A HYPOTHETICAL ROLE FOR PLAGUE IN THE SELECTION OF MEFV MUTATION CARRIERS IN THE MEDITERRANEAN AREA

Familial Mediterranean fever (FMF) is the most common autoinflammatory disease associated with mutations in the MEFV gene encoding Pyrin. MEFV mutations are frequent in the Mediterranean region. Increased resistance to an infection endemic to this area could have caused a selective advantage for individuals with MEFV mutations. Recent studies have shown that Pyrin is a part of host defense against microorganisms and it gets activated after sensing Rho GTPase inactivation by bacteria such as Clostridium difficile or Yersinia pestis. However, Yersinia species have another effector molecule, YopM which inhibits Pyrin in addition to RhoA modifiers YopE and YopT. Continuously overactive Pyrin in individuals with MEFV mutations could be a good host defense against Yersinia infections. Y. pestis causes plague, which led to a devastating pandemic in the Mediterranean basin. Thus, plague could be the infection which caused a selective biologic advantage for MEFV mutation carriers in this area.

Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease characterized by recurrent attacks of fever and serosa inflammation [1,2]. It is associated with mutations in the MEFV gene, which encodes Pyrin [3].MEFV mutations are frequent in the Mediterranean basin [4]. The carrier frequency is around 1/5 among Ashkenazi Jews, 1/5 among Turks, and 1/7 among Armenians [5,6,7]. Although it is considered an autosomal recessive disease, heterozygotes may also express the phenotype [4]. The mainstay of FMF treatment is colchicine which suppresses subclinical inflammation and prevents attacks in most patients [1]. Anti-interleukin 1 drugs  [8,9]. Based on the epidemiologic data of lower mortality from tuberculosis among Tunis Jews compared to the French living in the same area, Cattan et al. [8] hypothesized that lower severity of tuberculosis or decreased mortality from tuberculosis might have provided an advantage to MEFV carriers in the area. In a study testing the hypothesis of tuberculosis being the infection causing selection of MEFV heterozygotes, Ozen et al. [10] demonstrated that there was no statistically significant difference in MEFV variant carrier frequency between tuberculosis patients and healthy controls. Ross et al. [9] hypothesized that MEFV mutations might have been protective against intracellular microorganisms such as Brucella mellitensis since these mutations cause a pro-inflammatory state with high levels of interferon-gamma. Brucellosis is still endemic in Middle East area because of the reliance for meat and dairy products of goats and ships which are the main reservoirs for the disease [9]. This hypothesis has never been tested in a case-control study comparing the frequency of MEFV mutations between brucellosis patients and healthy controls.
It is not possible to disprove previous hypotheses on tuberculosis and brucellosis. However, recent advances in our understanding of FMF pathogenesis, including Rho GTPases, Pyrin, and pathogen interactions have paved the way for a new hypothesis.
RhoA activates serine-threonine kinases PKN1 and PKN2, which phosphorylates serine residues of human Pyrin at positions 208 and 242 [11]. Phosphopyrin binds to 14-3-3 proteins that inhibit inflammasome activation [11]. Several microorganisms such as Clostridium difficile, Clostridium botulinum, and Burkholderia cenocepacia modify Rho GTPases in order to disable host cell cytoskeletal organization and associated host defense mechanisms such as phagocytosis and leukocyte migration [11.12]. On the other hand, as a counter-reaction from the host, Pyrin senses Rho modification by microorganisms and gets activated through the mechanism mentioned above (lack of inhibition by RhoA). However, some pathogens like Yersinia pestis and Yersinia pseudotuberculosis are one step ahead with their clever strategy.

While bacterial effectors of YopE and YopT of
Yersinia species modify and inactivate Rho GTPases; Pyrin activation in response to RhoA inactivation is counteracted by another effector of Yersinia, YopM which causes inhibition of Pyrin [13,14]. Knock-in mice studies strongly suggest that MEFV mutations in FMF are "gain-of-function" mutation causing an overactive Pyrin inducing inflammasome formation and IL-1β production [15]. This continuously active Pyrin could be a good host defense against bacteria like Yersinia pestis. Yersinia pestis causes a flea-borne zoonosis called plague [16]. It caused a devastating pandemic,called the Justinian Plague, in 542 AD in the Mediterranean basin, which is estimated to have caused 100 million deaths [17]. Plague usually starts with nonspecific symptoms similar to flulike high fever and malaise [18]. It has different clinical forms such as bubonic (with swelling in the regional lymph nodes and dry, red, hot skin), pneumonic (with severe cough and chest X-ray findings), and septicemic (sudden high fever and chills) [18]. It usually causes skin lesions in the form of carbuncles (deep ulcers encased by dark scabs) [19].
Yersinia species have been evolved to overcome host defense, including activated Pyrin inflammasome in response to Rho inhibition. Also, the human host might have been evolved to counter-act by keeping the Pyrin inflammasome overactive constantly, which is the case in MEFV mutation carriers. Thus, plague could be a strong candidate for an infection causing selective biologic advantage for MEFV mutation carriers in the Mediterranean basin. This presented hypothesis could be tested by checking MEFV mutations in plague patients and healthy controls who live in the same area. However, the significant difference of MEFV mutation frequency could also appear between severe plague cases and patients with relatively milder infection.
It is important to emphasize two points. First, this hypothesis does not mean that FMF patients (or MEFV heterozygotes) are resistant to plague. Second, it is not acceptable to delay FMF treatment in areas where plague is endemic (such as areas in Africa or Asia) considering that the subclinical inflammation of FMF could be protective against this infection. In the modern era, we have effective antibiotics for treating Y. pestis infections. However, if left untreated, FMF could cause a significant complication, amyloidosis which is responsible for long-term morbidity and mortality in FMF [2]. Thus, this hypothesis could stimulate our thinking about FMF pathogenesis with possible links to infections, but it should not affect our clinical practice while evaluating/treating FMF patients or patients with plague.

AUTHOR CONTRIBUTIONS
EDB designed the structure of the article, drafted and critically revised the text, and approved the final version of the manuscript.

CONFLICTS OF INTEREST
EDB declares that she has no conflict of interest.

DISCLAIMER
No part of the review was copied from or published elsewhere.