Chronic exposure to arsenite enhances influenza virus infection in cultured cells

Abstract

Arsenic is a ubiquitous environmental toxicant that has been associated with human respiratory diseases. In humans, arsenic exposure has been associated with increased risk of respiratory infection. Considering the existing epidemiological evidence and the well‐established impact of arsenic on epithelial cell biology, we posited that the effect of arsenic exposure in epithelial cells could enhance viral infection. In this study, we characterized influenza virus A/WSN/33 (H1N1) infection in Madin‐Darby Canine Kidney (MDCK) cells chronically exposed to low levels of sodium arsenite (75 ppb). We observed a 27.3‐fold increase in viral matrix (M2) protein (24 hours postinfection [p.i.]), a 1.35‐fold increase in viral mRNA levels, and a 126% increase in plaque area in arsenite‐exposed MDCK cells (48 hours p.i.). Arsenite exposure resulted in 114% increase in virus attachment‐positive cells (2 hours p.i.) and 224% increase in α‐2,3 sialic acid‐positive cells. Interestingly, chronic exposure to arsenite reduced the effect of the antiviral drug, oseltamivir in MDCK cells. We also found that exposure to sodium arsenite resulted in a 4.4‐fold increase in viral mRNA levels and significantly increased cytotoxicity in influenza A/Udorn/72 (H3N2) infected BEAS‐2B cells. This study suggests that chronic arsenite exposure could result in enhanced influenza infection in epithelial cells, and that this may be mediated through increased sialic acid binding. Finally, the decreased effectiveness of the anti‐influenza drug, oseltamivir, in arsenite‐exposed cells raises substantial public health concerns if this effect translates to arsenic‐exposed, influenza‐infected people.

Toxic metal exposure as a possible risk factor for COVID-19 and other respiratory infectious diseases

“…These data generally are in agreement with the earlier observation of impaired antiviral response and higher pulmonary virus titer in a model of H1N1 influenza infection in C57BL/6J mice ( Kozul et al, 2009 ). Moreover, chronic arsenite exposure significantly increased susceptibility to H1N1 influenza infection through sialic acid binding as well as decreased efficiency of oseltamivir ( Amouzougan et al, 2020 ). In addition, prenatal As exposure significantly aggravated influenza A-induced pulmonary inflammation ( Ramsey et al, 2013 ).…”

Molecular mechanisms of stress-induced reactivation in mumps virus condensates

“… 63 Furthermore, acute phase replication of influenza virus is enhanced in cells exposed to arsenite. 64 However, little is known about how stress affects viruses at the chronic infection phase. Exceptions are studies of social stress reported to cause reactivation of latent DNA virus, e.g., HSV-1, 2 and of oxidative stress leading to reactivation of HIV-1.…”

Molecular mechanisms of stress-induced reactivation in mumps virus condensates

“…G3BP1) to promote viral gene expression (Bonenfant et al, 2019). Furthermore, acute phase replication of influenza virus is enhanced in cells exposed to arsenite (Amouzougan et al, 2020). However, little is known about how stress affects viruses, especially RNA viruses, at the chronic infection phase.…”