'Sialylated Glycan Bindings from SARS-CoV-2 Spike Protein to Blood and Endothelial Cells Govern the Severe Morbidities of COVID-19' (Scheim et al.): ACE 2 receptors for spike binding NOT critical?

hypoxia which emerged as a key morbidity of severe COVID was found in a large percentage of such patients to accompany nearly normal breathing mechanics and lung gas volume; how?

https://www.mdpi.com/1422-0067/24/23/17039

‘Although COVID-19 typically gains infectious penetration in the respiratory epithelium, microvascular occlusion is frequently observed in pulmonary septal capillaries and in other organ systems of COVID-19 patients [7,8,9,10,11,12,13,14,15,16,17,18,19,20], accompanying morbidities such as intravascular clotting and peripheral ischemia [2,3,8,18,21,22,23].

Lung inflammation and other pulmonary symptoms are common with COVID-19, yet in several cases of severe disease, histological examinations have revealed microthrombi and extensively damaged endothelium in the septal capillary microvasculature adjoining relatively intact alveoli [14,24].’

‘Consistent with well-established biochemical properties of coronaviruses, sialylated glycan attachments between SARS-CoV-2 spike protein (SP) and host cells are key to the virus’s pathology. SARS-CoV-2 SP attaches to and aggregates red blood cells (RBCs), as shown in many pre-clinical and clinical studies, causing pulmonary and extrapulmonary microthrombi and hypoxia in severe COVID-19 patients. SARS-CoV-2 SP attachments to the heavily sialylated surfaces of platelets (which, like RBCs, have no ACE2) and endothelial cells (having minimal ACE2) compound this vascular damage.

Notably, experimentally induced RBC aggregation in vivo causes the same key morbidities as for severe COVID-19, including microvascular occlusion, blood clots, hypoxia and myocarditis. Key risk factors for COVID-19 morbidity, including older age, diabetes and obesity, are all characterized by markedly increased propensity to RBC clumping. For mammalian species, the degree of clinical susceptibility to COVID-19 correlates to RBC aggregability with p = 0.033.

Notably, of the five human betacoronaviruses, the two common cold strains express an enzyme that releases glycan attachments, while the deadly SARS, SARS-CoV-2 and MERS do not, although viral loads for COVID-19 and the two common cold infections are similar. These biochemical insights also explain the previously puzzling clinical efficacy of certain generics against COVID-19 and may support the development of future therapeutic strategies for COVID-19 and long COVID patients.

The virus that caused COVID-19 was first named “severe acute respiratory syndrome coronavirus 2” (SARS-CoV-2) in February 2020 in recognition of the disease’s pulmonary symptoms and the lung’s role as its initial target organ, as with its SARS predecessor. Yet as clinical experience and histological findings accrued, the hypoxia which emerged as a key morbidity of severe COVID-19 was found in a large percentage of such patients to accompany nearly normal breathing mechanics and lung gas volume [1,2,3,4,5,6]. Although COVID-19 typically gains infectious penetration in the respiratory epithelium, microvascular occlusion is frequently observed in pulmonary septal capillaries and in other organ systems of COVID-19 patients [7,8,9,10,11,12,13,14,15,16,17,18,19,20], accompanying morbidities such as intravascular clotting and peripheral ischemia [2,3,8,18,21,22,23]. Lung inflammation and other pulmonary symptoms are common with COVID-19, yet in several cases of severe disease, histological examinations have revealed microthrombi and extensively damaged endothelium in the septal capillary microvasculature adjoining relatively intact alveoli [14,24].

Soon after the determination of SARS-CoV-2 as the viral cause of COVID-19, ACE2 was identified as the host cell receptor supporting its replication [25,26,27], with neurophilin-1 its replication receptor for astrocytes and possibly certain other cell types [28,29]. Yet ACE2 is one of a variety of host cell receptors that different coronavirus strains use for replication; other receptors include DPP4 for MERS, APN for HCoV-229E, and CEACAM1 for MHV [30]. The morbidities of SARS-CoV-2, in particular, as shown below, are less dependent on its host cell replication receptor, ACE2, than on glycans having sialic acid (SA) terminal moieties found on viral spike protein (SP) and host cells. For coronaviruses, these sialylated glycans on their SP serve as the initial points of viral attachment to the host cell surface [30,31,32,33,34,35,36,37,38,39,40,41,42], after which the virus can migrate to fuse with a replication receptor [40,42,43,44,45,46,47,48,49]. One clue to the centrality of glycan bindings to the morbidities of the five human betacoronaviruses is the expression by the two common cold strains, HKU1 and OC43, of hemagglutinin esterase (HE), which releases glycan bindings between viral SP and host cells [50,51,52,53,54]. These common cold infections are generally benign, while the SARS, SARS-CoV-2 and MERS viruses do not express HE [50,51,52,53,54] and are deadly, even though the viral loads for COVID-19 and these common cold infections are about the same [55].’

‘Consistent with coronavirus and RBC biochemistry established over past decades, the findings presented here demonstrate the central role of attachments from SARS-CoV-2 SP to sialylated glycans on RBCs and other blood cells in the severe morbidities of COVID-19. The glycans that decorate the SP of a coronavirus serve, metaphorically, as the virus’s arms and legs, its appendages of initial attachment to a host cell. The RBC, with its million strands of GPA per cell, along with platelets, offers an “immune adherence” defense of pathogens which can bind to glycans [72,82,83,84,85,86,87,88]. The associated hemagglutination is observed for many strains of coronaviruses [30,32,35,36,37,38,39,41,42], including SARS-CoV-2 [91].’

See McCullough’s substack on this topic:

How Does SARS-CoV-2 and COVID-19 Vaccination Cause Hemagglutination?

'Major manuscripts in clinical medicine require presentation and defense by their authors. This is the lifeblood of the science where there is free discussion and debate of emerging sources of data and the new insights that are formed.

I have always wondered why SARS-CoV-2 infection creates low oxygen levels in the bloodstream that are so well tolerated compared to forms of common consolidative pneumonia or heart failure. I have also been puzzled about why after COVID-19 to rates of myocardial infarction, stroke, and other cardiovascular events sharply rise.’