Human Lungs Show Limited Permissiveness for SARS-CoV-2 Due to Scarce ACE2 Levels But Strong Virus-Induced Immune Activation in Alveolar Macrophages

Expression of SARS-CoV-2 Entry Factors in the Pancreas of Normal Organ Donors and Individuals with COVID-19

“…Rather, preferential ACE2 gene and protein expression in microvascular and ductal structures suggests these cells constitute a more likely target for viral infection, a notion that is in principle supported by our observation of very limited SARS-CoV-2 NP expression in ductal epithelium, but not islet endocrine cells, of pancreata from individuals with COVID-19. While scarce ACE2 protein expression and limited SARS-CoV-2 propagation, as most recently documented for the lung ( Hönzke et al., 2020 ), do not preclude extensive tissue damage mediated by innate immune responses in particular, the absence of polymorphonuclear infiltrations in the three COVID-19 pancreata interrogated here indicates a very limited degree of inflammation consistent with that reported for many tissues other than the lung and reticulo-endothelial system ( Dorward et al., 2020 ). More detailed investigations of pancreatic tissue from fatal COVID-19 cases, to date a very limited resource, will be necessary to answer outstanding questions about the potential pathological involvement of the pancreas in COVID-19.…”

“…Without question and in addition to stem cell-derived endocrine cells and islet organoids, isolated human islets constitute an important model system for research discovery. Further work will be needed to precisely quantify the fractions and expression levels of ACE2 by islet endocrine cells in these islet preparations, to evaluate possible modulation of ACE2 by the prolonged and varied islet handling requirements (e.g., isolation, culture under different conditions, dispersion), to define the exact role of ACE2 in mediating SARS-CoV-2 infection in vitro and in vivo using extended islet xenotransplantation approaches, and to interrogate the precise relation of scarce ACE2 expression and immunopathology as most recently demonstrated for the lung in a manuscript available for public review ( Hönzke et al., 2020 ). Beyond this, contrasting epidemiological reports from the United Kingdom and Germany ( Tittel et al., 2020 ; Unsworth et al., 2020 ) not only underscore the requirement for data on diabetes incidence and SARS-CoV-2 infection rates in defined populations over time, but in addition raise the need for studying pancreatic tissues from donor cohorts of different demographics, ethnicities, and geographic populations.…”

Longitudinal omics in Syrian hamsters integrated with human data unravel cellular effector responses to moderate COVID-19

“…Presumably, in the lung SARS-CoV-2 primarily infects AT2 cells 23 . Of note, only few of them were infected and they reacted with only marginal transcriptional responses, which is probably explained by the recent observation in human lungs that less than 10% of AT2 cells express the crucial entry receptor ACE2 45 . Moreover, coronaviruses are endowed with a multitude of mechanisms that block immunological cascades downstream of interferon signaling and cytoplasmic RNA sensing 49 .…”

Multifunctional angiotensin converting enzyme 2, the SARS-CoV-2 entry receptor, and critical appraisal of its role in acute lung injury

“…Although, the respiratory system is not a prominent ACE2-expressing organ, such as the intestines and kidneys, due to the air-born nature of the virus, mucosal cells of the upper respiratory tract and bronchial cells of the lower respiratory tract have been suggested as main target regions for viral replication. Compared to intestines and kidneys, the expression of ACE2 is more than two orders of magnitude lower in the lungs of rodents [ 201 ] and humans [ 200 ], and a small fraction (1 %<) of alveolar type 2 cells expresses ACE2 [ [202] , [203] , [204] , [205] , [206] ].…”

“…In agreement with this study, a gradient of decreasing ACE2 expression from nasal to intrapulmonary bronchial regions was reported [ 208 ]. Notably, progressively reduced amounts of ACE2 expression were observed in the lower airway regions, culminating in minimal amounts in the alveolar region [ 205 , 208 ]. Thus, it was suggested that, due to scarce ACE2 expression, SARS-CoV-2 shows limited ability to propagate in the human alveolar compartment and that lung injury in COVID-19 most likely results from an immune activation rather than direct viral damage of the alveolar compartment [ 205 ].…”