При умеренном ковиде, у тех кто старше и моложе, у тех кто выздоровел, и кто остался долгоковидным. В динамике, начиная с симптомов, и примерно 3 месяца.
Интересные данные. Ниже- обсуждение результатов.
Вкратце- при умеренном ковиде наблюдается большой разброс симптомов и их амплитуды, но при этом, координированный и сильный иммунный ответ, включающий работу как врожденного, так и адаптивного секторов. У пожилых наблюдается более сильный и выраженный имумнный ответ, и клеточный и гуморальный, особенно специфический, и и вырабатывается больше интерферона. Так же, выше и воспалительный ответ. Тк их имумнная система была к стимуляции "более чувствительна", особенно к интерферону. Раньше включаются в работу В клетки и плазматические клетки. У молодых сильнее отвечали моноциты и натуральные киллеры, и лучше работали регуляторы клеточного стрессового ответа . Активность дендритных клеток не была зависма от возраста. Уровни воспалительных маркеров коррелируют с симптомами и тяжестью. Часть увеличенного количества плазматических клетов в крови, вероятно, может вырабатывать антитела на свои ткани. При том что большинство- на коронавирусные белки. Клеточный иммунитет на коронавирус вполне держится примерно на том же уровне что и через месяц (к этому времени он существенно подрастает с начала симптоматики), до 3 месяцев. А гуморальный- у большинства на пике во время острой фазы, а потом спадает, но у 70%, считают, неайтрализующей активности антител было достаточно и потом, хотя в крови количество плазматических клеток заметно снизилось.. У выздоравливающих прмерно через 2 недели после симптомов активируется "репарационная" система гомеостаза, и, в принципе, около 30 дней после первых симптомов все более менее нормализуется, включая и маркеры воспаления. Но иногда хемокины, активирующие воспалительный ответ и воспалительные маркеры в крови могут и расти после острой фазы ковида. Вероятно, это явление ответсвтенно за коагуляционные последствия у части больных. У тех, у кого образовлася постковид- адаптивный иммунитет был слабее во время острой фазы, да и не особо увеличился потом- но при этом осталось много реакций воспаления.
Постковид не столько связан с возрастом, сколько с изначальной симптоматикой, и у женщин- чаще.
Our study provided an in-depth longitudinal analysis of the immune response to SARS-CoV-2 natural infection and mild COVID-19 by integrating serum proteomics, single-cell transcriptomics and epigenomics, and cellular immunophenotype by flow cytometry with clinical metadata and comprehensive analysis of the SARS-CoV-2-specific adaptive immune response in T cells, memory B cells, and antibodies.
First, we define the immune response to early acute infection including inflammatory cytokine and innate sensor signaling, stronger IFN responses in older participants, and a potential IFN-plasmablast regulatory circuit. A subset of these changes were correlated with the humoral response to SARS-CoV-2 in convalescence.
We then confirmed the longitudinal resolution of these inflammatory pathways was coordinated with re-establishment of homeostasis in most participants.
Three PASC participants were exceptions to this resolution, and could be distinguished by dampened IFN and antiviral response in acute infection coupled with prolonged inflammation.
A defining characteristic in our mild COVID-19 cohort was robust immune activation in the first 2 weeks of acute infection that resolved over time. This included inflammatory cytokine responses (IFNs, TNF), innate immune sensor signaling pathways, and activation in adaptive and innate immune cells. The key innate immune sensors triggered in natural SARS-CoV-2 infection are not confirmed, but multiple data types strongly implicate RIG-I. Serum proteomics identified increased extracellular levels of multiple PRR pathway members including RIG-I during acute infection, but their source and function are unclear. These may derive from recent cell death or extracellular vesicles, which have been reported to potentially transfer TLRs between cells (Zhang et al., 2019). Innate danger sensors are key drivers of the IFN response, which was also robustly induced in our cohort along with other inflammatory signals such as TNF.
A subset of upregulated proteins (SAMD9L, CXCL10, CXCL11) is selective to type I/II IFN responses, suggesting bias away from type III IFNs systemically (Allenspach et al., 2021; Forero et al., 2019). As these pathways waned over time, activation marker-positive cells and inflammatory proteins largely returned to uninfected control levels around day 30 PSO. This temporal control is likely critical for successful resolution of mild COVID-19.
