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The impact of environmental microbiome on COVID-19 mortality

The impact of environmental microbiome on COVID-19 mortality

Study: The impact of environmental mycobiomes on geographic variation in COVID-19 mortality. Image Credit: Kateryna Kon / Shutterstock

There are huge differences in the mortality rate (COVID-19) and toll due to coronavirus disease 2019. This is likely to be due to socio-demographic, climatic or other factors. However, it is possible that there are additional factors that contribute to the variation in disease outcomes at local levels.

These factors can be used to predict the trajectories for pandemics. This may help with non-pharmaceutical interventions as well as research directions for the development of new therapeutic and immunological strategies.

Interactions between the host and non-pathogenic microbes can also have a significant impact on disease outcomes, such as those of COVID-19.

The following features are common to environmental microbes that promote health outcomes:

  • Environmental microbes having beneficial effects often originate from soils, freshwater environments, plants, and other non-anthropogenic sources – potentially reflecting a history of human evolutionary adaptation to them
  • These microbes can reduce the severity of diseases by stimulating the immune systems early in life.
  • It is important to be exposed to diverse microbes to achieve beneficial effects

Functional immune response is essential for moderating outcomes of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In addition, evidence suggests that COVID-19 disease severity correlates with bacterial community composition in patients and the hospital environment and with dysbiosis of the lung and the gut microbiomes.

A new study published on the medRxiv* preprint server was based on the hypothesis that the environmental mycobiome (fungi) is a likely important factor in determining area-level variation in COVID-19 mortality.

Study: The impact of environmental mycobiomes on geographic variation in COVID-19 mortality. Image Credit: Kateryna Kon / ShutterstockStudy: The impact of environmental mycobiomes on geographic variation in COVID-19 mortality. Image Credit: Kateryna Kon / Shutterstock

The study

The present study utilized taxonomic information on fungal communities from 1,135 homes nationwide, as well as COVID-19 data from across the United States. Paired samples were collected from each house—indoors and outdoors—allowing for comparison. An innovative approach was used to estimate the number of SARS-CoV-2 deaths per 1,000 infections in each county in the United States and in each home which provided fungal data.

Additionally, the influence of demographic, sociological, climate and soil factors was extensively explored, some of which influence Infection Fatality Ratios (IFR) and fungal community composition.

COVID-19 mortality is suppressed in homes where outdoor fungi occur indoors. (A) In United States homes where indoor and outdoor fungal communities are similar (low beta-diversity), COVID-19 mortality is reduced by over a factor of two compared to homes where the communities are dissimilar (high beta-diversity). Each point represents a United States county; shading indicates point density. Although the 90th percentile is sensitive to spatial autocorrelation, these trends are not driven by a single state or region of the United States (Figures E2 - E4). (B) The reductions in COVID-19 mortality (as measured by the standardized effect size, SES) are greatest in the upper quantiles of the COVID-19 mortality distribution, suggesting that outdoor fungi are sufficient but not necessary to reduce COVID-19 mortality. (C) The association between COVID-19 mortality and fungal beta-diversity is strongest early in the pandemic, before December 2020 when vaccination became widespread. Circles with black outlines indicate significant associations (SES> 3). (D) Fungal beta-diversity is a strong predictor of suppression of SARS-CoV-2 IFR relative to other variables [column graph; points represent individual variables, columns show means; correlations give the association between the given variable and the windowed 75th percentile of IFR (see Supplementary Information)]. Fungal beta-diversity is strongly linked to soil pH and other environmental variables (inset graph), suggesting that it does not serve as a proxy for demographic or other variables that can affect COVID-19 mortality. class=”rounded-img” height=”1005″ src=”https://d2jx2rerrg6sh3.cloudfront.net/images/news/ImageForNews_699908_16399736436415824.jpg”   title=”COVID-19 mortality is suppressed in homes where outdoor fungi occur indoors. (A) COVID-19 death is less common in homes where indoor and outdoors fungal communities are closely related (low beta-diversity). Each point represents an American county. The shading indicates point density. Although the 90th per centile is sensitive to spatial correlation, these trends do not reflect the influence of any one state or region of the United States. Figures E2 -E4 show that the trends are not driven solely by one state. (B) The COVID-19 mortality reductions (as measured using the standardized effect size (SES), are greatest in the upper quantiles. This suggests that outdoor fungi can be sufficient, but not essential, to reduce COVID-19 deaths. (C) The association of COVID-19 mortality with fungal beta-diversity was strongest before December 2020, when vaccination became widespread. Significant associations are indicated (SES>3) by black circles. (D) Fungal beta diversity is a strong predictor for suppression of SARS CoV-2 IFR relative other variables [column graph; points represent individual variables, columns show means; correlations give the association between the given variable and the windowed 75th percentile of IFR (see Supplementary Information)]. Fungal beta diversity is strongly linked to soil pH and other environmental variables (inset graph), suggesting that it does not serve as a proxy for demographic or other variables that can affect COVID-19 mortalities. width=”1280″/><figcaption class=Homes where outdoor fungal communities are indoors are less likely to have COVID-19 deaths. (A) COVID-19 death is less common in homes where indoor and outdoors fungal communities are closely related (low beta-diversity). This is in comparison to homes where the communities differ (high beta-diversity). Each point represents an American county. The shading indicates point density. The 90th percentile can be affected by spatial autocorrelation but these trends are not driven solely by one state or region of the United States. Figures E2 -E4 show that the trends are not driven primarily by one state. (B) The COVID-19 mortality reductions (as measured using the standardized effect size (SES), are greatest in the upper quantiles. This suggests that outdoor fungi can be sufficient, but not essential, to reduce COVID-19 deaths. (C) The association of COVID-19 mortality with fungal beta-diversity was strongest before December 2020, when vaccination became widespread. Significant associations (SES>3) are indicated by black circles. (D) Fungal beta diversity is a strong predictor for suppression of SARS CoV-2 IFR relative other variables [column graph; points represent individual variables, columns show means; correlations give the association between the given variable and the windowed 75th percentile of IFR (see Supplementary Information)]. Fungal beta diversity is strongly associated with soil pH (inset bar graph), suggesting it is not a proxy to demographic and other variables known to influence COVID-19 mortality.

