Post-mortem dissection of COVID-19: a pathogenic role for macrophages?

Pulmonary macrophages and SARS-Cov2 infection

“…Interestingly, that report demonstrated that patients with a longer duration of symptoms (who were more likely to have had established respiratory failure) and those receiving invasive mechanical ventilation had the greatest benefit, while in patients not on oxygen there was a trend towards worse outcomes with dexamethasone treatment. Overall, these data are consistent with a requirement for early robust inflammation in response to infection, but in later stage disease inflammation directly contributing to disease severity ( Velu et al, 2021 ). Understanding what “type” of inflammation drives disease pathogenesis remains critical to understanding how best to intervene with therapeutics in clinical trials and has been a major focus of COVID-19 research.…”

“…But can more targeted therapeutics aiming to disrupt inflammatory macrophages be beneficial? This could take the approach of interfering with recruitment, their longevity within inflamed pulmonary tissue or blocking liberation of pro-inflammatory molecules identified in the above studies ( Velu et al, 2021 ). Interestingly, both blocking ( Temesgen et al, 2021 ) and augmenting ( Bosteels et al, 2020 ) GM-CSF has been reported as having promise while preliminary studies on the tolerability of C5 blockade in human COVID-19 are beginning to appear ( Zelek, 2020 ), but further studies to test therapeutic efficacy are awaited.…”

“…These observations raised early suspicion that host factors were principally responsible for driving deleterious pulmonary inflammation and exacerbating organ damage, something that is now borne out by numerous studies of the host immune response as well as the reductions in mortality afforded by anti-inflammatory treatment with the glucocorticoid dexamethasone, as well as interleukin-6 receptor blockade ( NEJM, 2021 ; The Lancet, 2021 ). There is now compelling evidence that dysregulated monocytes and macrophages are a key feature of severe COVID-19 ( Velu et al, 2021 ). How and why these cells come to play such a deleterious role is incompletely understood.…”

Pannexin 1 drives efficient epithelial repair after tissue injury

“…Nras and Bcas2 were of particular interest as Ras family members are known to be activated downstream of EGF receptor signaling to regulate various physiological processes including proliferation ( 31 ), and Bcas2 is an oncogene known to positively affect clonogenicity and migration of breast cancer cells ( 32 , 33 ). Further, Bcas2 is in the top 1% of host genes linked to SARS-CoV-2 infection per the 'metaanalysis by information content' (MAIC) algorithm ( 34 ), with severe disease characterized by impaired epithelial regeneration ( 5 , 35 ).…”

Modelling the within-host spread of SARS-CoV-2 infection, and the subsequent immune response, using a hybrid, multiscale, individual-based model. Part I: Macrophages

“…Although the model presented supports macrophages, monocytes, neutrophils, and natural killer cells, we choose to focus only on macrophages for the purposes of this article. The reason for this choice, is primarily due to model complexity, but is also informed by mounting evidence suggesting an important role for macrophages [58, 59]. Evidence suggests that there is an early loss of resident alveolar macrophages, as well as a recruitment of inflammatory interstitial and monocyte-derived macrophages (see e.g.…”