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A negative feedback modulator of antigen processing evolved from a frameshift in the cowpox virus genome.

ABSTRACT: Coevolution of viruses and their hosts represents a dynamic molecular battle between the immune system and viral factors that mediate immune evasion. After the abandonment of smallpox vaccination, cowpox virus infections are an emerging zoonotic health threat, especially for immunocompromised patients. Here we delineate the mechanistic basis of how cowpox viral CPXV012 interferes with MHC class I antigen processing. This type II membrane protein inhibits the coreTAP complex at the step after peptide binding and peptide-induced conformational change, in blocking ATP binding and hydrolysis. Distinct from other immune evasion mechanisms, TAP inhibition is mediated by a short ER-lumenal fragment of CPXV012, which results from a frameshift in the cowpox virus genome. Tethered to the ER membrane, this fragment mimics a high ER-lumenal peptide concentration, thus provoking a trans-inhibition of antigen translocation as supply for MHC I loading. These findings illuminate the evolution of viral immune modulators and the basis of a fine-balanced regulation of antigen processing.

SUBMITTER: Lin J

PROVIDER: S-EPMC4263761 | biostudies-other | 2014 Dec

REPOSITORIES: biostudies-other

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A negative feedback modulator of antigen processing evolved from a frameshift in the cowpox virus genome.

Lin Jiacheng J Eggensperger Sabine S Hank Susanne S Wycisk Agnes I AI Wieneke Ralph R Mayerhofer Peter U PU Tampé Robert R

PLoS pathogens 20141211 12

Coevolution of viruses and their hosts represents a dynamic molecular battle between the immune system and viral factors that mediate immune evasion. After the abandonment of smallpox vaccination, cowpox virus infections are an emerging zoonotic health threat, especially for immunocompromised patients. Here we delineate the mechanistic basis of how cowpox viral CPXV012 interferes with MHC class I antigen processing. This type II membrane protein inhibits the coreTAP complex at the step after pep ...[more]

PMID: 25503639

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Project description:ObjectiveInflammatory cardiomyopathy is characterised by inflammatory infiltrates leading to cardiac injury, left ventricular (LV) dilatation and reduced LV ejection fraction (LVEF). Several viral pathogens and autoimmune phenomena may cause cardiac inflammation.The effects of the gain of function FOXO3A single-nucleotide polymorphism (SNP) rs12212067 on inflammation and outcome were studied in a cohort of patients with inflammatory dilated cardiomyopathy (DCMi) in relation to cardiac viral presence.MethodsDistribution of the SNP was determined in virus-positive and virus-negative DCMi patients and in control subjects without myocardial pathology. Baseline and outcome data were compared in 221 virus-negative patients with detection of cardiac inflammation and reduced LVEF according to their carrier status of the SNP.ResultsDistribution of SNP rs12212067 did not differ between virus-positive (n=22, 19.3%), virus-negative (n=45, 20.4 %) and control patients (n=18, 23.4 %), indicating the absence of susceptibility for viral infection or inflammation per se (p=0.199). Patients in the virus-negative DCMi group were characterised by reduced LVEF 35.5% (95% CI) 33.5 to 37.4) and increased LVEDD (LV end-diastolic diameter) 59.8 mm (95% CI 58.5 to 61.2). Within the group, SNP and non-SNP carriers had similarly impaired LVEF 39.2% (95% CI 34.3% to 44.0%) vs 34.5% (95% CI 32.4 to 36.5), p=0.083, and increased LVEDD 58.9 mm (95% CI 56.3 to 61.5) vs 60.1 mm (95% CI 58.6 to 61.6), p=0.702, respectively. The number of inflammatory infiltrates was not different in both SNP groups at baseline. Outcome after 6 months showed a significant improvement in LVEF and clinical symptoms in SNP rs12212067 carriers 50.9% (95% CI 45.4 to 56.3) versus non-SNP carriers 41.7% (95% CI 39.2 to 44.2), p≤0.01. The improvement in clinical symptoms and LVEF was associated with a significant reduction in cardiac inflammation (ΔCD45RO+ p≤0.05; ΔMac-1+ p≤0.05; ΔLFA-1+ p≤0.01; ΔCD54+ p≤0.01) in the SNP cohort versus non-SNP cohort, respectively. Subgroup analyses identified ΔMac-1+, ΔLFA-1+, ΔCD3+ and Δperforin+ as predictors for improvement in cardiac function in SNP-positive patients.ConclusionFOXO3A might act as modulator of the cardiac immune response, diminishing cardiac inflammation and injury in pathogen-negative DCMi.

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A negative feedback modulator of antigen processing evolved from a frameshift in the cowpox virus genome.

Publications

A negative feedback modulator of antigen processing evolved from a frameshift in the cowpox virus genome.

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