Findings

It was noted that a majority of the citizens primarily interact with indoor microbes only—as they spend most of their time in their homes or other constructed environments. For fungi, two major types were of concern – non-pathogenic outdoor species (which are sometimes also found indoors) and pathogenic or opportunistic species that proliferate in damp indoor environments. These types elicited notable differences.

SARS-CoV-2 IFR was reduced by the presence of outdoor fungal genera in the built environment. Based on the analysis, a marginal impact was observed of the relative abundances of fungal genera or indoor-outdoor beta diversity—after taking into account demographic, sociological, climate and soil factors. The relative abundances for fungal genera had a statistically significant, but very small effect on the mean IFR when considering all the other factors.

Quantile analysis revealed that indoor/outdoor beta-diversity was associated with lower SARS-2 IFR, which indicates decreased mortality. However, it was found that indoor-outdoor mycological flora is associated with higher SARS-CoV-2IFR. These results were consistent across all counties.

The occurrence of at least four outdoor fungal genera indoors suppresses COVID-19 mortality. (A) Seven prevalent genera significantly increase the predictiveness of indoor-outdoor fungal beta-diversity on COVID-19 mortality. Abbreviations are L: Alternaria, S : Aspergillus, P : Epicoccum, U : Eurotium, T : Toxicocladosporium, W : Wallemia, M : Mycosphaerellaceae genus. (B) For some of these genera, including Alternaria spp., high relative abundance both outdoors and indoors is necessary for suppressed COVID-19 mortality. (C) However, the full beneficial effects result from synergistic effects of multiple genera: vertices represent sets of genera (colored by predictive power), while edges represent interactions when sets of genera are considered jointly as predictors (colored by interaction strength). Genera with correlated relative abundances are grouped together (e.g., LM : Alternaria and Mycosphaerellaceae genus). The graphs around the edges show examples of predictive power and interactions; gray lines demarcate null (randomized) expectations plus or minus one standard deviation. Except for when the full set of genera is considered (top right vertex), super-additive effects dominate, pointing to synergistic effects.
COVID-19 mortality can be suppressed if there are at least four indoor fungal genera. (A) Seven common genera significantly increase indoor-outdoor fungal beta diversity on COVID-19 mortality. L: Alternaria; S: Aspergillus; P : Epicoccum; U : Eurotium. T : Toxicocladosporium. W : Wallemia. M : Mycosphaerellaceae. Genus. (B) High relative abundance indoors and outdoors is required for some genera, including Alternaria species, to suppress COVID-19 mortalities. (C) However, the full benefit of multiple genera is achieved through synergistic effects: vertices are sets of genera (colored according to predictive power), while edges are interactions when sets of genes are considered together as predictors (colored according to interaction strength). Genera with correlated relative amounts are grouped together (e.g. LM : Alternaria genus and Mycosphaerellaceae genus). The graphs around edges illustrate examples of predictive power, interactions; the gray lines demarcate null (randomized), expectations plus or minus 1 standard deviation. Except when the full set is considered (top left vertex), super-additive effect dominates, pointing out synergistic results.

