CC BY
15Central Asian Journal of Medical Hypotheses and Ethics
2020; Vol 1 (1)
© 2020 by the authors. This work is licensed under Creative Commons Attribution 4.0 International License
https://creativecommons.org/licenses/by/4.0/
HYPOTHESIS eISSN: 2708-9800 https://doi.org/10.47316/cajmhe.2020.H07
A HYPOTHETICAL ROLE FOR PLAGUE IN THE SELECTION OF MEFV MUTATION CARRIERS IN THE MEDITERRANEAN AREA
Received: Aug 19, 2019 Accepted: Sept 30, 2019
Ezgi Deniz Batu1* https://orcid.org/0000-0003-1065-2363
department of Pediatrics, Division of Rheumatology, Ankara Training and Research Hospital, University of Health Sciences, Ankara, Turkey
Corresponding author:
Ezgi Deniz Batu, MD, Department of Pediatrics, Division of Rheumatology, Ankara Training and Research Hospital, University of Health Sciences, Ankara 06100, Turkey; Twitter handle: @EzgiDenizBatu1; E-mail: ezgidenizbatu@yahoo.com
Abstract
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.
Keywords: Familial Mediterranean fever, Plague, Missense mutation, Hypothesis
How to cite: E. D. Batu. A hypothetical role for plague in the selection of MEFV mutation carriers in the
Mediterranean area. Cent Asian J Med Hypotheses Ethics 2020;1(1):55-59.
https://doi.org/10.47316/cajmhe.2020.11.07
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
55
are used in colchicine-resistant or colchicine-intolerant patients [1].
Evolution of the human genome has been affected by infectious diseases. Especially infections that cause epidemics/pandemics with high mortality could have significant effects on genome evolution through selective biologic advantage. Thus, it has been an appealing hypothesis that increased resistance to an infectious agent endemic to the Mediterranean area caused a selective advantage for MEFV heterozygotes. Previously, two alternative hypotheses have been put forward as tuberculosis and brucellosis being candidate infections that might have caused the selection of individuals with MEFV mutations in the Mediterranean basin [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-10 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
56
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.
FUNDING
None
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.
REFERENCES
1. Ozen S, Batu ED and Demir S. Familial Mediterranean Fever: Recent Developments in Pathogenesis and New Recommendations for Management. Front Immunol 2017;8:253.
2. Sonmez HE, Batu ED and Ozen S. Familial Mediterranean fever: current perspectives. J Inflamm Res 2016;9:13-20.
3. Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. The International FMF Consortium. Cell 1997;90(4):797-807.
4. Ozen S, Batu ED. The myths we believed in familial Mediterranean fever: what have we learned in the past years? Semin Immunopathol 2015;37(4):363-369.
5. Aksentijevich I, Torosyan Y, Samuels J, et al. Mutation and haplotype studies of familial Mediterranean fever reveal new ancestral relationships and evidence for a high carrier frequency with reduced penetrance in the Ashkenazi Jewish population. Am J Hum Genet 1999;64(4):949-962.
6. Yilmaz E, Ozen S, Balci B, et al. Mutation frequency of Familial Mediterranean Fever and evidence for a high carrier rate in the Turkish population. Eur J Hum Genet 2001 ;9(7):553-555.
7. Rogers DB, Shohat M, Petersen GM, et al. Familial Mediterranean fever in Armenians: autosomal recessive inheritence with high gene frequency. Am J Med Genet 1989;34(2):168-172.
8. Cattan D. MEFV mutation carriers and diseases other than familial Mediterranean fever: proved and non-proved associations; putative biological advantage. Curr Drug Targets Inflamm Allergy 2005;4(1):105-112.
9. Ross JJ. Goats, germs, and fever: Are the pyrin mutations responsible for familial Mediterranean fever protective against Brucellosis? Med Hypotheses 2007;68(3):499-501.
10. Ozen S, Balci B, Ozkara S, et al. Is there a heterozygote advantage for familial Mediterranean fever carriers against tuberculosis infections: speculations remain? Clin Exp Rheumatol 2002;20(4 Suppl 26):S57-S58.
57
11. Park YH, Wood G, Kastner DL and Chae JJ. Pyrin inflammasome activation and RhoA signaling in the autoinflammatory diseases FMF and HIDS. Nat Immunol 2016;17(8):914-921.
12. Xu H, Yang J, Gao W, et al. Innate immune sensing of bacterial modifications of Rho GTPases by the Pyrin inflammasome. Nature 2014;513(7517):237-241.
13. Chung LK, Park YH, Zheng Y, et al. The Yersinia Virulence Factor YopM Hijacks Host Kinases to Inhibit Type III Effector-Triggered Activation of the Pyrin Inflammasome. Cell Host Microbe 2016;20(3):296-306.
