The coronavirus disease 2019 (COVID-19) pandemic, caused by a single-stranded RNA virus, 1 has demonstrated considerable variations in rate and mortality globally. 2 These variations have been explained by several factors, including age, data accuracy, and obesity. 2
Inflammation contributes to colon cancer initiation. The disease along with allergy and autoimmunity has been on the rise in Western and more recently in developing countries. This shared rise may imply a shared cause. Streptomycetes are known as soil residents and produce numerous antiproliferative, anti-inflammatory/immunosuppressive compounds, e.g. rapamycin and tacrolimus. Recently, Streptomyces has been shown in gut microbiome with a lower prevalence in humans than nonhumans whose microbiomes might be more representative of past humans' in a hunter-gatherer and farming environment. It was previously suggested that Streptomyces producing antiproliferatives/immunosuppressants would be 'old friends' against allergy and autoimmunity as well as inflammatory bowel diseases. Here, it is suggested that these streptomycetes within gut microbiome have also been evolved as 'old friends' to suppress colon tumorigenesis through their numerous antiproliferatives/immunosuppressants. Subsequently, the shortage of exposure to nature in our current lifestyle has cost us the shortage of these friends and vulnerability to colon cancer. An attractive research area in the future would be whether the shortage of Streptomyces exposure can be the underlying reason for colon cancer, allergy and autoimmunity rise, and if the restoration of these 'old friends' through probiotics or more exposure to nature can prevent colon cancer.
Resistance to a drug and the suppression of inflammatory disorders with immunosuppressive drugs might have happened upon exposure to natural compounds during evolution. Streptomycetes are soil bacteria, but they produce therapeutic drugs. They have been reported to be the low-abundant members of mucosal microbiomes with a higher prevalence in nonhumans ingesting soil compared with humans. Their lower abundance in the human microbiome might be the representations of our current hygienic lifestyle. We suggest that the Streptomyces bacteria producing antiproliferative/immunosuppressive compounds (e.g., rapamycin and tacrolimus) contribute to the rapalog resistance of certain mucosal tumours (e.g., colon cancer) and the 'hygiene hypothesis'. If so, the shortage of exposure to these compounds in the current lifestyle might be an underlying reason for the increase of inflammatory diseases, such as inflammatory bowel diseases (IBD). An investigation on adding certain Streptomycetes (e.g., S. hygroscopicus and S. tubercidicus) to the list of probiotics against inflammatory diseases would be an interesting research area in the future.
Natural killer (NK) cells target the cells losing MHC-I in cancer, a phenotype that is similar to certain cells in immune-privileged sites whose milieus are separated from peripheral blood. NK cells are reported to be quantitatively and qualitatively different in immune-privileged sites from those cytotoxic ones in the blood. We hypothesize that cytotoxic and expanded NK cells induced in cancer patients may be turned into pathogenic factors if they enter immune-privileged microenvironments in susceptible individuals, such as, patients with brain cancer or a blood-brain barrier dysfunction. Therefore, in susceptible individuals, different levels of caution should be taken based on the seriousness of the side effect as discussed in this perspective.
So far, the COVID-19 pandemic has caused less casualty in Eastern Asia areas compared to the other parts of the world. The pattern of less casualty in the pandemic origin has also been observed in the three main flu pandemics in the last century. It is reasonable to speculate that less casualty of COVID-19/flu in the pandemic origin is likely due to the preexisting cross-immunity to some close viruses being more prevalent in those regions. Experts and modelers should scale up the severity of a flu-like viral epidemic to predict its real severity for the rest of the world.
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