Spatiotemporal interplay of severe acute respiratory syndrome coronavirus and respiratory mucosal cells drives viral dissemination in rhesus macaques

Abstract

Innate immune responses play a critical role in the control of early virus replication and dissemination. It remains unknown, however, how SARS-CoV evades respiratory innate immunity to establish a systemic infection. Here, we show in Chinese macaques that SARS-CoV traversed the mucosa through the respiratory tract within 2 days, resulting in extensive mucosal infiltration by T cells, MAC387+ and CD163+ monocytes/macrophages followed by limited viral replication in the lung but persistent viral shedding into the upper airway. Mucosal monocytes/macrophages sequestered virions in intracellular vesicles together with infected Langerhans cells (LCs) and migrated into the tonsils and/or draining lymph nodes (LNs) within 2 days. In lymphoid tissues, viral RNA and proteins were detected in infected monocytes upon differentiation into dendritic cells (DCs) within 3 days. Systemic viral dissemination was observed within 7 days. This study provides a comprehensive overview of the spatiotemporal interactions of SARS-CoV, monocytes/macrophages and the dendritic cell network in mucosal tissues and highlights the fact that while these innate cells contribute to viral clearance, they probably also serve as shelters and vehicles to provide a mechanism for the virus to escape host mucosal innate immunity and disseminate systemically.

Anti–spike IgG causes severe acute lung injury by skewing macrophage responses during acute SARS-CoV infection

“…In our previous study, i.n. inoculation of Chinese macaques with SARS-CoV PUMC (1 × 10 5 TCID 50 ) led to lower respiratory tract infection in all animals within 2 days (25). However, most of them rapidly cleared infection in the lungs, and all of the animals (n = 8) exhibited mild lung lesions before 3 dpi (25).…”

“…Naive macaques were challenged i.n. with 1 × 10 5 TCID 50 SARS-CoV PUMC and sacrificed at 2, 3, and 7 dpi (4 macaques/group) ( Figure 5A) (25). Successful lower respiratory tract infection was confirmed by detection of viral NP using IHC staining in the lungs of all macaques (25).…”

“…We previously found that pulmonary infection of Chinese macaques could be rapidly controlled. Viral RNA + cells were detectable in the lungs of only 2 of 4 animals at 2 dpi, although all of them were viral nucleoprotein-positive (NP + ) in the lungs and the hilar lymph nodes (LNs), where the lymphatics of the lungs drain (25). Therefore, we measured viral RNA + cells by in situ hybridization (ISH), as well as NP signals in the lungs and the hilar LNs by IHC staining to evaluate the actual pulmonary infection of each macaque.…”

“…To understand the S-IgG-caused excessive inflammation, we further defined macrophage heterogeneity and activation statues in the lung lesions of C-IgG (n = 1) and S-IgG recipients (n = 3) at 2 dpi. Three healthy macaques and 4 naive Chinese macaques challenged with the same dose of SARS-CoV PUMC and scarified at 2 dpi from a previous study were included as controls (25).…”

“…with 1 × 10 5 TCID 50 SARS-CoV PUMC and sacrificed at 2, 3, and 7 dpi (4 macaques/group) ( Figure 5A) (25). Successful lower respiratory tract infection was confirmed by detection of viral NP using IHC staining in the lungs of all macaques (25). Viral RNA + alveolar pneumocytes were primarily found at 2 dpi (2 of 4 macaques), and infrequently at 3 dpi (0 of 4 macaques; Figure 5B and Supplemental Table 4) (25).…”