Discriminating Mild from Critical COVID-19 by Innate and Adaptive Immune Single-cell Profiling of Bronchoalveolar Lavages

Abstract

<jats:p>How innate and adaptive lung immune responses to SARS-CoV-2 synchronize during COVID-19 pneumonitis and regulate disease severity is poorly established. To address this, we applied single-cell profiling to bronchoalveolar lavages from 44 patients with mild or critical COVID-19 versus non-COVID-19 pneumonia as control. Viral RNA-tracking delineated the infection phenotype to epithelial cells, but positioned mainly neutrophils at the forefront of viral clearance activity during COVID-19. In mild disease, neutrophils could execute their antiviral function in an immunologically controlled fashion, regulated by fully-differentiated T-helper-17 (TH17)-cells, as well as T-helper-1 (TH1)-cells, CD8+ resident-memory (TRM) and partially-exhausted (TEX) T-cells with good effector functions. This was paralleled by orderly phagocytic disposal of dead/stressed cells by fully-differentiated macrophages, otherwise characterized by anti-inflammatory and antigen-presenting characteristics, hence facilitating lung tissue repair. In critical disease, CD4+ TH1- and CD8+ TEX-cells were characterized by inflammation-associated stress and metabolic exhaustion, while CD4+ TH17- and CD8+ TRM-cells failed to differentiate. Consequently, T-cell effector function was largely impaired thereby possibly facilitating excessive neutrophil-based inflammation. This was accompanied by impaired monocyte-to-macrophage differentiation, with monocytes exhibiting an ATP-purinergic signalling-inflammasome footprint, thereby enabling COVID-19 associated fibrosis and worsening disease severity. Our work represents a major resource for understanding the lung-localised immunity and inflammation landscape during COVID-19.</jats:p>

Broad transcriptional dysregulation of brain and choroid plexus cell types with COVID-19

“…For centrifuge, a preprocessed virus index compiled by genexa containing among other viruses 138 SARS-CoV-2 genomes was used. We also adopted a complementary approach 161 focusing on SARS-CoV-2 reads, whereby barcoded but unmapped BAM reads were aligned using STAR to the SARS-CoV-2 reference genome, with a less stringent mapping parameter (outFilterMatchNmin 25-30) than the original Viral-Track pipeline.…”

Necroptosis in Immuno-Oncology and Cancer Immunotherapy

“…For instance, concurrent release of such complex and often contradictory modulators of immune responses, at high concentrations, from necroptotic cells has the potential to create a localized "inflammatory storm"-like situation, which is often seen during response to infection [83,171,172]. This can facilitate chronic inflammation thereby eliciting differentiation of immunosuppressive myeloid or lymphoid cells [173][174][175]. This scenario, depending upon the disease context, can be substantially detrimental and impede disease amelioration.…”

SARS-CoV-2 causes a different cytokine response compared to other cytokine storm-causing respiratory viruses in severely ill patients

“…Indeed, major efforts are now concentrating on how severe acute respiratory syndrome β -coronavirus 2 (SARS-CoV-2) alters normal antiviral immune responses (6)(7)(8)(9)(10)(11)(12)(13)(14)(15). SARS-CoV-2 causes a wide range of clinical symptoms from asymptomatic, through mild (fever, persistent cough, loss of taste and smell), to severe inflammation-driven pneumonia resulting in multiple organ failure and ultimately death (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). SARS-CoV2 induces an anti-inflammatory response attacking both the upper and lower respiratory tract as well as the gut.…”

“…Although these different viruses cause similar clinical symptoms, the pathogenesis may be driven by different triggers, depending upon the virus. Multiple studies have described an exacerbation of the pro-inflammatory host immune response associated with severe forms of the diseases, including cytokine storms, or cytokine release syndrome (CRS) (1)(2)(3)(4)(5)(9)(10)(11)(12)(13)(14)(15)(16). Although CRS usually resolves following completion of the antiviral response, it persists in severe cases leading to tissue damage, multiple organ failure and death in critically-ill patients if the clinical intervention is not rapid.…”

“…In the case of SARS-CoV, the build-up of activated macrophages in the lungs can cause tissue damage, while MERS-CoV can intensify engagement by neutrophils, leading to an increase in the production of pro-inflammatory cytokines (33,34). Furthermore, Influenza A and coronaviruses infections can trigger increased levels of the type-I interferons IFN-and IFN-β, reflecting the normal initiation of this signalling pathway in response to viral infections (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)26,(34)(35)(36)(37)(38). However, in severe infections with SARS-CoV-2, the type-I IFN signalling is impaired, culminating in an altered development of adaptive immunity (9)(10)(11)(12)(13)(14)(15)35,39,40) The broadly similar clinical symptoms and the range of disease severity of different respiratory viral infections tend to blur the accuracy of initial diagnosis (41,42), and explain why systemic nonprescription medications are given to patients to initially treat broad symptoms rather than acting on virus-specific parameters (41).…”