Although fever is one of the main presenting symptoms of COVID-19 infection, little public attention has been given to fever as an evolved defense. Fever, the regulated increase in the body temperature, is part of the evolved systemic reaction to infection known as the acute phase response. The heat of fever augments the performance of immune cells, induces stress on pathogens and infected cells directly, and combines with other stressors to provide a nonspecific immune defense. Observational trials in humans suggest a survival benefit from fever, and randomized trials published before COVID-19 do not support fever reduction in patients with infection. Like public health measures that seem burdensome and excessive, fevers involve costly trade-offs but they can prevent infection from getting out of control. For infections with novel SARS-CoV-2, the precautionary principle applies: unless evidence suggests otherwise, we advise that fever should be allowed to run its course.Lay summary: For COVID-19, many public health organizations have advised treating fever with medicines such as acetaminophen or ibuprofen. Even though this is a common practice, lowering body temperature has not improved survival in laboratory animals or in patients with infections. Blocking fever can be harmful because fever, along with other sickness symptoms, evolved as a defense against infection. Fever works by causing more damage to pathogens and infected cells than it does to healthy cells in the body. During pandemic COVID-19, the benefits of allowing fever to occur probably outweigh its harms, for individuals and for the public at large.

Glutathione is one of the most important and potent antioxidants. The development of pharmacological compounds that can either increase or decrease glutathione concentrations has allowed investigation into the role of glutathione in various biological processes, including immune responses. Recent findings have shown that glutathione not only affects certain factors involved in immunological processes but also modifies complex immune reactions such as fever. Until recently, it was not known why some patients do not develop fever during infection. Data suggest that fever induction is associated with oxidative stress; therefore, antioxidants such as glutathione can reduce pyrexia. Surprisingly, new studies have shown that low glutathione levels can also inhibit fever. In this review, we focus on recent advances in this area, with an emphasis on the role of glutathione in immune responses accompanied by fever. We describe evidence showing that disturbed glutathione homeostasis may be responsible for the lack of fever during infections. We also discuss the biological significance of the antipyretic effects produced by pharmacological glutathione modulators.

Bacterial DNA containing unmethylated cytosine-phosphate-guanosine motif (CpG-DNA) has been identified as a pathogen-associated molecular pattern, which is recognized by Toll-like receptors and activates immune cells to produce cytokines. The aim of the study was to characterize the ability of CpG-DNA to induce fever in mice. Intravenous administration of unmethylated CpG-DNA 1826 triggered an elevation of body temperature (T_b) lasting several hours. The magnitude of T_belevation increased with an increase of dose of the oligonucleotide (administered in a range from 0.01 mg/kg to 1.0 mg/kg). A fever-like increase of T_bin mice was partially dependent on IL-6, as IL-6 deficient mice responded with reduced fever to the CpG-DNA 1826. Meloxicam and sulindac sulfide, inhibitors of cyclooxygenases, reduced fever in mice challenged with CpG-DNA 1826, indicating that the process may also depend on prostaglandins. In fact, plasma levels of prostaglandin E₂, as well as IL-6, increased at 4 h postinjection of CpG-DNA 1826 into mice. These data demonstrate that the pathophysiological mechanism of the increase of T_binduced by CpG-DNA 1826 is similar to fever induced by LPS. Both LPS and CpG-DNA 1826 failed to produce elevation of T_bin mice deficient for a nuclear factor-κB (NF-κB) gene, further supporting the hypothesis that the two pyrogens provoke fever, using the same components of the cellular signaling metabolism. However, parthenolide, an inhibitor of I-κB kinase reduced fever due to CpG-DNA 1826, and did not affect fever to LPS, suggesting that the two structurally dissimilar pyrogens may affect different intracellular pathways leading to the upregulation of NF-κB. In support of this hypothesis, we demonstrate that C3H/HeJ mice, known to exhibit a mutation in the Toll-like receptor-4 gene, do not respond with fever to LPS. They respond, however, with fever after injection of CpG-DNA 1826. We conclude that bacterial DNA shares with components of the bacterial wall the capacity to elicit fever and may, consequently, be part of a novel class of exogenous pyrogens.

The induction of necroptosis, a form of caspase-independent cell death, represents one of the most promising anticancer therapeutic modalities, as necroptosis serves as an alternative way to eliminate apoptosis-resistant tumor cells. Here, we investigated whether protein-bound polysaccharides (PBPs) derived from the fungus Coriolus versicolor (CV) induce the necroptotic death pathway in breast cancer and melanoma cells. MCF-7 and SKMel-188 cells were exposed to PBPs either alone or in combination with necrostatin-1 (Nec-1), GSK'872 or necrosulfonamide (NSA), pharmacological inhibitors of the kinases receptor-interacting protein 1 kinase (RIPK1), receptor interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like protein (MLKL), respectively, which are involved in necroptotic processes. The effects of cellular treatment with these inhibitors were quantified by measuring cell viability and reactive oxygen species (ROS) generation via 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) and 2',7'-dichlorofluorescein diacetate (DCF-DA) assays, respectively. The morphological changes induced in these cells were detected using holotomographic (HT) microscopy. Activation of the TNF-α/TNFR1 pathway in the PBP-stimulated cells was evaluated using TNF-α-neutralizing antibody, qRT-PCR and immunofluorescence-based assays. PBPs showed effective antitumor activity against MCF-7 and SKMel-188 cells. Cotreatment of the cells with Nec-1, GSK'872 or NSA abrogated PBP-induced cell death, and the cells were protected against membrane rupture. Moreover, breast cancer cell death caused by PBPs was mediated by induced activation of the TNF-α/TNFR1 pathway. Interestingly, the melanoma cells did not express TNF-α or TNFR1 after PBP stimulation; instead, PBPs triggered intracellular ROS generation, which was partially diminished by the inhibitors Nec-1, GSK'872 and NSA. These results suggest that PBPs from the fungus CV induce RIPK1/RIPK3/MLKL-mediated necroptosis in breast cancer and melanoma cells, providing novel insights into the molecular effects of PBPs on cancer cells.

Chronic inflammation is a well-recognised tumour-enabling component, which includes bioactive molecules from cells infiltrating the tumour microenvironment and increases the risk of cancer progression. Since long-term use of the currently available anti-inflammatory drugs used in cancer therapy causes numerous side effects, the aim of this study was to investigate the effect of an extract isolated from the Coriolus versicolor fungus (CV extract) on HUVEC endothelial cells and MCF-7 breast cancer cells in a pro-inflammatory microenvironment mimicked by lipopolysaccharide (LPS). The cells were simultaneously stimulated with the LPS and CV extract. After co-treatment, the cell viability, generation of reactive oxygen species (ROS), wound-healing assay, production of the pro-inflammatory and pro-angiogenic factors (interleukin (IL) 6, IL-8, and metalloproteinase (MMP) 9)), as well as expression of Toll-like receptor (TLR) 4 and phosphorylated IκB (p-IκB) were evaluated. The results showed that the CV extract inhibited IL-6, IL-8, and MMP-9 production by the LPS-stimulated cells. This effect was accompanied by a decrease in TLR4 and p-IκB expression. The CV extract also had anti-migratory properties and induced a cytotoxic effect on the cells that was enhanced in the presence of LPS. The observed cytotoxicity was associated with an increase in ROS generation. We conclude that the CV extract possesses cytotoxic activity against cancer cells and endothelial cells and has the ability to inhibit the expression of the pro-tumorigenic factors associated with inflammation.