Pre-Treatment with Zirconia Nanoparticles Reduces Inflammation Induced by the Pathogenic H5N1 Influenza Virus

Huo, Caiyun; Xiao, Jin; Xiao, Kai; Zou, Shumei; Wang, Ming; Qi, Peng; Liu, Tianlong; Hu, Yanxin

Influenza A virus is one of the most common respiratory pathogens worldwide. In 1997, the first major epidemic of highly pathogenic avian influenza virus H5N1 occurred in Hong Kong. Since then, it has become well known for its potential to cause global pandemics in humans and mammals at all ages with considerable risks of morbidity and high fatality rates; it is now considered a growing threat to public health around the world. 45, 46 To date, it has been classified as a List A disease by the World Organisation for Animal Health (OIE) and as a Category 1 animal disease in China. A variety of antiviral drugs and vaccines have been adopted to prevent and control influenzainduced illness. However, it remains difficult to limit the spread of these viruses due to their highly contagious nature, frequent mutation of viral genes, and the emergence of resistant influenza strains due to the widespread abuse of antiviral drugs. Therefore, new approaches to fighting influenza virus infection are urgently needed. Due to unique structure and chemical characteristics, including large surface area, strong targeting performance, good biocompatibility, and high adsorption capacity, NPs have many benefits over conventional materials. Therefore, NPs have been widely applied in clinical trials. As carriers of anti-tumor drugs, NPs can significantly improve the curative effects of tumor therapies and reduce toxic drug side effects, making them attractive candidates for cancer therapy. 47, 48 For anti-viral therapy, NPs can be used as adjuvants or carriers to enhance the immune response. 49 However, while NPs are commonly used as efficient antigen delivery systems, their antiviral effects have only been recently reported. Herein, we have demonstrated that NPs alone effectively inhibit viral replication in a mouse model and protect mice from H5N1 infection. Our data further confirm the feasibility of the use of NPs alone as therapeutic agents to control influenza infection. H5N1 influenza virus can cause severe respiratory diseases in humans and mammals. The clinical symptoms include fever, muscle aches, cough, headache, diarrhea, viral pneumonia, encephalitis, and acute respiratory distress syndrome (ARDS). 50 In the mouse model, it can cause hair thickening, bowed limbs, blindness, trembling, significant weight loss, severe pathological tissue changes, and even death. 51 Previous studies have shown that virusinduced acute lung injury or ARDS is triggered by a cytokine storm and is a serious consequence of inflammation resulting from the release of pro-inflammatory cytokines and the recruitment of immune cells to the infected area. 52 Excessive inflammation can cause systemic inflammatory response syndrome, during which the body enters a state of high metabolic activity and energy usage. High levels of pro-inflammatory cytokines, including IL-6, IFN-γ, MCP-1, and TNF-α, have been detected in humans and mice infected with highly pathogenic H5N1 influenza virus. 53, 54 In the present study, we investigated the antiviral effects of positively-charged ZrO 2 on IAV in Figure 6 Overview of findings. Positively-charged ZrO 2 of 200 nm size and 100 mg/kg dose conferred protection against H5N1 infection in mice. The mechanisms are related to ZrO 2 -mediated enhancement of innate immunity in the early stage of H5N1 infection. The appropriate nanoparticle treatment could reduce viral load and suppress the inflammatory cytokine storm in the lungs of H5N1-infected mice,