Defining the Innate Immune Responses for SARS-CoV-2-Human Macrophage Interactions

Abstract

Host innate immune response follows severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and it is the driver of the acute respiratory distress syndrome (ARDS) amongst other inflammatory end-organ morbidities. Such life-threatening coronavirus disease 2019 (COVID-19) is heralded by virus-induced activation of mononuclear phagocytes (MPs; monocytes, macrophages, and dendritic cells). MPs play substantial roles in aberrant immune secretory activities affecting profound systemic inflammation and end-organ malfunctions. All follow the presence of persistent viral components and virions without evidence of viral replication. To elucidate SARS-CoV-2-MP interactions we investigated transcriptomic and proteomic profiles of human monocyte-derived macrophages. While expression of the SARS-CoV-2 receptor, the angiotensin-converting enzyme 2, paralleled monocyte-macrophage differentiation, it failed to affect productive viral infection. In contrast, simple macrophage viral exposure led to robust pro-inflammatory cytokine and chemokine expression but attenuated type I interferon (IFN) activity. Both paralleled dysregulation of innate immune signaling pathways, specifically those linked to IFN. We conclude that the SARS-CoV-2-infected host mounts a robust innate immune response characterized by a pro-inflammatory storm heralding end-organ tissue damage.

Macrophages only sense infectious SARS-CoV-2 when they express sufficient ACE2 to permit viral entry, where rapid cytokine responses then limit viral replication

“…This is in line with multiple reports of abortive SARS-CoV-2 infection of macrophages in vitro ( 8 , 9 , 20 , 21 ). While these studies observe that macrophage infection results in decreasing viral RNA levels ( 8 , 9 , 20 ), lack of new infectious virus ( 8 , 20 ), and decreasing viral protein ( 21 ), they nevertheless report virus entry into macrophages via quantification of SARS-CoV-2 nucleoprotein-positive cells. This is in contrast to studies reporting no infection of macrophages ( 3 , 22 ).…”

“…Our results agree with published observations that SARS-CoV-2 does not trigger cytokine production from HMDM ( 22 ), and that SARS-CoV-2 also fails to trigger the interferon system in human alveolar macrophages ( 21 ). Findings from us and others ( 21 , 22 ) are, however, at odds with other reports that SARS-CoV-2 selectively induces a pro-inflammatory response (e.g., TNF, IL-6, CXCL10) from HMDM ( 8 , 9 , 20 ). It is possible that differences in the preparation or quantification of viral stocks may underpin these divergent observations.…”

“…The contribution of macrophages to potent and effective innate responses to control SARS-CoV-2 infection is controversial. While there is consensus that SARS-CoV-2 infection of human monocyte derived macrophages (HMDM) is abortive (3,8,9,(20)(21)(22), some studies report that macrophages are susceptible to the early-stages of SARS-CoV-2 infection (i.e. viral entry) and replication, (i.e.…”

“…viral entry) and replication, (i.e. viral RNA replication and protein synthesis) ( 8 , 9 , 20 ), while others report no viral entry into macrophages ( 3 , 22 ). Accordingly, whether macrophage susceptibility to SARS-CoV-2 is required to trigger inflammatory and anti-viral signalling is unclear, with multiple reports suggesting that macrophage infection triggers pro-inflammatory responses ( 8 , 9 , 23 ) while others report that infection does not activate macrophage inflammatory functions ( 3 , 22 ).…”

Dynamic Changes in Central and Peripheral Neuro-Injury vs. Neuroprotective Serum Markers in COVID-19 Are Modulated by Different Types of Anti-Viral Treatments but Do Not Affect the Incidence of Late and Early Strokes

“…Furthermore, ferritin is used to gauge the degree of inflammation in several inflammatory processes and COVID-19 [ 122 , 125 , 126 , 127 ]. The activation of macrophages, frequently reflected by an increase in ferritin, was suggested as one of the major drivers of COVID-19 evolution and was related to the degree of neuronal degeneration and injury in general [ 26 , 83 , 122 , 125 , 128 , 129 , 130 ]. Elevations in CCL23, a cytokine involved in the recruitment of leukocytes to nervous system compartments and linked to vascular injury-related stroke, could suggest an influx of peripheral leukocytes into the brain [ 68 , 69 , 70 ].…”