Low-dose cadmium potentiates lung inflammatory response to 2009 pandemic H1N1 influenza virus in mice

• Type of Material: Article
• Authors: Joshua Chandler, Emory University; Xin Hu, Emory University; Eunju Ko, Georgia State University; Soojin Park, Georgia State University; Jolyn Fernandes, Emory University; Young-Tae Lee, Georgia State University; Michael L. Orr, Emory University; Li Hao, Emory University; M. Ryan Smith, Emory University; David Neujahr, Emory University; Karan Uppal, Emory University; Sang-Moo Kang, Georgia State University; Dean Jones, Emory University; Young-Mi Go, Emory University
• Language: English
• Date: 2019-06-01
• Publisher: Elsevier Science Ltd.
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2019 The Authors. Published by Elsevier Ltd.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.envint.2019.03.054
• Title of Journal or Parent Work: Environment International
• Volume: 127
• Start Page: 720
• End Page: 729
• Grant/Funding Information: This study was supported by NIEHS Grant R01 ES023485 (DPJ and YMG), R21 ES025632 (DPJ and YMG), NIH S10 OD018006 (DPJ), NIH/NIAID grants R01 AI105170 (SMK), R01 AI093772 (SMK), and R21 AI119366 (SMK), and NHLBI F32 1F32HL132493 (JDC) and Cystic Fibrosis Foundation CHANDL16F0 (JDC).
• Keywords: Expression; NF-KAPPA-B; National health; Regulatory factor 1; Influenza A virus; Science & Technology; Environmental Sciences & Ecology; Gamma; Life Sciences & Biomedicine; Gene; Blood; Transcription; Exposome; Environmental safety; Chronic exposure; Public health; Respiratory syncytial virus; Environmental Sciences; Heavy metals
• Research Categories: Health Sciences, Public Health; Biology, Virology; Biology, Genetics; Environmental Sciences

Abstract

Cadmium (Cd) is a toxic, pro-inflammatory metal ubiquitous in the diet that accumulates in body organs due to inefficient elimination. Responses to influenza virus infection are variable, particularly severity of pneumonia. We used a murine model of chronic low-dose oral exposure to Cd to test if increased lung tissue Cd worsened inflammation in response to sub-lethal H1N1 infection. The results show that Cd-treated mice had increased lung tissue inflammatory cells, including neutrophils, monocytes, T lymphocytes and dendritic cells, following H1N1 infection. Lung genetic responses to infection (increasing TNF-α, interferon and complement, and decreasing myogenesis) were also exacerbated. To reveal the organization of a network structure, pinpointing molecules critical to Cd-altered lung function, global correlations were made for immune cell counts, leading edge gene transcripts and metabolites. This revealed that Cd increased correlation of myeloid immune cells with pro-inflammatory genes, particularly interferon-γ and metabolites. Together, the results show that Cd burden in mice increased inflammation in response to sub-lethal H1N1 challenge, which was coordinated by genetic and metabolic responses, and could provide new targets for intervention against lethal inflammatory pathology of clinical H1N1 infection.