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2021 Sep 16
Retired, San Jose, CA, USA
How major fungal infections can initiate severe autoimmune diseases
https://pubmed.ncbi.nlm.nih.gov/34537272/

Abstract

Several autoimmune diseases have long been linked to viral and bacterial infections. In contrast, the possibility of fungal infections causing autoimmune diseases has received almost no attention. However, major fungal infections can cause severe autoimmune diseases, by decreasing TREG cells and increasing production of interleukin-23, CD4 TH17 T cells, interleukin-17 and other cytokines, including interleukin-22. Several factors can cause fungal infections, including antibiotic usage. Bacterial and fungal populations compete in mammalian oropharyngeal, respiratory, gastrointestinal, and genitourinary tracts. Antibiotic usage decreases bacteria and thereby favors fungal populations over bacterial populations. This leads to an explanatory hypothesis for the pathogenesis of severe autoimmune diseases by major fungal infections. The increase in fungal populations in individuals susceptible to major fungal infections can also explain the higher incidence of autoimmune diseases. CD4 TH17 T cells and certain interleukins can be one path of pathogenesis between major fungal infections and increased incidences of major autoimmune diseases, including type 1 diabetes, multiple sclerosis, and various types of arthritis.

2020
Peter Frost
Are Fungal Pathogens Manipulating Human Behavior?
https://pubmed.ncbi.nlm.nih.gov/33416798/


Abstract

Many pathogens, especially fungi, have evolved the capacity to manipulate host behavior, usually to improve their chances of spreading to other hosts. Such manipulation is difficult to observe in long-lived hosts, like humans. First, much time may separate cause from effect in the case of an infection that develops over a human life span. Second, the host-pathogen relationship may initially be commensal: the host becomes a vector for infection of other humans, and in exchange the pathogen remains discreet and does as little harm as possible. Commensalism breaks down with increasing age because the host is no longer a useful vector, being less socially active and at higher risk of death. Certain neurodegenerative diseases may therefore be the terminal stage of a longer-lasting relationship in which the host helps the pathogen infect other hosts, largely via sexual relations. Strains from the Candida genus are particularly suspect. Such pathogens seem to have co-evolved not only with their host population but also with the local social environment. Different social environments may have thus favored different pathogenic strategies for manipulation of human behavior.

2021 Sep 14
Department of Chemistry and Biological Sciences, Institute of Biosciences, São Paulo State University (UNESP), Brazil
Candida tropicalis Systemic Infection Redirects Leukocyte Infiltration to the Kidneys Attenuating Encephalomyelitis
https://pubmed.ncbi.nlm.nih.gov/34575795/

Abstract

Environmental factors, including infections, are strongly associated with the pathogenesis of multiple sclerosis (MS), which is an autoimmune and demyelinating disease of the central nervous system (CNS). Although classically associated with bacterial and viral agents, fungal species have also been suspected to affect the course of the disease. Candida tropicalis is an opportunistic fungus that affects immunocompromised individuals and is also able to spread to vital organs. As C. tropicalis has been increasingly isolated from systemic infections, we aimed to evaluate the effect of this fungus on experimental autoimmune encephalomyelitis (EAE), a murine model to study MS. For this, EAE was induced in female C57BL/6 mice 3 days after infection with 106 viable C. tropicalis yeasts. The infection decreased EAE prevalence and severity, confirmed by the less inflammatory infiltrate and less demyelization in the lumbar spinal cord. Despite this, C. tropicalis infection associated with EAE results in the death of some animals and increased urea and creatinine serum levels. The kidneys of EAE-infected mice showed higher fungal load associated with increased leukocyte infiltration (CD45+ cells) and higher expression of T-box transcription factor (Tbx21) and forkhead box P3 (Foxp3). Altogether, our results demonstrate that although C. tropicalis infection reduces the prevalence and severity of EAE, partially due to the sequestration of leukocytes by the inflamed renal tissue, this effect is associated with a poor disease outcome.

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2018 Summer
Cross-talks between the kidneys and the central nervous system in multiple sclerosis
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6121345/

October 05, 2021
Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, United States
Fungal microbiome and multiple sclerosis: The not-so-new kid on the block
https://www.thelancet.com/journals/ebio ... X/fulltext

Human hosts and commensal gut microbes have a symbiotic relationship, with hosts providing space and nutrients to microbes, and microbes supporting numerous physiological processes of the host, including digestion food, preventing pathogen colonization, and immune system modulation [1]
Thus, it is not surprising that perturbations in this homeostasis are linked with a number of diseases [1]
In last two decades non-culture-based sequencing techniques have afforded a better understanding of the human microbiome in health and disease, including multiple sclerosis (MS). Several groups, including ours, have shown that patients with MS have gut dysbiosis (specific bacteria either enriched or depleted) [2]
However, most studies have only analyzed bacteria even though the microbiome also consists of fungi and viruses. In this article, Shah et al. [3]
profile the fungal microbiome (mycobiome) in patients with MS (pwMS) and show that these patients have a distinct mycobiome compared to healthy control (HC) participants. Study by Shah et. al and another in preprint by Yadav et. al. showing fungal dysbiosis in pwMS [4]
begin to highlight the importance of the mycobiome in MS.
Shat et al. compared the mycobiomes of 25 pwMS and 22 HCs and showed that the mycobiome of pwMS had higher fungal richness than that of HCs, with mycobiome composition remaining mostly stable over six-months [3]
The mycobiome of pwMS was enriched for certain fungi such as Saccharomyces and Aspergillus. Interestingly, disease-modifying therapies, including dimethyl fumarate, which possesses anti-fungal properties, did not alter the mycobiome composition. The authors also associated mycobiome profiles with different microbiome compositions by classifying mycobiome profiles into two fungal clusters (i.e., mycotypes). Mycotype 1 was dominated by Saccharomyces, whereas Mycotype 2 had greater diversity with presence of Penicillium, Malassezia and Mucor besides Saccharomyces. There was a positive correlation between Saccharomyces and circulating basophil levels, and increased levels of effector memory CD4+ T cells in participants with the Mycotype 2 cluster. Collectively, these results demonstrate that the mycobiota is altered in the context of MS, which likely has implications on disease progression and severity, particularly considering a previous report showing a distinct mycobiome signature in patients with other diseases, such as inflammatory bowel disease, cancers, atherosclerosis, diabetes, obesity, and alcoholic liver disease [5]
[6]

