Candida Enfeksiyonlarına Karşı Toll-benzeri Reseptörlerin ve Antimikrobiyal Peptitlerin Özelleştirilmesine Yönelik Hesaplamalı Yaklaşımlardaki Son Gelişmeler

Yıl 2025, Cilt: 21 Sayı: 3, 1 - 9, 26.09.2025

Mesude Biçer , Onur Serçinoğlu , Tuba Okur

https://doi.org/10.18466/cbayarfbe.1593863

Öz

Candida albicans'ın insan sağlığı üzerindeki kayda değer patojenik etkisine rağmen, hücresel tanıma mekanizmalarının ve ardından gelen konakçı savunma aktivasyonunun anlaşılmasındaki boşluk yeterince anlaşılmamıştır. Son bilgiler, Toll benzeri reseptörlerin (TLR'ler) patojenlere karşı doğuştan gelen bağışıklık tepkilerini düzenlemedeki önemli rolünün altını çiziyor. Özellikle, son yıllardaki ampirik araştırmalar, TLR'lerin memelilerde en önemli model tanıma reseptörleri olduğunun altını çizmiştir. Örneğin TLR2, peptidoglikanlar, lipoarabinomannan ve bakteriyel lipoproteinler için afinite sergilerken TLR4, lipopolisakkarit (LPS) ve lipo-teikoik asidin saptanmasında rol oynar. Benzer şekilde TLR5 flagellini tanır ve TLR9 bakteriyel DNA tanımayla ilişkilidir. Toll'un Drosophila'da antifungal mekanizmaların düzenleyicisi olarak ilk tanımlanması, TLR'lerin memeli antifungal savunmasında potansiyel olarak dahil olduğunu düşündürmektedir. Bununla birlikte, Drosophila'daki Toll ile antifungal mekanizmalar arasındaki evrimsel bağlantıya rağmen, insanlarda fungal patojenlerle mücadelede TLR'lerin rolünün tanımlanmasına çok az önem verilmiştir; bu, TLR'lerin memeli antifungal savunmasında makul bir rol oynadığını düşündürmektedir. Özellikle kanıtlar, Aspergillus fumigatus'a yanıt olarak proinflamatuar sitokinleri indüklemede TLR4'ü gösterir ancak TLR2'yi kapsamaz; bu arada rolünün, hücrelerin Cryptococcus neoformans ile uyarılmasından sonra TNF üretimi olmasa da hücre içi sinyalleşmeye aracılık ettiği iddia edilir. Bununla birlikte, TLR aktivasyon kurallarına ilişkin içgörüler, antimikrobiyal peptit (AMP) ile TLR etkileşimlerinin incelenmesini mümkün kılmaktadır ve çeşitli moleküllerin immünomodülatör kapasitelerine ilişkin tahminleri kolaylaştırmaktadırç Bu ilerlemelere rağmen, TLR'lerin önde gelen bir insan patojeni olan Candida albicans'ı tanımadaki spesifik rolü hala belirsizliğini koruyor ve daha fazla araştırma yapılmasını gerektiriyor. Bu hesaplamalı yaklaşım, AMP'ler ve TLR'ler arasındaki etkileşimleri aydınlatan, TLR aktivasyonunu yöneten yapısal belirleyicileri tanımlayan ve böylece çeşitli moleküler varlıkların immünomodülatör potansiyeline ilişkin öngörüler sağlayan son bulguları sentezlemektedir.

Anahtar Kelimeler

Toll-benzeri reseptörler , antimikrobiyal peptit , Candida enfeksiyonlar , hesaplamalı yaklaşımlar , protein-protein docking , moleküler dinamik simülasyonu , doku mühendisliği

Recent Advancements in Computational Approaches for Tailoring Toll-like Receptors and Antimicrobial Peptides Against Candida Infections

Öz

Despite the considerable pathogenic impact of Candida albicans in human health, the gap in understanding the cellular recognition mechanisms and subsequent host defence activation remain insufficiently understood. Recent insights underscore the pivotal role of Toll-like receptors (TLRs) in organising innate immune responses against pathogens. Notably, empirical investigations over recent years have underscored TLRs as paramount pattern-recognition receptors in mammals. TLR2, for examples, exhibits affinity for peptidoglycans, lipoarabinomannan, and bacterial lipoproteins, while TLR4 implicated in detecting lipopolysaccharide (LPS) and lipo-teichoic acid. Similarly, TLR5 recognizes flagellin, and TLR9 is associated with bacterial DNA recognition. The initial identification of Toll in Drosophila as a regulator of antifungal mechanisms suggests the potential involvement of TLRs in mammalian antifungal defence. However, scant attention has been devoted to delineating the role of TLRs in combating fungal pathogens in humans, despite the evolutionary link between Toll in Drosophila and antifungal mechanisms, suggesting a plausible involvement of TLRs in mammalian antifungal defense. Notably, evidence implicates TLR4, but not TLR2, in inducing proinflammatory cytokines in response to Aspergillus fumigatus, while its role is purported to mediate intracellular signaling, albeit not TNF production, after stimulation of cells with Cryptococcus neoformans. However, insights into TLR activation rules have enabled the examination of antimicrobial peptide (AMP) interactions with TLRs, facilitating predictions regarding the immunomodulatory capacities of diverse molecules. Despite these advancements, the specific role of TLRs in recognizing Candida albicans, a prominent human pathogen, remains elusive, warranting further investigation. This computational approach synthesizes recent findings elucidating the interactions between AMPs and TLRs, delineating the structural determinants governing TLR activation, thus enabling predictive insights into the immunomodulatory potential of diverse molecular entities

Anahtar Kelimeler

Toll-like receptors , antimicrobial peptide , candida infections , computational approaches , protein-protein docking , molecular dynamics simulation , tissue engineering

Kaynakça

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