This contrasts with persistent CRS reported in severe COVID-19, which includes mechanisms of inflammatory damage to tissue such as TNF/IFN# -mediated cell death (Karki et al., 2021). Proteins involved in homeostatic functions (EMT, coagulation, angiogenesis) increased from acute infection to convalescence. The longitudinal increase of multiple coagulation pathway proteins may contribute to reported increases in risk of immune thrombocytopenia, a complication associated with severe COVID-19 infection (Guan et al., 2020). We found levels of THBD were significantly increased in convalescence of mild COVID-19, and has been reported to strongly correlate with duration of hospitalization and risk of mortality in hospitalized COVID-19 (Goshua et al., 2020). These results suggest a link between the inflammatory response in acute infection, the kinetics of inflammatory resolution, and their dysregulation in long-term coagulopathy risk and severe COVID-19. We observed a clear increase in immune responses with advancing age in mild COVID-19. Age is among the strongest risk factors for severe COVID-19 and mortality, but the mechanisms underlying these effects remain poorly defined (Williamson et al., 2020). Many studies are confounded by age when comparing younger controls and mild COVID-19 cases with typically older individuals in moderate and severe COVID-19. A male-specific age effect was correlated to poorer CD8+ T cell responses and disease severity with advanced age (Takahashi et al., 2020).
Our cohort was age-matched between COVID-19 participants and uninfected controls, and age was not significantly correlated with illness severity score. However, IFN responses showed a dramatic age-related effect in increased responsiveness of PBMCs from older COVID-19 participants to IFNs, as evidenced by both more pathway enrichment and higher enrichment scores from scRNAseq, and cell type-specific enrichment of IRF motifs in scATACseq.
Enhanced IFN in older participants is contrary to expectations from prior studies on inflammaging, where advanced age is associated with impaired IFN responses (Molony et al., 2017; Pillai et al., 2016).
Older participants also showed increased cytokine and danger sensor signaling in innate immune cells. These observations could be due to cells from older participants being more intrinsically reactive to cytokines, the magnitude of inflammatory cytokine response being higher, or persistence of inflammatory cytokines longer in older participants.
We also observed increased adaptive immune cell activation, which contrasts with expectations from prior studies showing immunosenescence in elderly healthy individuals. Differences between our results and prior studies on age-related effects in immunity may be due to our cohort including more young and middle-aged adults >55 years old compared to elderly adults typically >65 years old.
Collectively, our results indicate that SARS-CoV-2 infection triggers enhanced inflammatory responses in older individuals in mild COVID-19, which may underlie increased risk for severe COVID-19 in older populations. Robust plasmablast expansion is a feature of viral infections (dengue, Ebola), vaccines, and chronic autoimmune diseases (Kim et al., 2016; McElroy et al., 2015; Wrammert et al., 2012). Previous studies in moderate and severe COVID-19 reported robust plasmablast and extrafollicular B cell responses (Bernardes et al., 2020; Kaneko et al., 2020; Kuri-Cervantes et al., 2020; Mathew et al., 2020; Ren et al., 2021; Stephenson et al., 2021; Woodruff et al., 2020).
We also observed a robust plasmablast expansion in acute infection. A fraction of these plasmablasts were CoV-2 spike protein-specific, indicating these cells can in principle contribute to early control of viral replication and are at least partly CoV-2-specific. PD-1high CXCR5- Tph cells were also positively correlated with plasmablasts, potentially providing help as observed in autoimmune diseases (Rao et al., 2017). IFN responses are among the key drivers of extrafollicular B cell subsets in autoimmunity (Manni et al., 2018; Soni et al., 2020), which was consistent with scRNAseq data showing enhanced IFN signaling and scATACseq data showing IRF motif enrichments in plasmablasts. The functional consequence of these plasmablasts in SARS-CoV-2 infection remains unclear, but may connect IFN responses to antibody titers. Priming of adaptive immunity is critical to successful resolution of acute infection and protection against reinfection.