The presence of indoor fungi with high diversity was associated with lower COVID-19 deaths than indoor fungi. This association was valid in the first few months of the pandemic and weaker during the later phases—December 2020 to January 2021—after vaccine availability and in the setting of access to pharmaceutical treatments.

Remarkably, soil edaphic factors – particularly pH, appeared to affect COVID-19 severity by affecting microbial distributions. A causal link was also found between indoor-outdoor fungal beta diversity and SARS-CoV-2IFR, even after considering other variables.

The results revealed that at least four of these fungal genera play a key role in suppressing SARS-CoV-2 IFR, which are – Alternaria, Aspergillus, Epicoccum, Eurotium, Toxicocladosporium, Wallemia spp., Novel Mycosphaerellaceae genus. Some of these have interdependent occurrences. It is therefore difficult to determine the effects of individual genera. For significant SARS-CoV-2 IFR decrease, it is important to have three of these genera in high relative abundance both indoors as well as outdoors.

These findings are a new illustration of the positive effects of seven mycological genises on COVID-19 mortality. These genera can be pathogenic in some environments, but they may have positive effects on others.

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A view from the parapet of Nine Arches viaduct.

Additionally, different species of endemic and environmental microbes can have different effects depending on host genetics, age, immune status and interactions with other microbial exposures.

Positive synergistic effects were identified among the seven genera studied in this study. This makes it possible to predict how their beta-diversity will affect each other. Fungal beta diversity was also strongly associated with SARS/CoV-2 IFR suppression in areas with stable human habitation. Hence, these observations could accurately map locations to forecast regions with strong suppression of COVID-19 mortality in the US – the Desert Southwest, Intermountain West, and Upper Midwest.

The occurrence of outdoor fungi indoors is more predictive of COVID-19 mortality in locations where people have been less transient from 2010-2017 than in regions where there are many new residents.
Outdoor fungi indoors are more predictive of COVID-19 death in areas where people have been more permanent between 2010-2017 than those where there are many new residents.

pH, in addition to the US climate, may indicate the microbial composition of the US and the propensity for microbial transportation into homes via dust. There is a correlation between bioaerosol counts and incidence of respiratory diseases.

In conclusion, high levels of outdoor fungal species in your home can protect you from poor COVID-19 outcomes. These results highlight the utility of the environment mycobiome as an indicator. The beneficial effects of environmental mushrooms may not only be applicable to COVID-19, but may also be applicable to other immune-mediated and autoimmune diseases.

Further research is needed to understand the role of fungal interactions with the host immune systems and the role they play in this process. Recent advancements in the classification and sequencing of environmental fungi will improve future efforts and highlight the utility of biosurveillance in future pandemics.

Fungal suppression of COVID-19 mortality varies regionally. In regions where soils tend to be basic (red background shading), indoor-outdoor fungal beta-diversity tends to be low, and fungal suppression of SARS-CoV-2 IFR is high (red dots). By contrast, the opposite trend holds in regions with acidic soils (blue background shading and dots); here, where fungal suppression of SARS-CoV-2 IFR is lessened, SARS-CoV-2 IFR can be high or low depending on whether other factors (e.g., climate, demographics) reduce SARS-CoV-2 IFR.
The region determines how fungal suppression of COVID-19 mortality. Indoor-outdoor fungal beta diversity tends to be low in regions with basic soils (red background shading). Fungal suppression of SARS-2 IFR is high in these regions (red dots). The opposite trend is seen in regions with acidic soils (blue backgrounds shading and dots). Here, fungal suppression of SARS-2 IFR is lessened, SARS-2 IFR can be either high or low depending upon whether other factors (e.g. climate, demographics) reduce SARS-2 IFR.

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

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