bulb, recapitulating human neuropathology. In the second deer mouse passage, an insertion of 4 amino acids occurred to fixation in the N-terminal domain of the spike protein that is predicted to form a solvent-accessible loop. Subsequent examination of the source virus from BEI Resources determined the mutation was present at very low levels, demonstrating potent purifying selection for the insert during in vivo passage. Collectively, this work has determined that deer mice are a suitable animal model for the study of SARS-CoV-2 respiratory disease and neuropathogenesis, and that they have the potential to serve as secondary reservoir hosts in North America.

Predicting the zoonotic capacity of mammals to transmit SARS-CoV-2

“…These are among the most well-studied mammals in North America, in part due to their status as zoonotic reservoirs for multiple zoonotic pathogens and parasites [116][117][118]. Experimental infection, viral shedding, and sustained intraspecific transmission of SARS-CoV-2 were recently confirmed for P. maniculatus [51,52], but similar studies have not been conducted for P. leucopus, which is widely distributed across the eastern United States and Mexico.…”

“…Our model predictions matched the results of several recently published in vivo studies on SARS-CoV-2 infection (Figure 1). For instance, experiments on deer mice (Peromyscus maniculatus; [51,52]) and raccoon dogs (Nyctereutes procyonoides; [47]) confirmed SARS-CoV-2 infection and transmission to naive conspecifics. Our model also estimated a high probability of zoonotic capacity of American mink for SARS-CoV-2 (Neovison vison, probability=0.83, 90th percentile), in which farmed individuals present severe infection from human spillback, and demonstrate the capacity to transmit to conspecifics as well as to humans [11,46].…”

But Mouse, you are not alone: On some severe acute respiratory syndrome coronavirus 2 variants infecting mice

“…Further details are provided under Supplementary Methods for Molecular Modelling. We then compared our insilico findings with experimental results reported by different research groups with mouse adapted strains/isolates [6][7][8]13,[21][22][23][24][25][26][27][28][29] and VOC 14,[30][31][32][33][34] (Table 1). Taken together, we were able to gain valuable insights into the likely effects of different mutations of consequence.…”

Neuropsychiatric manifestations of COVID-19, potential neurotropic mechanisms, and therapeutic interventions

“…Previous studies in mice showed that the neurotropic influenza virus could invade the CNS from the respiratory mucosa and the vagus nerve directly [ 130 ]. SARS-CoV-2 was directly injected into deer mice, and immunohistochemistry examinations showed the presence of SARS-CoV-2 in trigeminal ganglionic neurons, neurons, and microglia of the afferent nerves, and the glomerular layer of the olfactory bulb, indicating that this virus may enter into the brain via the gustatory-olfactory-trigeminal pathway [ 131 ]. SARS-CoV-2 was also shown to invade the CNS in rhesus monkeys primarily via the olfactory bulb, subsequently spreading to multiple brain regions, including the hippocampus, thalamus, and medulla oblongata, and causing neuroinflammation and local pathological changes [ 132 ].…”