Novel mutations in TLR genes cause hyporesponsiveness to Mycobacterium avium subsp. paratuberculosis infection.
BACKGROUND
Toll like receptors (TLR) play the central role in the recognition of pathogen associated molecular patterns (PAMPs). Mutations in the TLR1, TLR2 and TLR4 genes may change the ability to recognize PAMPs and cause altered responsiveness to the bacterial pathogens.


RESULTS
The study presents association between TLR gene mutations and increased susceptibility to Mycobacterium avium subsp. paratuberculosis (MAP) infection. Novel mutations in TLR genes (TLR1- Ser150Gly and Val220Met; TLR2 - Phe670Leu) were statistically correlated with the hindrance in recognition of MAP legends. This correlation was confirmed subsequently by measuring the expression levels of cytokines (IL-4, IL-8, IL-10, IL-12 and IFN-gamma) in the mutant and wild type moDCs (mocyte derived dendritic cells) after challenge with MAP cell lysate or LPS. Further in silico analysis of the TLR1 and TLR4 ectodomains (ECD) revealed the polymorphic nature of the central ECD and irregularities in the central LRR (leucine rich repeat) motifs.


CONCLUSIONS
The most critical positions that may alter the pathogen recognition ability of TLR were: the 9th amino acid position in LRR motif (TLR1-LRR10) and 4th residue downstream to LRR domain (exta-LRR region of TLR4). The study describes novel mutations in the TLRs and presents their association with the MAP infection.
Bhide
Mangesh R
MR
Laboratory of Biomedical Microbiology and Immunology, University of Veterinary Medicine, Komenskeho-73, Kosice, Slovakia. mangeshbhide@hotmail.com
Mucha
Rastislav
R
Mikula
Ivan
I
Kisova
Lucia
L
Skrabana
Rostislav
R
Novak
Michal
M
Mikula
Ivan
I
D020816:Amino Acid Motifs / Q000235:genetics / Q000276:immunology; D000595:Amino Acid Sequence; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D016927:Mycobacterium avium subsp. paratuberculosis / Q000276:immunology; D010283:Paratuberculosis / Q000276:immunology*; D018807:Polymorphism, Single-Stranded Conformational; D012333:RNA, Messenger / Q000378:metabolism; D012756:Sheep / Q000235:genetics* / Q000276:immunology / Q000382:microbiology; D012757:Sheep Diseases / Q000235:genetics* / Q000276:immunology; D051193:Toll-Like Receptors / Q000235:genetics* / Q000276:immunology
D016207:Cytokines; D012333:RNA, Messenger; D051193:Toll-Like Receptors