However, most of these neutralizing antibodies seem ineffective for patients with severe disease [158]. 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. and transcription [86]. In addition to TLR4, myeloid cells use specialized endosomal PRR, including TLR3 (receptor for double-stranded RNA (dsRNA)), TLR7 (receptor for single-stranded RNA (ssRNA)), TLR8 (receptor for ssRNA), and TLR9 (receptor for double-stranded DNA (dsDNA)), to mediate sensing of viral genomes and replication products [87]. Upon endocytosis of viruses, endosomal TLRs sense viral genomes, presumably after the envelopes and capsids are uncoated by the degradative enzymes therein, and trigger cytokine and type I IFN production. However, SARS-CoV-2 is unlikely to directly enter the endosome in non-epithelial cells through endocytosis downstream of the spike-ACE2 interaction, as the canonical cellular receptor ACE2 is not abundantly expressed in these cells. Instead, viral products of SARS-CoV-2 may be delivered into the endosomal/lysosomal compartment through phagolysosomal fusion, a process by which the phagosome formed upon phagocytosis fuses with the lysosome and acquires lysosomal contents, such as PRRs and hydrolytic enzymes [88]. By doing so, viral particles or PAMPs in which viral endocytosis does not normally occur can be delivered to and sampled by the endosomal PRRs to initiate an antiviral response. The phagocytic process can be further augmented by Fc-mediated phagocytosis of antibody-virion immune complexes [89]. However, we note that phagocytosis is a general viral uptake mechanism, and the specific features of SARS-CoV-2 infection, such as the hyperactivation of myeloid cells, have yet to be thoroughly explained by this theory. In addition to initiating PRR activation gene expression and IL-1 maturation [111]. Interestingly, infection of K18-hACE2 transgenic mice with an ORF3a-deficient SARS-CoV-2 mutant results in less pathology and improved survival compared to that of wild type virus [112]. Whether the observed attenuation of disease severity is mediated by reduced immunopathology remains to be determined. In addition, it was recently reported that SARS-CoV-2 ORF7a directly triggers the activation of CD14+ monocytes = 0.0028)Tocilizumab (“type”:”clinical-trial”,”attrs”:”text”:”NCT04320615″,”term_id”:”NCT04320615″NCT04320615, phase 3); Sarilumab (“type”:”clinical-trial”,”attrs”:”text”:”NCT04327388″,”term_id”:”NCT04327388″NCT04327388, phase 3); Olokizumab (“type”:”clinical-trial”,”attrs”:”text”:”NCT04380519″,”term_id”:”NCT04380519″NCT04380519, phase 2/3)Clazakizumab (IL-6 antagonist)”type”:”clinical-trial”,”attrs”:”text”:”NCT04363502″,”term_id”:”NCT04363502″NCT04363502 (phase 2, RCT)Life-threatening COVID-19 infection, receive SoC and either SNF2 clazakizumab or placeboNot yet publishedClazakizumab (“type”:”clinical-trial”,”attrs”:”text”:”NCT04494724″,”term_id”:”NCT04494724″NCT04494724, phase 2); Siltuximab (“type”:”clinical-trial”,”attrs”:”text”:”NCT04322188″,”term_id”:”NCT04322188″NCT04322188, observational); Sirukumab (“type”:”clinical-trial”,”attrs”:”text”:”NCT04380961″,”term_id”:”NCT04380961″NCT04380961, phase 2)Lenzilumab (GM-CSF antagonist)”type”:”clinical-trial”,”attrs”:”text”:”NCT04351152″,”term_id”:”NCT04351152″NCT04351152 (phase 3, RCT) [131]SpO2 94 % or requiring supplemental oxygen, but not IMV, receive SoC and either lenzilumab or placeboLenzilumab improved the likelihood of SWOV by 54 % in the mITT population (= 0.041) compared to placeboGimsilumab (“type”:”clinical-trial”,”attrs”:”text”:”NCT04351243″,”term_id”:”NCT04351243″NCT04351243, phase 2); Otilimab (“type”:”clinical-trial”,”attrs”:”text”:”NCT04376684″,”term_id”:”NCT04376684″NCT04376684, phase 2)Mavrilimumab (GM-CSF receptor antagonist)”type”:”clinical-trial”,”attrs”:”text”:”NCT04399980″,”term_id”:”NCT04399980″NCT04399980, “type”:”clinical-trial”,”attrs”:”text”:”NCT04463004″,”term_id”:”NCT04463004″NCT04463004, “type”:”clinical-trial”,”attrs”:”text”:”NCT04492514″,”term_id”:”NCT04492514″NCT04492514, (MASH-COVID) (phase 2, RCT) [133]Severe COVID-19 pneumonia and systemic hyperinflammation, receive Anamorelin HCl SoC and either mavrilimumab or placeboNo significant increase in the proportion of patients free of supplemental oxygen at day 14 in mavrilimumab group compared to placebo (57 % vs. 47 %; = 0.76)Mavrilimumab (“type”:”clinical-trial”,”attrs”:”text”:”NCT04397497″,”term_id”:”NCT04397497″NCT04397497, phase 2; “type”:”clinical-trial”,”attrs”:”text”:”NCT04447469″,”term_id”:”NCT04447469″NCT04447469, phase 2/3)Baricitinib (JAK 1/2 inhibitor), EUA”type”:”clinical-trial”,”attrs”:”text”:”NCT04421027″,”term_id”:”NCT04421027″NCT04421027, (COV-BARRIER) (phase 3, RCT) [136]Hospitalized COVID-19, receive Anamorelin HCl SoC and either baricitinib or placeboBaricitinib resulted in a reduction in mortality by day 28 as compared to placebo (8 % vs. 13 %; = 0.0018)Tofacitinib, selective JAK1/3 inhibitor, and to lesser extent JAK2 (“type”:”clinical-trial”,”attrs”:”text”:”NCT04469114″,”term_id”:”NCT04469114″NCT04469114, phase 3)CERC-002 (TNFSF14 antagonist)”type”:”clinical-trial”,”attrs”:”text”:”NCT04412057″,”term_id”:”NCT04412057″NCT04412057 Anamorelin HCl (phase 2, RCT) [142]Mild to moderate ARDS, randomly receive a single dose of CERC-002 or placebo, in addition to standard of care that included high dose corticosteroidsCERC-002 increased the rate of survival and free of respiratory failure status through day 28 as compared to placebo (83.9 % vs. 64.5 %; = 0.044)Adalimumab, TNF- antagonist, (“type”:”clinical-trial”,”attrs”:”text”:”NCT04705844″,”term_id”:”NCT04705844″NCT04705844, phase 3); Infliximab, TNF- antagonist, (“type”:”clinical-trial”,”attrs”:”text”:”NCT04922827″,”term_id”:”NCT04922827″NCT04922827, phase 2); Etanercept, TNF- receptor fusion protein, (pre-clinical)Anakinra (IL-1 receptor antagonist)”type”:”clinical-trial”,”attrs”:”text”:”NCT04341584″,”term_id”:”NCT04341584″NCT04341584 (CORIMUNO-ANA-1) (phase 2, RCT) [144]Mild-to-moderate COVID-19 pneumonia, receive usual care plus anakinra or usual care aloneNo significant difference in WHO-CPS score of 5 points at day Anamorelin HCl 4 in anakinra group compared to placebo (36 % vs. 38 %)Anakinra (“type”:”clinical-trial”,”attrs”:”text”:”NCT04680949″,”term_id”:”NCT04680949″NCT04680949, phase 3)Canakinumab (IL-1 antagonist)”type”:”clinical-trial”,”attrs”:”text”:”NCT04362813″,”term_id”:”NCT04362813″NCT04362813 (CAN-COVID) (phase 3, RCT) [145]Patients with COVID-19 pneumonia, receive SoC and either canakinumab or placeboNo significant.