Molecular mimicry may explain multi-organ damage in COVID-19.

To the Editor,

Molecular mimicry has been proposed as a cause of the autoimmune phenomena observed in COVID-19 [[1], [2], [3], [4]], the syndrome associated with the infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Lucchese and Flöel [4] have recently reported three human proteins (namely DAB1, AIFM, and SURF1, as catalogued at www.uniprot.org) – that are present in neurons of the respiratory pacemaker in the brainstem – that share potentially antigenic epitopes with SARS-CoV-2, as shown by in silico analysis.

Particularly, they postulated that damage to the brainstem pacemaker may contribute to respiratory failure in COVID-19 as a consequence of molecular mimicry between neuronal and viral proteins, in turn causing the clinical dissociation between well-preserved lung mechanics and severity of hypoxemia.

Here, we would like to direct attention to some features of COVID-19 – such as anosmia, leukopenia, and multi-organ failure brought about by vascular damage – that could also be the consequence of molecular mimicry phenomena (Table 1 ).

Table 1

Peptides of immunologic relevance shared between SARS-CoV-2 and human proteins.

Shared ≥6 mer (amino acids)	SARS-CoV-2 protein	Human protein	Putative Epitopes [NCBI Reference, SARS-CoV-2]	Localization of human protein [predicted by uniprot.org]
IIFWFSL	ORF7b	OR7D4 [Q8NG98]	LVLIMLIIFWFSLELQ [YP_009725318.1]	Cellular: olfactory receptor.Subcellular: plasma membrane.
VVNAAN	ORF1ab	PARP9 [Q8IXQ6]	VVNAANVYLKHGGGVAG [YP_009724389.1]	Cellular: B cells; macrophage. Subcellular: cytosol, nucleus.
SSRSSSR	Nucleocapsid phosphor-protein	SLC12A6 [Q8NG98]	SSRSSSRSRNSSRNSTP [YP_009724397]	Cellular: endothelial cells; heart; brain; kidney; liver; lung. Subcellular: plasma membrane.

Observations

Odorant Receptor 7D4 (OR7D4) is one of the most important odorant receptors on the plasma membrane of olfactory sensory neurons, responding to sex steroid-derived odours, e.g., androstenone and androstadienone [5]. Its alterations have been associated with anxiety and depression [6].

Poly (ADP-Ribose) Polymerase Family Member 9 (PARP9), also known as mono-ADP-ribosyltransferase (ARTD)-9, is a protein involved in differentiation and function of immune cells such as B lymphocytes [7] and macrophages [8].

Solute Carrier Family 12 Member 6 (SLC12A6) is a member of the K—Cl cotransporters (KCC), integral membrane proteins that lower intracellular chloride concentrations [9]. Alternative splicing in its gene results in multiple transcript variants encoding different isoforms, the most important one being KCC3 [10]. The latter has been found in endothelial cells of various organs, including vessels, heart, brain, kidney, liver, and lung [11].

Working hypothesis

We hypothesize that anosmia, leukopenia, and vascular damage with multi-organ damage are associated with molecular mimicry of the following proteins:

OR7D4: Anosmia. It could also be implicated in the mood disorders observed in these patients.

PARP9: Leukopenia. It could be implicated in plaque destabilization in patients with atherosclerosis.

SLC12A6: Vascular damage, in turn inducing thrombosis, disseminated intravascular coagulation, and multiorgan failure. It could also induce Kawasaki vasculitis. Interestingly, the shared epitope SSRSSSR in SLC12A6 (Table 1) was found to be highly immunogenic by SVMTriP (http://sysbio.unl.edu/SVMTriP/), a tool used to predict protein surface regions that are preferentially recognized by antibodies (i.e., antigenic epitopes), that is helping in the design of vaccine components [12].

Although plasma membrane localization has been demonstrated only for OR7D4 and SLC12A6, we cannot exclude that, after cell stress, post-translational modifications could induce PARP9 trafficking to plasma membrane and its exposure on the cell surface, as for other intracellular proteins [13]. Other studies, including the analysis of anatomical specimens from autopsies of subjects who died from severe forms of COVID-19, are necessary to verify these predictions.