Like bacteria, fungi are also proposed to play an important (symbiotic) role in maintaining immune homeostasis at mucosal surfaces by regulating both innate and adaptive immunity. Recognition of fungi through innate immune receptors such as Dectin-1, Dectin-2, c-type lectin receptors, and macrophage-inducible Ca2+-dependent lectin receptor help fine-tune immune responses in the gut [6]
Additionally, fungi specifically Candida and Malassezia, are potent inducers of a systemic Th17 response and promote expansion of the neutrophil population 5, 6, 7
The importance of the mycobiome for T cell activation and granulocytes expansion is highlighted by two recent studies that show the mycobiome was enriched in the offspring of wild mice that received embryos from laboratory mice or in laboratory mice that were reintroduced to the wild [8],[9]
]. Laboratory mice differ from human immune system as they have reduced numbers of activated T cells and polymorphonuclear lymphocytes in their blood and these studies suggest that lack of complex commensal fungi in mice might be responsible for these differences in immune parameters.
The study discussed here is limited by its small sample size, classification of fungi at low resolution, and the absence of a validation cohort of patients. As Candida and Saccharomyces are two of the most abundant fungi in the human mycobiome, the significantly reduced abundance of Candida observed here [3]
is surprising. Several human studies have shown relatively higher abundance of Candida both in healthy participants [10]
and in patients with disease, such as inflammatory bowel disease, atherosclerosis and type 2 diabetes mellitus [5],[6]
We have also observed higher Candida levels in pwMS compared to HC using marker-based fungal classification [4]
Lower Candida levels in the current study may be due to the geographic location, lifestyles, or dietary habits of the participants, or the bioinformatics pipeline used. Further, Saccharomyces has been associated with both a healthy mycobiome and certain diseases, suggesting either a strain-specific role of Saccharomyces in promoting disease, or that the overall composition of the mycobiome, and the bacterial microbiome, affects its disease-protective or promoting properties. Correlating the abundance of Saccharomyces and Candida with other components of the microbiome in the context of MS will be an important next step in beginning to uncover how fungi might protect or promotes disease.
In conclusion, this study provides first evidence that the fungal component of the microbiome is disrupted in pwMS. This paves the way for future work characterizing the mycobiome in the context of disease using shotgun metagenomic sequencing and larger sample sizes, which, combined with mechanistic studies, will help in understanding the precise role of fungi in the pathobiology of MS.

2024 Jun 14
Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore, India
From Skin and Gut to the Brain: The Infectious Journey of the Human Commensal Fungus Malassezia and Its Neurological Consequences
https://pubmed.ncbi.nlm.nih.gov/38871941/

Abstract

The human mycobiome encompasses diverse communities of fungal organisms residing within the body and has emerged as a critical player in shaping health and disease. While extensive research has focused on the skin and gut mycobiome, recent investigations have pointed toward the potential role of fungal organisms in neurological disorders. Among those fungal organisms, the presence of the commensal fungus Malassezia in the brain has created curiosity because of its commensal nature and primary association with the human skin and gut. This budding yeast is responsible for several diseases, such as Seborrheic dermatitis, Atopic dermatitis, Pityriasis versicolor, Malassezia folliculitis, dandruff, and others. However recent findings surprisingly show the presence of Malassezia DNA in the brain and have been linked to diseases like Alzheimer's disease, Parkinson's disease, Multiple sclerosis, and Amyotrophic lateral sclerosis. The exact role of Malassezia in these disorders is unknown, but its ability to infect human cells, travel through the bloodstream, cross the blood-brain barrier, and reside along with the lipid-rich neuronal cells are potential mechanisms responsible for pathogenesis. This also includes the induction of pro-inflammatory cytokines, disruption of the blood-brain barrier, gut-microbe interaction, and accumulation of metabolic changes in the brain environment. In this review, we discuss these key findings from studies linking Malassezia to neurological disorders, emphasizing the complex and multifaceted nature of these cases. Furthermore, we discuss potential mechanisms through which Malassezia might contribute to the development of neurological conditions. Future investigations will open up new avenues for our understanding of the fungal gut-brain axis and how it influences human behavior. Collaborative research efforts among microbiologists, neuroscientists, immunologists, and clinicians hold promise for unraveling the enigmatic connections between human commensal Malassezia and neurological disorders.