Пораженные макрофаги
Ученые из Стенфорда приходят к выводу, что за тяжелый ковид (ТОРС), могут быть ответственны активированные макрофаги брюшной полости. С началом инфекции в легких они прибегают "спасать", но в результате, в них оказывается слишком много вирусного материала (возможно и заражение, включая и не через АСЕ2 рецепторы (тк накопление вируса идет и при блокировке этих рецепторов, и в макрофагах обнаруживается синтезированная РНК вируса), и из-за чрезмерного фагоцитоза). Альвеолярные макрофгаи так от коронавируса не страдают (и не выделяют стлько цитокинов).
Нахватавшиеся вируса чрезмерно (или зараженные) популяции макрофагов и ответственны за зашкаливающие уровни цитокиинов воспаления (и разлаженного иммунного овтета), которые выделяются при инфекции и приводят к обширным поражениям завирушенных и окружающих тканей.
Возможно, если каким-то образом повлиять на эту популяцию макрофагов, которая является мишенью для коронавируса, можно "умерить" течение ковида.
[Spoiler (click to open)]
Early stages of deadly respiratory diseases such as COVID-19 have been challenging to elucidate due to lack of an experimental system that recapitulates the cellular and structural complexity of the human lung, while allowing precise control over disease initiation and systematic interrogation of molecular events at cellular resolution. Here we show healthy human lung slices cultured ex vivo can be productively infected with SARS-CoV-2, and the cellular tropism of the virus and its distinct and dynamic effects on host cell gene expression can be determined by single cell RNA sequencing and reconstruction of "infection pseudotime" for individual lung cell types. This revealed the prominent SARS-CoV-2 target is a population of activated interstitial macrophages, which as infection proceeds accumulate thousands of viral RNA molecules per cell, comprising up to 60% of the cellular transcriptome and including canonical and novel subgenomic RNAs. During viral takeover, there is cell-autonomous induction of a specific host interferon program and seven chemokines (CCL2, 7, 8, 13, CXCL10) and cytokines (IL6, IL10), distinct from the response of alveolar macrophages in which neither viral takeover nor induction of a substantial inflammatory response occurs. Using a recombinant SARS-CoV-2 Spike pseudotyped lentivirus, we show that entry into purified human lung macrophages depends on Spike but is not blocked by cytochalasin D or by an ACE2-competing monoclonal antibody, indicating a phagocytosis- and ACE2-independent route of entry. These results provide a molecular characterization of the initiation of COVID-19 in human lung tissue, identify activated interstitial macrophages as a prominent site of viral takeover and focus of inflammation, and suggest targeting of these macrophages and their signals as a new therapeutic modality for COVID-19 pneumonia and progression to ARDS. Our approach can be generalized to define the initiation program and evaluate therapeutics for any human lung infection at cellular resolution.
Нахватавшиеся вируса чрезмерно (или зараженные) популяции макрофагов и ответственны за зашкаливающие уровни цитокиинов воспаления (и разлаженного иммунного овтета), которые выделяются при инфекции и приводят к обширным поражениям завирушенных и окружающих тканей.
Возможно, если каким-то образом повлиять на эту популяцию макрофагов, которая является мишенью для коронавируса, можно "умерить" течение ковида.
[Spoiler (click to open)]
Early stages of deadly respiratory diseases such as COVID-19 have been challenging to elucidate due to lack of an experimental system that recapitulates the cellular and structural complexity of the human lung, while allowing precise control over disease initiation and systematic interrogation of molecular events at cellular resolution. Here we show healthy human lung slices cultured ex vivo can be productively infected with SARS-CoV-2, and the cellular tropism of the virus and its distinct and dynamic effects on host cell gene expression can be determined by single cell RNA sequencing and reconstruction of "infection pseudotime" for individual lung cell types. This revealed the prominent SARS-CoV-2 target is a population of activated interstitial macrophages, which as infection proceeds accumulate thousands of viral RNA molecules per cell, comprising up to 60% of the cellular transcriptome and including canonical and novel subgenomic RNAs. During viral takeover, there is cell-autonomous induction of a specific host interferon program and seven chemokines (CCL2, 7, 8, 13, CXCL10) and cytokines (IL6, IL10), distinct from the response of alveolar macrophages in which neither viral takeover nor induction of a substantial inflammatory response occurs. Using a recombinant SARS-CoV-2 Spike pseudotyped lentivirus, we show that entry into purified human lung macrophages depends on Spike but is not blocked by cytochalasin D or by an ACE2-competing monoclonal antibody, indicating a phagocytosis- and ACE2-independent route of entry. These results provide a molecular characterization of the initiation of COVID-19 in human lung tissue, identify activated interstitial macrophages as a prominent site of viral takeover and focus of inflammation, and suggest targeting of these macrophages and their signals as a new therapeutic modality for COVID-19 pneumonia and progression to ARDS. Our approach can be generalized to define the initiation program and evaluate therapeutics for any human lung infection at cellular resolution.