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. 2009 Sep;117(9):1441-7.
doi: 10.1289/ehp.0900911. Epub 2009 May 20.

Low-dose arsenic compromises the immune response to influenza A infection in vivo

Courtney D Kozul  1 , Kenneth H Ely, Richard I Enelow, Joshua W Hamilton
Affiliations

Low-dose arsenic compromises the immune response to influenza A infection in vivo

Courtney D Kozul et al. Environ Health Perspect. 2009 Sep.

Abstract

Background: Arsenic exposure is a significant worldwide environmental health concern. We recently reported that 5-week exposure to environmentally relevant levels (10 and 100 ppb) of As in drinking water significantly altered components of the innate immune response in mouse lung, which we hypothesize is an important contributor to the increased risk of lung disease in exposed human populations.

Objectives: We investigated the effects of As exposure on respiratory influenza A (H1N1) virus infection, a common and potentially fatal disease.

Methods: In this study, we exposed C57BL/6J mice to 100 ppb As in drinking water for 5 weeks, followed by intranasal inoculation with a sub lethal dose of influenza A/PuertoRico/8/34 (H1N1) virus. Multiple end points were assessed postinfection.

Results: Arsenic was associated with a number of significant changes in response to influenza, including an increase in morbidity and higher pulmonary influenza virus titers on day 7 post-infection. We also found many alterations in the immune response relative to As-unexposed controls, including a decrease in the number of dendritic cells in the mediastinal lymph nodes early in the course of infection.

Conclusions: Our data indicate that chronic As exposure significantly compromises the immune response to infection. Alterations in response to repeated lung infection may also contribute to other chronic illnesses, such as bronchiectasis, which is elevated by As exposure in epidemiology studies.

Keywords: arsenic; dendritic cells; influenza; innate immune system; mouse lung.

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Figures

Figure 1
Figure 1
Morbidity of influenza infection (measured by weight loss) in mice exposed to control water or water containing 100 ppb As. One experiment was conducted for days 0–16 (n = 6–8 per group), and three additional experimental repeats were conducted for days 0–7 (n = 6 per group per experiment). See “Materials and Methods” for experimental details. Values shown are mean ± SEM. The p-value for overall significance between groups exposed to flu alone or As + flu is p < 0.0001 (two-way ANOVA). **p < 0.01, and #p < 0.001, for individual time point exposures.
Figure 2
Figure 2
Viral titers for flu on day 7 p.i. in mice exposed to control water or water containing 100 ppb As. Whole-lung homogenates were assessed for viral titers by the TCID50 method. See “Materials and Methods” for experimental details. Values shown are mean ± SEM from two experimental repeats (n= 3–6 per group). *p < 0.05 by two-tailed Student’s t-test.
Figure 3
Figure 3
Effect of chronic exposure to As (100 ppb) in drinking water for 5 weeks followed by inoculation with influenza A. (A, B ) Gross histology of representative lungs from mice given control drinking water (Flu alone; A) and As in drinking water (Flu + As; B) at day 7 p.i. after lungs were perfused with PBS and inflated. (C ) BALF assessed for albumin by ELISA on day 0 and day 3 and day 7 p.i. (D ) Oxygen saturations measured with the MouseOx system at day 0 and day 7 p.i. In B and C, values are mean ± SEM from one representative experiment (n= 6 per group). **p < 0.01, and #p < 0.001, by two-tailed Student’s t-test.
Figure 4
Figure 4
Alteration in cell numbers at day 0, 36 hr, day 3, and day 7 p.i. in BALF of mice exposed to control water or water containing 100 ppb As (Flu + As) followed by inoculation with influenza A. (A) Number of viable nucleated cells recovered from BALF. (B, C) Extrapolation of the total number of macrophages (B) and neutrophils (C) recovered from BALF. See “Materials and Methods” for experimental details. For A–C, data represent mean ± SEM from one representative experiment (n = 5–6 per group). (D) Neutrophils, macro phages (Macs), and lymphocytes shown as percentages of the total cells recovered. *p < 0.05, **p < 0.01, and #p < 0.001 determined by two-tailed Student’s t-test.
Figure 5
Figure 5
Effects of flu alone and flu plus chronic exposure to As (100 ppb) in drinking water shown at 36 hr, day 3, and day 7 p.i. in representative cytospin preparations. See “Materials and Methods” for experimental details. (A, C, E) Flu alone. (B, D, F) Flu + As. (A, B) 36 hr p.i. (C, D) Day 3 p.i. (E, F ) Day 7 p.i
Figure 6
Figure 6
Effects of chronic exposure to As (100 ppb) in drinking water on CD8+ cells in BAL in response to influenza A. (A ) Representative fluorescence-activated cell sorting plots showing isolated BALF cells stained with fluorochrome-conjugated antibodies against CD4 and CD8. (B, C ) Percentage of CD8+ cells (B) and average number of total CD8+ cells (C) recovered from BALF at day 7 p.i.; values shown are mean ± SEM from one representative experiment (n = 5–6 per group). *p < 0.05, determined by two-tailed Student’s t-test.
Figure 7
Figure 7
Effects of chronic exposure to As (100 ppb) in drinking water on cytokine and chemokine levels in BALF at day 3 and day 7 p.i. (A) RANTES. (B) MIP-2. (C) MCP-1. See “Materials and Methods” for experimental details. Values shown are mean ± SEM (n = 5–6 per group). *p < 0.05, **p < 0.01, and #p < 0.001, determined by two-tailed Student’s t-test.
Figure 8
Figure 8
Effect of chronic exposure to As (100 ppb) in drinking water on DCs. See “Materials and Methods” for experimental details. Total number of MLN cells (A), CD11c+/CD103+ cells (B), and CD11c+/B220+ cells (C); values shown are mean ± SEM from three representative experiments (n = 5 per group). (D ) Results of a trans-well assay showing migration capability of DCs toward ADP; Values shown are mean ± SEM from three representative experiments (n = 3 per experiment) and are expressed as mean cell migration relative to control mice. *p < 0.05, **p < 0.01, and #p < 0.001, determined by two-tailed Student’s t-test.
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