Low-Level Aflatoxin B1 Promotes Influenza Infection and Modulates a Switch in Macrophage Polarization from M1 to M2

Abstract

Background/Aims: Swine influenza virus (SIV) is a major pathogen of both animals and humans. Afatoxin B1 (AFB₁) is one of the most common mycotoxins in feed and food. However, the central contribution of AFB₁ to SIV infection remains unclear. Methods: Here, TCID₅₀ assays, fluorescence-based quantitative real-time PCR, western blotting, immunofluorescence staining, histopathological examination, flow cytometry and scanning electron microscopy were performed to investigate the involvement and underlying mechanism of AFB₁ in SIV infection in vivo and in vitro using mouse models and porcine alveolar macrophage (PAM) models, respectively. Results: The in vivo study showed that low levels of AFB₁ promoted SIV infection and increased its severity, as demonstrated by the increased mRNA expression of viral matrix protein (M); by the increased protein expression of nucleoprotein (NP), matrix protein 1 and ion channel protein; and by animal weight loss, lung index and lung histologic damage. In addition, the increased occurrence of SIV infection accompanied by increases in the level of IL-10 in sera and lungs, in the spleen index and in the number of CD206-positive mouse alveolar macrophages but decreases in the level of TNF-α in sera and lungs, in the thymus index and in the number of CD80-positive mouse alveolar macrophages was observed in SIV-infected mice after low-level AFB₁ exposure. The in vitro study showed that low concentrations of AFB₁ promoted SIV infection, as demonstrated by the increases in viral titers and viral M mRNA and NP expression levels in SIV-infected PAMs as well as by the number of cells positive for NP protein expression. Furthermore, AFB₁ promoted the polarization of SIV-infected PAMs to the M1 phenotype at 8 hpi and to the M2 phenotype at 24 hpi, as measured by the increases in IL-10 expression and in the number of CD206-positive PAMs as well as by the morphological changes observed by scanning electron microscopy. The administration of the immune stimulant lipopolysaccharide (LPS) reversed the switch in PAM polarization from M2 to M1 and thereby counteracted the promotion of influenza virus infection induced by AFB₁. Conclusion: Our results are the first to confirm that low-level exposure to AFB₁ promotes SIV infection and modulates a switch in macrophage polarization from M1 to M2. The work reported here provides important data that point to a role for AFB₁ in SIV infection, and it opens a new field of study.

The Toxic Effects of Aflatoxin B1: An Update

“…This result was in accordance with the observation of Hendrickse et al long back in 1989 that heroin addicts often experienced rapid progression of HIV infection, while street heroin was often contaminated with aflatoxin and that aflatoxin derivatives were commonly found in the body fluids of the addicts [20]. Recent researches also show that when exposed to a low dose of AFB1, people were more vulnerable to SIV infection and suffered increased severity [21].Another chronic adverse effect of AFB1 is malnutrition and growth impairment. Several observations in developing countries have pointed out the accordance of kwashiorkor occurrence with high AFB1 concentration in sera [22][23][24].…”

“…This result was in accordance with the observation of Hendrickse et al long back in 1989 that heroin addicts often experienced rapid progression of HIV infection, while street heroin was often contaminated with aflatoxin and that aflatoxin derivatives were commonly found in the body fluids of the addicts [20]. Recent researches also show that when exposed to a low dose of AFB1, people were more vulnerable to SIV infection and suffered increased severity [21].…”

Baicalin Inhibits Influenza A Virus Infection via Promotion of M1 Macrophage Polarization

“…Their shift between the classically activated (M1, proinflammatory) and alternatively activated (M2, anti-inflammatory) phenotypes has been recognized as a crucial factor in the initiation, progression, and termination of numerous inflammatory diseases (Zhang et al, 2018) and especially in influenza virus infection (Halstead et al, 2018). Modulation of macrophage polarization has previously been shown to inhibit or promote influenza infection by applying GM-CSF (Sun et al, 2018) or Afatoxin B1 (Han et al, 2019), respectively. In this study, we confirm that the high mortality of infected mice is correlated with an abundant recruitment of macrophages to the lung and a high proportion of M1-polarized macrophages.…”

EB virus-induced ATR activation accelerates nasopharyngeal carcinoma growth via M2-type macrophages polarization

“…HPV detected in the rectal squamous cell carcinoma is associated with the increased macrophage M2 polarization 31 . In addition, the swine influenza virus 32 and rhinovirus 33 can also be involved in the regulation of macrophage conversion from M1 to M2 polarization. Saha et al 34 also found that hepatitis C virus can induce monocytes to differentiate into polarized M2 macrophages, which promotes the activation of stellate cells by TGF-β.…”