title: Heterozygous mutants of TIRAP (S180L) polymorphism protect adult patients with Plasmodium falciparum infection against severe disease and mortality.
abstract: Toll-interleukin-1 receptor domain containing adapter protein (TIRAP) plays a crucial role in TLR2 and TLR4 signaling pathways. Glycosylphospatidylinositol (GPI), considered a toxin molecule of Plasmodium falciparum, interacts with TLR2 and 4 to induce an immune inflammatory response. A single nucleotide polymorphism at coding region of TIRAP (S180L) has been reported to influence TLRs signaling. In the present study, we investigated the association of TIRAP (S180L) polymorphism with susceptibility/resistance to severe P. falciparum malaria in a cohort of adult patients from India. TIRAP S180L polymorphism was typed in 347 cases of severe malaria (SM), 232 uncomplicated malaria and 150 healthy controls. Plasma levels of TNF-α was quantified by ELISA. Heterozygous mutation (S/L) conferred significant protection against MOD (multi organ dysfunction), NCSM (non-cerebral severe malaria) as well as mortality. Interestingly, homozygous mutants (L/L) had 16 fold higher susceptibility to death. TIRAP mutants (S/L and L/L) were associated with significantly higher plasma TNF-α levels compared to wild type (S/S). The results of the present study demonstrate that TIRAP S180L heterozygous mutation may protect patients against severe malaria and mortality.
authors.affiliation: Centre for Life Sciences, Central University of Jharkhand, Brambe, Ranchi, India; Infectious Disease Biology Group, Institute of Life Sciences, Bhubaneswar, Odisha, India. Electronic address: adityarmrc@gmail.com.
authors.forename: Aditya K
authors.initials: AK
authors.lastname: Panda
authors.affiliation: Infectious Disease Biology Group, Institute of Life Sciences, Bhubaneswar, Odisha, India; Department of Medicine, S.C.B. Medical College, Cuttack 753007, Odisha, India. Electronic address: bidyutdas@hotmail.com.
authors.forename: Bidyut K
authors.initials: BK
authors.lastname: Das
authors.affiliation: Department of Medicine, S.C.B. Medical College, Cuttack 753007, Odisha, India. Electronic address: drnashville@gmail.com.
authors.forename: Abhinash
authors.initials: A
authors.lastname: Panda
authors.affiliation: Department of Biochemistry, S.C.B. Medical College, Cuttack 753007, Odisha, India. Electronic address: rinatripathy@hotmail.com.
authors.forename: Rina
authors.initials: R
authors.lastname: Tripathy
authors.affiliation: Department of Medicine, S.C.B. Medical College, Cuttack 753007, Odisha, India. Electronic address: saritsekhar@gmail.com.
authors.forename: Sarit S
authors.initials: SS
authors.lastname: Pattnaik
authors.affiliation: Centre for Life Sciences, Central University of Jharkhand, Brambe, Ranchi, India.
authors.forename: Harishankar
authors.initials: H
authors.lastname: Mahto
authors.affiliation: Basic and Clinical Immunology of Parasitic Diseases Group, Centre for Infection and Immunity of Lille, 59019 Lille Cedex, France. Electronic address: sylviane.pied@pastur-lille.fr.
authors.forename: Sylviane
authors.initials: S
authors.lastname: Pied
authors.affiliation: Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai 400005, India. Electronic address: pathaksue@gmail.com.
authors.forename: Sulabha
authors.initials: S
authors.lastname: Pathak
authors.affiliation: Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai 400005, India. Electronic address: shobhona@gmail.com.
authors.forename: Shobhona
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Infectious Disease Biology Group, Institute of Life Sciences, Bhubaneswar, Odisha, India. Electronic address: ravindran8@gmail.com.
authors.forename: Balachandran
authors.initials: B
authors.lastname: Ravindran
mesh_terms: D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D006579:Heterozygote; D006801:Humans; D016778:Malaria, Falciparum / Q000235:genetics / Q000401:mortality* / Q000517:prevention & control*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D017472:Receptors, Interleukin-1 / Q000235:genetics*; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D008562:Membrane Glycoproteins; D017472:Receptors, Interleukin-1; C434984:TIRAP protein, human; C439524:TNF protein, human; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha
keywords: Meta-analysis; P. falciparum malaria; Polymorphism; TIRAP; TNF-α