Myeloid dysregulation and therapeutic intervention in COVID-19.

The dysregulation of myeloid cell responses is increasingly demonstrated to be a major mechanism of pathogenesis for COVID-19. The pathological cellular and cytokine signatures associated with this disease point to a critical role of a hyperactivated innate immune response in driving pathology. Unique immunopathological features of COVID-19 include myeloid-cell dominant inflammation and cytokine release syndrome (CRS) alongside lymphopenia and acute respiratory distress syndrome (ARDS), all of which correlate with severe disease. Studies suggest a range of causes mediating myeloid hyperactivation, such as aberrant innate sensing, asynchronized immune cellular responses, as well as direct viral protein/host interactions. These include the recent identification of new myeloid cell receptors that bind SARS-CoV-2, which drive myeloid cell hyperinflammatory responses independently of lung epithelial cell infection via the canonical receptor, angiotensin-converting enzyme 2 (ACE2). The spectrum and nature of myeloid cell dysregulation in COVID-19 also differs from, at least to some extent, what is observed in other infectious diseases involving myeloid cell activation. While much of the therapeutic effort has focused on preventative measures with vaccines or neutralizing antibodies that block viral infection, recent clinical trials have also targeted myeloid cells and the associated cytokines as a means to resolve CRS and severe disease, with promising but thus far modest effects. In this review, we critically examine potential mechanisms driving myeloid cell dysregulation, leading to immunopathology and severe disease, and discuss potential therapeutic strategies targeting myeloid cells as a new paradigm for COVID-19 treatment.

Mechanical activation of spike fosters SARS-CoV-2 viral infection.

The outbreak of SARS-CoV-2 (SARS2) has caused a global COVID-19 pandemic. The spike protein of SARS2 (SARS2-S) recognizes host receptors, including ACE2, to initiate viral entry in a complex biomechanical environment. Here, we reveal that tensile force, generated by bending of the host cell membrane, strengthens spike recognition of ACE2 and accelerates the detachment of spike's S1 subunit from the S2 subunit to rapidly prime the viral fusion machinery. Mechanistically, such mechano-activation is fulfilled by force-induced opening and rotation of spike's receptor-binding domain to prolong the bond lifetime of spike/ACE2 binding, up to 4 times longer than that of SARS-S binding with ACE2 under 10 pN force application, and subsequently by force-accelerated S1/S2 detachment which is up to ~103 times faster than that in the no-force condition. Interestingly, the SARS2-S D614G mutant, a more infectious variant, shows 3-time stronger force-dependent ACE2 binding and 35-time faster force-induced S1/S2 detachment. We also reveal that an anti-S1/S2 non-RBD-blocking antibody that was derived from convalescent COVID-19 patients with potent neutralizing capability can reduce S1/S2 detachment by 3 × 106 times under force. Our study sheds light on the mechano-chemistry of spike activation and on developing a non-RBD-blocking but S1/S2-locking therapeutic strategy to prevent SARS2 invasion.

SARS-CoV-2 exacerbates proinflammatory responses in myeloid cells through C-type lectin receptors and Tweety family member 2.

Despite mounting evidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) engagement with immune cells, most express little, if any, of the canonical receptor of SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2). Here, using a myeloid cell receptor-focused ectopic expression screen, we identified several C-type lectins (DC-SIGN, L-SIGN, LSECtin, ASGR1, and CLEC10A) and Tweety family member 2 (TTYH2) as glycan-dependent binding partners of the SARS-CoV-2 spike. Except for TTYH2, these molecules primarily interacted with spike via regions outside of the receptor-binding domain. Single-cell RNA sequencing analysis of pulmonary cells from individuals with coronavirus disease 2019 (COVID-19) indicated predominant expression of these molecules on myeloid cells. Although these receptors do not support active replication of SARS-CoV-2, their engagement with the virus induced robust proinflammatory responses in myeloid cells that correlated with COVID-19 severity. We also generated a bispecific anti-spike nanobody that not only blocked ACE2-mediated infection but also the myeloid receptor-mediated proinflammatory responses. Our findings suggest that SARS-CoV-2-myeloid receptor interactions promote immune hyperactivation, which represents potential targets for COVID-19 therapy.

Association of insomnia disorder with sociodemographic factors and poor mental health in COVID-19 inpatients in China.

PURPOSE: To examine insomnia disorder and its association with sociodemographic factors and poor mental health in 2019 novel coronavirus (COVID-19) inpatients in Wuhan, China. DESIGN: and Methods: A total of 484 COVID-19 inpatients in Wuhan Tongji Hospital were selected and interviewed with standardized assessment tools. Insomnia disorder was measured by the Chinese version of the Insomnia Severity Index (ISI-7), a total score of 8 or more was accepted as the threshold for diagnosing insomnia disorder. RESULTS: The prevalence of insomnia disorder in the whole sample was 42.8%. Binary logistic regression analysis revealed that female gender, younger age, and higher fatigue and anxiety severity were more likely to experience insomnia disorder. CONCLUSION: Given the high rate of insomnia disorder status among COVID-19 inpatients in Wuhan, China, and its negative effects, follow-up assessments and appropriate psychological interventions for insomnia disorder are needed in this population.