Immunoproteome of anti-TB drug associated DRESS in HIV TB co-infection

Buck, Chloe

Immunoproteome of anti-TB drug associated DRESS in HIV TB co-infection

Master Thesis

2022

Abstract

Introduction: A greater incidence of severe cutaneous adverse drug reaction (SCAR) such as Drug Reaction with Eosinophilia Systemic Symptoms (DRESS) occur among HIV-infected patients. We sought to characterize the immunoproteomic profile of DRESS to first-line TB drugs in HIV infected cases. We hypothesize that differentially regulated proteins would be found interindividually and with disease evolution that may provide a mechanistic understanding of DRESS underlying pathways. Participants and Methods: HIV cases with DRESS (probable or definite) and confirmed reactions to either one or many first-line anti-TB (FLTB) drugs were chosen (n=8). Discovery High Performance Liquid Chromatography Mass Spectrometry (HPLC-MS) (data independent proteomic) analysis was carried out on plasma samples with downstream protein identification and quantification analysis done on Spectronaut ™. (https://biognosys.com/resources/spectronaut-15-expand-biological-insights-with-diaproteomics/) Data and statistical analysis was carried out using Perseus and R programming language. Results: Overall protein clustering suggested greater plasma proteome differences between individuals than intraindividually between DRESS disease states and drug rechallenge reactions. Acute phase proteins and immunoglobulin kappa variable chains dominate the serum proteome of acute DRESS in TB/HIV co-infected patients, with CRP having the highest fold change (q = 2.5) in acute versus early recovery samples. LRG and L-Selectin (q < 0.05, FC > 1.5), both proteins involved in maintenance and regulation of the immune system especially at endothelia, were found to be upregulated in acute compared to recovery samples. Multiple non-immune related proteins, linked to actin-binding and thus cell structure, morphology, and functioning, were also upregulated (p < 0.05, FC > 1.5) in acute samples (including (ACTB) Actin, cytoplasmic 1, (ACTC1) Actin, alpha cardiac muscle 1, (VCL) Viculin). (MPO) Positive drug reaction samples from single versus multiple drug reactors had differentially regulated immune proteins: myeloperoxidase (p = 0.04, FC = 1.4), CRP (p = 0.04, FC = 5.2) and (LYST) Lysosomal-trafficking regulator (p = 0.04, FC > 2.7), proteins linked to polymorphonuclear cell inflammation, acute phase response and antiviral lymphocyte responses respectively. Conclusion: Acute phase proteins and non-discriminatory hypergammaglobulinemia dominated the plasma proteome of HIV/TB co-infection and DRESS to FLTD, with drivers including TB disease burden and acute DRESS being hard to discriminate. A few differentially regulated immune proteins, particularly when comparing single versus multiple drug reactors, highlight roles for polymorphonuclear cell inflammation, and antiviral lymphocyte responses beyond the exaggerate innate acute phase response. Further work with increased sample size is warranted to confirm these preliminary findings.

Keywords

Medicine

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