We found the magnitude of RBD IgM and CoV-2-specific CD4+ T cells negatively correlated with severity score, suggesting quality of immune response may be one driver of clinical heterogeneity in mild COVID-19. IgA titer was also correlated with severity score, extending prior observations that correlated IgA with disease severity (Ma et al., 2020; Ravichandran et al., 2021). Correlates from acute infection were also identified that explain interindividual heterogeneity in magnitude of humoral immune responses. Serum proteins involved in innate immune pathways, including IFN responses, chemokines, and PRR signaling, were positively correlated with RBD IgG titer, neutralizing antibody titer, and CoV-2-specific memory B cell frequency. These were also positively correlated with activation of T and B cells, indicating the importance of coordination in acute infection for an optimal humoral response. Complement proteins were also enriched, consistent with prior studies showing complement can facilitate antigen retention in follicular DCs (Phan et al., 2007) and enhancing BCR-mediated signaling (Fischer et al., 1998; Lyubchenko et al., 2005). Plasmablasts were a positive correlate of antibodies and memory B cells, but it is unclear whether they play a functional role in clearing infection. Overall, these findings demonstrate that the immune response to acute infection is critical to an effective humoral response, emphasizing importance of coordination between innate and adaptive arms of immunity.
PASC or long COVID is one of the most enigmatic consequences of the ongoing pandemic. The involvement of many organ systems coupled with the highly subjective nature of symptoms has made it difficult to define consensus, objective criteria for diagnosis or clear therapeutic options. In our cohort, a subset of 3 COVID-19 participants progressed to PASC. All 3 PASC participants in our study were female, consistent with prior reports of female-biased presentation. Females are known to have stronger inflammatory responses in vaccines and infections, and predisposition to autoimmune disease, suggesting hyperinflammatory responses may be a risk factor for PASC (Klein and Flanagan, 2016). Significant correlation was observed between PASC and number of initial symptoms, as previously reported, but correlation with age was not reproduced, potentially due to our small sample size (Sudre et al., 2021). Elevated inflammatory proteins in serum distinguished PASC participants from recovered COVID-19 participants. These signatures were coupled with evidence of persistent activation and inflammatory cytokine signaling in innate immune cells based on gene expression and chromatin accessibility after 30 days PSO. DCs and CD14 monocytes in PASC showed the most transcription factor motif enrichments. Among these, AP-1, STAT, IRF, BATF, and BACH suggest ongoing cellular stress, immune cell activation and differentiation, and inflammatory cytokine signaling during PASC. Gene expression signatures similarly showed stronger TNF signaling in CD14 monocytes from PASC participants. Early infection signaling and kinetics were also unique in PASC, including lower RLR and IFN responses in acute infection that did not wane longitudinally. This combination of changes mirrors severe COVID-19: dampened antiviral responses may fail to control viral replication in both, which can drive innate immune responses to persist beyond acute infection and cause ongoing pathology. Integrative analysis identified multiple secreted proteins as potential therapeutic targets. Persistently elevated TNF may be an appealing target given the potential for TNF-driven pathogenic cell death and correlations with disease severity and mortality (Del Valle et al., 2020; Karki et al., 2021). TNF can also drive IL-1β expression as well as AP-1 and STAT/IRF enrichment observed in motif analyses, motivating therapeutic targeting and blockade of these cytokines to potentially prevent the onset of PASC. LTA/TNFβ is a TNF family member and similarly upregulated in autoimmune diseases such as rheumatoid arthritis. Blockade in PASC may be beneficial and achieved by receptor antagonists (Browning, 2008) or TNF blockade (e.g., etanercept). Another promising target is IL-1β, which was significantly elevated in serum from PASC participants, coexpressed among pathways in CD14 monocytes by scRNAseq, and was both a predicted ligand signal and common downstream target of predicted ligand-receptor interactions. Both of these targets are consistent with risk factors observed in hyperinflammation from severe COVID-19, again suggesting similarities between severe disease and PASC. Broader anti-inflammatory therapy such as corticosteroids may be useful to attenuate pathogenic inflammation in PASC, and has been tested in COVID-19 patients with persistent inflammatory lung disease (Myall et al., 2021). These novel insights into PASC can focus future studies on pathogenic mechanisms and therapeutic targets. Molecular classification disease heterogeneity in PASC may identify disease subsets to further enhance clinical management and optimize therapeutic strategies.
И еще, статья о том, какие происходят изменения в дендритных клетках и моноцитах при ковиде, в заивисмости от тяжести болезни. Вкратце- они страдают, и чем тяжелее ковид, тем больше нарушаются их функции, и снижаются количества общие и субпопуляций, и затрудняется восстановление - и это может способствовать длительности выздоровления и возникновению вторичных (сопутствующих) инфекций из-за ослабленного иммунитета.