14. Ratner D, Orning MP, Proulx MK, et al. The Yersinia pestis Effector YopM Inhibits Pyrin Inflammasome Activation. PLoS Pathog 2016;12(12):e1006035.
15. Chae JJ, Cho YH, Lee GS, et al. Gain-of-function Pyrin mutations induce NLRP3 protein-independent interleukin-1 beta activation and severe autoinflammation in mice. Immunity 2011 ;34(5):755-768.
16. Gage KL and Kosoy MY. Natural history of plague: perspectives from more than a century of research. Annu Rev Entomol 2005;50:505-528.
17. Khan IA. Plague: the dreadful visitation occupying the human mind for centuries. Trans R Soc Trop Med Hyg 2004;98(5):270-277.
18. Yang R. Plague: Recognition, Treatment, and Prevention. J Clin Microbiol 2018; 56(1):pii:e01519-e01517.
19. Nikiforov VV, Gao H, Zhou L, Anisimov A. Plague: Clinics, Diagnosis and Treatment. Adv Exp Med Biol 2016;918:293-312.
Жерорта Teni3i аймагындагы MEFV мутациясынын тасымалдаушыларын тандаудагы
обаньщ гипотетикалык рeлi
Туйшдеме
Отбасылык Жерорта те^зЫщ безгеп (FMF) - бул MEFV геынщ пиринФ кодтайтын мутацияларымен байланысты ец кеп таралган ауто-кабыну ауруы. MEFV мутациясы Жерорта те^ аймагында жиi кездеседi. Осы аймактагы эндемиялык инфекцияга карсы турактылыктыц жогарылауы MEFV мутациясы бар адамдар Yшiн тацдаулы артыкшылык болуы мYмкiн. Жакында жYргiзiлген зерттеулер пириннщ микроорганизмдерден коргану белИ болып табылады жэне Clostridium difficile немесе Yersinia pestis сиякты бактериялардыц Rho GTPase инактивациясынан кейiн белсе^Ф болады. Алайда, Yersinia тYрлерiнде RhoAmodifiersYopE жэне YopT-га косымша пириндi тежейтЫ тагы бiр эффекторлы молекула бар - YopM. MEFV мутациясы бар адамдардагы Yнемi байкалатын шамадан тыс белсендi пирин Yersinia инфекцияларынан жаксы корганыс болуы мYмкiн. Y. pestis Жерорта те^ бассейнiнде жойкын пандемияга алып келген обаны тудырушы. Осылайша, оба осы аймактагы MEFV мутациясыныц тасымалдаушылары Yшiн тацдамалы биологиялык артыкшылыкты тудыратын инфекция болуы мYмкiн.
Ty^h сездер: Орталык Азия, такырып ретЫде мерзiмдi басылымдар, гипотеза, зерттеу дизайны
Дэйексез Yшiн: Бату Е. Жерорта тецiзi аймагындагы MEFV мутациясыныц тасымалдаушыларын тацдаудагы обаныц гипотетикалык релi. Медициналык гепотиза мен этиканыц Орта Азиялык журналы. - 2020. - №1 (1). - Б. 55 - 59. https://doi.orq/10.47316/caimhe.2020.1.1.07
Гипотетическая роль чумы в селекции носителей мутации MEFV в районе
Средиземноморья
Резюме
Семейная средиземноморская лихорадка (ССЛ) является наиболее распространенным ауто -воспалительным заболеванием, связанным с мутациями в гене MEFV, который кодирует пирин. MEFV мутации часто встречаются в средиземноморском регионе. Повышенная устойчивость к заболеванию, эндемичному для этой области, могла бы стать селективным
58
преимуществом людей с мутациями MEFV. Недавние исследования показали, что пирин является частью защиты хозяина от микроорганизмов и активируется после инактивации Rho GTPase бактериями, такими как Clostridium difficile или Yersinia pestis. Однако Yersinia species имеет другую эффекторную молекулу, YopM, которая ингибирует пирин в дополнение к модификаторам RhoA YopE и YopT. Непрерывно сверхактивный пирин может быть защитным фактором людей с мутациями MEFV хозяина от иерсиниозных инфекций. Y. pestis вызывает чуму, которая привела к разрушительной пандемии в бассейне Средиземного моря. Таким образом, чума могла быть инфекцией, которая стала причиной селективного биологического преимущества носителей мутации MEFV в этой области.
Ключевые слова: Центральная Азия, Периодика как тема, Гипотеза, дизайн исследования Для цитирования: Бату Е. Гипотетическая роль чумы в селекции носителей мутации MEFV в районе Средиземноморья. Центральноазиатский журнал медицинских гипотез и этики. -2020. - №1(1). - С. 55 - 59. https://doi.org/10.47316/cajmhe.2020.1.1.07
59
