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Makrofagi i komórki dendrytyczne nie są głównym źródłem cytokin prozapal

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Recent studies showed that the observed cytokine storm in COVID-19 patients might be an important factor in disease progression. The role of innate immune cells in the production of pro-inflammatory cytokines is still under discussion. Surprisingly, we could not observe production of pro-inflammatory cytokines by SARS-CoV-2 infected mDC, M1-, or M2 macrophages in vitro (see Figure 4). In stark contrast to our data, several ex vivo and in vitro studies showed that SARS-CoV-2 infected macrophages, but not DC, are capable of producing pro-inflammatory cytokines such as IL-6 or TNF-α (18, 2831). Moreover, a recent study performed by Zheng et al. demonstrated in vitro differentiated mDC and macrophages to produce IFN-α, TNF-α, and IL-6 upon SARS-CoV-2 infection (35).In correlation with this, high levels of IL-6 in critically ill COVID-19 patients are assumed to be produced by highly inflammatory macrophages (40). It was previously shown that SARS-CoV-2 efficiently suppresses the antiviral type I IFN response in monocytes and macrophages which might result in a delay of viral clearance and contribute to COVID-19 pathogenesis (29, 30, 41). In line with this, alveolar macrophages did not produce type I IFN upon in vitro infection with SARS-CoV-2 (42). Furthermore, Delagado-Ortega et al. revealed that rather epithelial cells than alveolar macrophages are capable to produce cytokines such as IFN-β upon swine influenza infection (43). Of note, in most severe cases of COVID-19, the immune dysregulation leading to the massive cytokine release is observed around day 7-10 post infection supporting our data that cells others than innate immune cells are the source of the first wave of pro-inflammatory cytokines (17, 44, 45).
Co-infections can cause altered disease severity and transmissibility by viral interference or modulation of viral replication or cytokine production (46). To investigate the influence of SARS-CoV-2 infection on secondary infections, co-infection/-stimulation experiments were performed. Our data revealed that SARS-CoV-2 infection did not significantly increase IL-6 production induced by most stimuli tested. Flu-induced IL-6 production was slightly enhanced in M2 macrophages. This minor increase was statistically significant but whether the levels of induced IL-6 are of biological relevance is not clear yet. A study by Ma et al. demonstrated a more severe inflammatory response and organ injury in critically ill COVID-19 patients when co-infected with influenza A virus. The authors claim that co-infection may lead to an earlier and stronger cytokine storm. In correlation with our data, no differences in IL-6, TNF-α, and other clinical parameters, such as white blood cell counts, levels of c-reactive protein (CRP), alanine aminotransferase (ALT), aspartate transaminase (AST), lactate dehydrogenase (LDH), and creatinine, could be observed (47). In vitro and in vivo studies revealed that pre-infection with influenza strongly enhances infectivity of SARS-CoV-2 by boosting viral entry in the cells and by elevating viral loads resulting in a more severe lung damage in infected mice (48). In line with this, Stowe et al. reported that co-infection with influenza and SARS-CoV-2 was associated with an increased risk of death or severe disease (49). Furthermore, Saade et al. demonstrated that porcine reproductive and respiratory syndrome virus (PRRSV) does not infect respiratory epithelial cells but is able to inhibit replication of swine influenza A upon co-infection. In addition, type I IFN responses were modulated indicating that interaction between swine influenza A and its targets cells might are altered upon co-infection (50). In contrast, SeV, human rhinovirus (HRV3), human parainfluenza virus (HPIV), human respiratory syncytial virus (HRSV), and human enterovirus 71 (EV71) were all unable to facilitate SARS-CoV-2 infection of transgenic hACE2 mice (48). Interestingly, a large-scale assessment of SARS-CoV-2 co-infection with 38 other respiratory pathogens revealed that infection rates were significantly higher when patients were infected with SARS-CoV-2 when compared to SARS-CoV-2 negative patients (51).
In conclusion, our study demonstrated that in vitro differentiated human innate immune cells are able to be infected by SARS-CoV-2 without generating progeny. The activation status of all cell types analyzed changes only slightly upon SARS-CoV-2 infection. In addition, neither mDC nor M1- nor M2 macrophages were stimulated to produce pro-inflammatory cytokines upon SARS-CoV-2 infection. In contrast to several studies defining DC and macrophages as a potential source of IL-6 (18, 2831), our data indicate that innate immune cells are unlikely the main source of the initial wave of pro-inflammatory cytokines upon severe SARS-CoV-2 infection. Even upon co-infection/-stimulation with a broad range of other TLR stimuli or viruses, production of pro-inflammatory cytokines by the cells analyzed was not substantially altered upon infection with SARS-CoV-2.

https://www.frontiersin.org/articles/10.3389/fimmu.2021.647824/full

Przeprowadzone przez Grupę Kapitałową Emitenta w latach ubiegłych, badania kliniczne fazy II w Kanadzie w dyslipidemii, wykazały, że 1-MNA obniżał istotnie statystycznie poziom TNF-alpha. W ocenie Emitenta 1-MNA może być skuteczną terapią w leczeniu pacjentów z COVID-19, ponieważ jego zastosowanie obniża poziom TNF-alpha, a w nawiązaniu do opublikowanych badań może zmniejszać ryzyko ciężkiego przebiegu choroby oraz ryzyko zgonu u pacjentów z koronawirusem.
  • Makrofagi i komórki dendrytyczne nie są głównym źródłem cytokin prozapal Autor: ~wuj

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