Environmental exposures are hidden modifiers of anti-viral immunity

Abstract

Significant advances have been made recent years elucidating antiviral immune mechanisms that protect the host from viral infection. Similarly, our understanding of how viruses bind, enter, and replicate within host cells has continued to grow. Yet, viruses continue to take a toll on human health. The influence of chemicals in the environment is among key factors that influence outcomes of viral infection. There is a growing appreciation of the effects that exogenous environmental chemical exposures have on the immune system and antiviral immunity. Epidemiological studies have linked a variety of chemical exposures to poorer health, increased incidence of infection, and worsened vaccine responses. However, the mechanisms that govern these associations are not well understood, limiting our ability to predict or mitigate the effects of environmental exposures on public health. This brief review focuses on recent advances in the field, highlighting novel and findings informed by past foundational studies. Furthermore, current information suggests avenues of investigation that have yet to be explored, but which will significantly impact on our understanding about how environmental exposures impact viral defenses, vaccine efficacy, and the spread of contemporary and emerging viral pathogens.

The Aryl Hydrocarbon Receptor as a Modulator of Anti-viral Immunity

“…Recent genome wide transcriptional analyses of DCs isolated from lungs of IAV-infected mice treated with TCDD detected a strong down-regulation of CD209a and CCL17 expression. Indeed, Ingenuity Pathway Analysis (IPA) revealed that the most altered signaling pathways in these DCs are related to immune cell trafficking, cellular movement and hematological system development and function ( 85 ). Interestingly, although AHR activation increases morbidity and mortality caused by IAV infection, the kinetics of viral growth and the efficacy of the viral clearance, are not significantly different between control and TCDD-treated mice in primary infections nor even during homotypic reinfections ( 86 – 89 ).…”

“…Studies using AHR mutant mice suggest that changes in the host response to IAV are mainly driven by direct interactions of AHR with XREs ( 85 , 91 ). However, the specific AHR gene targets involved in the altered host responses to IAV induced by TCDD remain to be determined.…”

“…Neural progenitor cells (NPCs) are the primary target of the ZIKV, and this may partly explain the high number of abnormalities detected in neuroimaging examinations ( 103 ). It was reported that environmental factors strongly correlate with nutrition and socioeconomic position affecting the immune status and response to ZIKV infections ( 85 ). When analyzing this relationship for Recife (Pernambuco, Brazil), a city that was severely hit by ZIKV, it was found that cases of reported microcephaly in 2015 and 2016 were largely concentrated in areas with more impoverished living conditions ( 104 ).…”

Genome-Wide Transcriptional Analysis Reveals Novel AhR Targets That Regulate Dendritic Cell Function during Influenza A Virus Infection

“…Viral infections continue to pose a major disease burden, accounting for millions of lost disability-adjusted life years (1). Emerging evidence points to environmental factors as important modulators of host responses to infection; yet, precisely how signals from the environment influence immune responses to infection are not fully understood (2). However, there is clear evidence leukocyte function is influenced by environmental factors that bind the aryl hydrocarbon receptor (AhR).…”

“…In the context of infection, AhR activation by TCDD modulates host responses in rodent models of infection, such as influenza A virus (IAV) and HSV (2,19,20). For instance, during infection with IAV, AhR activation significantly reduced the response of CD8 + T cells.…”