Familial Mediterranean Fever and COVID-19: Friends or Foes?

Abstract

Familial Mediterranean Fever (FMF) and COVID-19 show a remarkable overlap of clinical symptoms and similar laboratory findings. Both are characterized by fever, abdominal/chest pain, elevation of C-reactive protein, and leukocytosis. In addition, colchicine and IL-1 inhibitors treatments that are effective in controlling inflammation in FMF patients have recently been proposed for off-label use in COVID-19 patients. Thus, FMF may resemble a milder recapitulation of the cytokine storm that is a hallmark of COVID-19 patients progressing to severe disease. We analyzed the sequence of the MEFV-encoded Pyrin protein - whose mutations cause FMF- in mammals, bats and pangolin. Intriguingly, although Pyrin is extremely conserved in species that are considered either a reservoir or intermediate hosts for SARS-CoV-2, some of the most common FMF-causing variants in humans are present as wildtype residues in these species. We propose that in humans, Pyrin may have evolved to fight highly pathogenic infections.

Keywords: COVID-19; FMF disease; cytokine storm; innate immunity; pyrin.

FIGURE 1

Alignment of 19 MEFV orthologs from top to bottom as follow: Homo sapiens NP_000234.1, Mus musculus NP_001155263.1, Rattus norvegicus XP_017452974.1, Rattus rattus XP_032769237.1, Bos taurus XP_015315767.1, Sus scrofa XP_013851182.1, Manis javanica XP_017515721.1, Pteropus vampyrus XP_011374846.1, Pteropus alecto XP_006913958.1, Rousettus aegyptiacus XP_015977766.1, Rhinolophus ferrumequinum XP_032957625.1, Desmodus rotundus XP_024409044.1, Phyllostomus discolor XP_028366066.1, Miniopterus natalensis XP_016066853.1, Hipposideros armiger XP_019488407.1, Eptesicus fuscus XP_028001472.1, Myotis brandtii XP_014400628.1, Myotis davidii XP_015414020.1, Myotis lucifugus XP_023611041.1. The common names for species analyzed are as follow: M. musculus (mouse), R. norvegicus (Norway or brown rat), R. rattus (black rat), B. taurus (cattle), S. scrofa (pig), M. javanica (Malayan pangolin), P. vampyrus (Large flying fox), P. alecto (black flying fox), R. aegyptiacus (Egyptian rousettes or Egyptian fruit bat), R. ferrumequinum (greater horseshoe bat), D. rotundus (common vampire bat), P. discolor (pale spear-nosed bat), M. natalensis (Natal long-fingered bat), H. armiger (great roundleaf bat), E. fuscus (big brown bat), M. brandtii (Brandt’s bat), M. davidii (David’s myotis), M. lucifugus (little brown bat). Alignment were performed using the Cobalt software (Papadopoulos JS and Agarwala R, Bioinformatics 23:1073-79, 2007). Boxes highlight the amino acid residues corresponding to common FMF-causing variants. In green homo sapiens Pyrin, in blue pyrin from mammal species, in orange pangolin Pyrin, in red bats pyrin proteins.

FIGURE 2

Alignment of 19 Pyrin orthologs from amino acid 148 to amino acid 202 (human gene). Alignment order and color coding as in Figure 1.

FIGURE 3

Phylogenetic tree of the Pyrin orthologs reconstructed from the COBALT multiple sequence alignment tool. The human Pyrin is boxed.

FIGURE 4

Phylogenetic tree of the NLRP3 orthologs reconstructed from the COBALT multiple sequence alignment tool. The human NLRP3 protein is boxed.

FIGURE 5

Alignment of 14 NLRP3 orthologs from amino acid 235 to amino acid 394 (human gene). The four residues whose mutations are responsible of more than 40% of NLRP3 –associated autoinflammatory diseases are boxed.

FIGURE 6

Proposed model of competitive binding to ASC of MEFV-encoded Pyrin and NLRP3. Abbreviations used: PYD, Pyrin domain, CARD, Caspase recruitment domain, NACHT/NBD NACHT-, Nucleotide binding- domain, LRR, Leucine-rich repeats.